Funded Awards

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Title Investigator Institute Fiscal Year FOA Number Status Project Number Priority Area Summary
CENTER FOR EPIGENOMICS OF THE MOUSE BRAIN ATLAS (CEMBA) Ecker, Joseph R Salk Institute For Biological Studies 2017 Active
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Dr. Ecker's group will use signatures of epigenetics, the switching on-and-off of genes in response to experience, in mouse frontal cortex to help identify different classes of cells and understand their function.

A BRAIN Initiative Resource: The Neuroscience Multi-omic Data Archive White, Owen R University Of Maryland Baltimore 2017 Active
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A thorough understanding of the complexities of the brain’s different cell types requires the sharing and integration of myriad genomic information generated from various data sources. Owen White proposes creating a Neuroscience Multi-Omic (NeMO) Archive, a cloud-based data repository for -omic data. White and his team of researchers will establish an archive for multi-omic data and metadata of the BRAIN Initiative. The group will document and archive data processing workflows to ensure standardization, as well as create resources for user engagement and data visualization. The NeMO Archive will provide an accessible community resource for raw -omics data and for other BRAIN Initiative project data, making them available for computation by the general research community.

A Cellular Resolution Census of the Developing Human Brain Huang, Eric J Kriegstein, Arnold (contact) University Of California, San Francisco 2017 Active
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Scientists have yet to achieve high-resolution classification of the billions of neurons and non-neuronal cells in the human brain. To attempt this feat, Arnold Kriegstein and Eric Huang will perform high-throughput, droplet-based single-cell RNA and transposase-accessible chromatin sequencing techniques to collect genetic and epigenetic information from individual cells, which will be sampled from multiple regions of post-mortem human brains that are developmentally between early gestation and adolescence. They will further classify living neurons cultured from select brain regions based on their calcium imaging responses to various chemical stimuli. Finally, they plan to use multiplexed single-molecule fluorescent in situ hybridization (smFISH) to identify the spatial distribution of these various cell types in the brain. After these data are compiled, we will have the most detailed picture to date of genetically and functionally defined cell types in the human brain throughout development.
A Community Resource for Single Cell Data in the Brain Gee, James C Hawrylycz, Michael (contact) Martone, Maryann E Ng, Lydia Lup-ming Philippakis, Anthony Allen Institute 2017 Active
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One major technical challenge for the BRAIN Initiative is the storage and dissemination of large amounts of data collected by different project teams. Hawrylycz and colleagues will support the cell census efforts of the BRAIN Initiative by hosting the BRAIN Cell Data Center (BCDC). Through the BCDC, they will store single-cell data on genetics, histology, electrophysiology, morphology, anatomical location, and synaptic connections from multiple species in a standardized manner. They will also develop and provide training for web-based tools to ease data visualization and analysis efforts. This will facilitate the integration of multiple data streams to better identify and characterize the different cell types in the brain.
A Comprehensive Center for Mouse Brain Cell Atlas Huang, Z Josh Cold Spring Harbor Laboratory 2017 Complete
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Identifying individual cell types in the brain is a monumental task that is complicated by the limitations of current molecular technologies. To measure genetic diversity in the whole mouse brain, Huang and Arlotta will lead a team using next-generation droplet-based single-cell transcriptome sequencing along with other highly sensitive single-cell techniques that allow for high-throughput data collection. They plan to map these data onto the spatial locations of forebrain neurons with the help of high-resolution microscopy and genetically driven cell markers. These efforts will provide the scientific community with unprecedented detail about neurons’ molecular and spatial characteristics that can be used to develop additional tools for cell-specific manipulations.

A comprehensive whole-brain atlas of cell types in the mouse Zeng, Hongkui Allen Institute 2017 Complete
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The large number of cells in the brain and the complexity of their molecular and functional characteristics make it difficult to define individual cell types. Zeng and colleagues plan to complement high throughput droplet-based transcriptome survey with deep sequencing technique and multiplexed error-robust fluorescence in situ hybridization (MERFISH) to comprehensively characterize gene expression information from anatomically mapped cells across the entire mouse brain. Additionally, they will use patch clamp method to measure neuronal function in specific brain regions, and combine electrophysiological with transcriptomic and morphological information to provide integrative profiles of individual cell types. These efforts will refine how we define cell types and will produce a census of individual cells in the mouse brain that can then be targeted for further study.

A Confocal Fluorescence Microscopy Brain Data Archive Bruchez, Marcel P Ropelewski, Alexander J (contact) Watkins, Simon C Carnegie-mellon University 2017 Active
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Advances in microscopy and imaging have created new possibilities in many fields of research, but these advances have also generated large amounts of data that can overwhelm traditional data management systems. Along with collaborators at Carnegie Mellon University and the University of Pittsburgh, Alexander Ropelewski plans to establish a BRAIN Imaging Archive that takes advantages of infrastructure and personnel resources at the Pittsburgh Supercomputing Center. The Archive will include a pipeline for data submission, user access and support, and BRAIN Initiative community engagement through an online presence, workshops, and hackathons. This unique resource will provide an accessible and cost-effective way for the research community to analyze, share, and interact with large image datasets of the BRAIN Initiative.

A data science toolbox for analysis of Human Connectome Project diffusion MRI Rokem, Ariel Shalom University Of Washington 2019 Active
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The Human Connectome Project provides one of the largest publicly available datasets of diffusion MRI from a sample of healthy individuals. Dr. Rokem and team will create an end-to-end pipeline for analysis of human white matter connections by using “tractometry” methods to analyze the diffusion MRI dataset from the Human Connectome Project. In tractometry, tissue properties are estimated in the long-range connections between remote brain regions. This project aims to generate a normative distribution of tissue properties in the major white matter connections, develop novel statistical methods to connect the properties of white matter connections to cognitive abilities, and create visualization tools to further explore and communicate the data. These tools may create an easily accessible platform that could be applied to other important neuroscience datasets.

A Facility to Generate Connectomics Information Lichtman, Jeff HARVARD UNIVERSITY 2018 Active
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Connectomics describes a field of study that builds maps of the connections within the brain. Dr. Lichtman and colleagues have developed a facility for generating high-resolution, large-volume serial section electron microscopy data that can be used to generate connectomic maps. In this project, access to the facility, techniques, and analytical software will be provided to the broader neuroscience community. This will allow other research groups who may be inexperienced in these techniques to generate data in projects aimed at mapping brain circuitry, a high priority goal in the BRAIN 2025 report. By providing this resource, Dr. Lichtman and colleagues will help researchers classify the cell types within healthy and diseased brains or model systems, which will improve our understanding of brain function and neurological disorders.

A Fast, Accurate and Cloud-based Data Processing Pipeline for High-Density, High-Site-Count Electrophysiology Kimmel, Bruce VIDRIO TECHNOLOGIES, LLC 2018 Active
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The community’s need for an integrated open-source analysis platform is rapidly growing due to the increasing capacity of extracellular electrodes and the limited number of new and validated spike- sorting methods. JRCLUST, a free, open-source, standalone spike sorting software, offers a scalable, automated and well-validated spike sorting workflow for analysis of data generated by large multielectrode arrays. The software can tolerate experimental recording conditions from behaving animals, and it can handle a wide range of datasets using a set of pre-optimized parameters making it practical for wide use in the community. JRCLUST has been adopted in 20+ labs worldwide since its inception less than a year ago. Drs. Kimmel and Nathan seek to expand and maintain JRCLUST, thus empowering researchers to elucidate how functionally defined subpopulations of neurons mediate specific information-processing functions at key moments during behavior.

A Functional and Selective Toolkit for Choroid Plexus Networks Lehtinen, Maria (contact) Moore, Christopher I Boston Children's Hospital 2019 Active
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Composed of epithelial cells and primary non-neuronal cells, the choroid plexus (ChP) produces cerebrospinal fluid (CSF) and forms the blood-CSF barrier. Studies of the ChP have been limited by a lack of tools to target and characterize ChP cells in vivo. Leveraging new single-cell transcriptomic data, Dr. Lethinen and her team aim to engineer genetic driver lines in mice that will allow precision monitoring and control of specific ChP cell types. In collaboration with the Andermann and Moore labs, the team will develop new 3D two-photon imaging methods to observe and control calcium activity, as well as visualize motility, of defined ChP cells, before developing opto- and chemogenetic protocols for ChP regulation. This toolkit aims to improve access and control of cells within the choroid plexus, advancing the knowledge of this deep brain tissue.

A General Approach for the Development of New Cell-Type-Specific Viral Vectors Greenberg, Michael E Harvard Medical School 2017 Active
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The limited ability to genetically access specific neural cell types, based on distinctive gene expression patterns, impedes brain function probing and therapy development. Greenberg and colleagues will generate recombinant viral reagents that target specific cortical cell types, using recent advances in genetics and a novel application of single-cell transcriptome analysis. They propose to identify genetic drivers specific for excitatory and inhibitory mouse cortical neuronal subtypes. If successful, this may establish a general method for identifying cell-type-specific genetic elements that can be used in viral vectors to drive gene expression, could be applied to other brain regions and mammalian species, and may assist cell-type-specific applications like neuronal activity monitoring, optogenetic and chemogenetic manipulation, axonal tracing, gene delivery, and genome editing.
A Massive Library of AAVs to Target Transcriptionally-Defined Primate Cell Types Stauffer, William Richard University Of Pittsburgh At Pittsburgh 2019 Active
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Development of targeted gene therapeutics to treat neurological and psychiatric disorders requires improved tools to probe circuit-specific functions. Dr. Stauffer and collaborators plan to combine single-cell RNA-Seq (scRNA-Seq) with high-throughput screening of engineered adeno-associated viruses (AAVs) to create a toolbox to minimally invasively monitor and manipulate of neurons in macaques. The researchers plan to create large libraries of mutated AAV vectors and synthetic regulatory elements, in which each variant is paired with a unique DNA barcode and use scRNA-Seq to capture the transcriptome for each cell, as well as quantify barcode expression. The team will then perform validation studies using the optimized AAVs to explore and inventory cell type-specific circuits for mood, learning, and vision in non-human primates, potentially producing a toolkit that could be applied to other large brains.

A method for anterograde trans-synaptic tracing Arnold, Donald B University Of Southern California 2018 Active
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To understand how the activation of individual neurons in the brain leads to particular behaviors, it is necessary to identify synaptic connections to downstream neurons. Although considerable information about neuronal circuits has been generated using rabies virus to trace trans-synaptic connections in the retrograde direction, there is no comparable technique for trans-synaptic tracing in the anterograde direction. In rodent brains, Arnold and colleagues will optimize a non-toxic method for anterograde monosynaptic tracing from single neurons to virtually any postsynaptic receptor. Their method labels only active synapses, ensuring the technique’s physiological relevance.

A Molecular and Cellular Atlas of the Marmoset Brain Feng, Guoping Massachusetts Institute Of Technology 2017 Active
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Although rodents are a highly accessible model and relatively simple to use for genetic studies, it is unclear whether the cell types found in rodent brains match those of primates. To help fill the evolutionary gap in knowledge between rodents and humans, Feng will lead a team to classify cells across the marmoset brain. They will use high-throughput single-cell RNA sequencing to identify cell types in the prefrontal cortex, striatum, and thalamus and will then spatially map the cell types they find in the brain using multiplexed error-robust in situ hybridization (MERFISH). By combining MERFISH with viral expression of marker proteins in subsets of neurons, the team will also correlate cell morphology with genetic information. Altogether these efforts will produce a census of cell types in the marmoset brain, which will be valuable information for future work into the genetics and circuits of the primate brain.
A multimodal atlas of human brain cell types Lein, Ed Allen Institute 2017 Active
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Because of technical limitations, most studies identifying individual cell types in the brain have focused on animal models rather than on human tissue, despite a lack of knowledge about how cell types differ between species. Ed Lein and colleagues will perform broad, high-throughput single-cell RNA sequencing techniques across the whole human brain and spinal cord, along with deep sequencing of single cells in select regions of adult post-mortem brain. They will then determine the spatial distribution of various cell types identified through these sequencing experiments by using multiplexed single-molecule fluorescent in situ hybridization (smFISH). To integrate information about neuronal function into their classifications, the team will make combined electrophysiology, morphology, and transcriptome measurements from single cells in adult human cortex obtained via live surgical resection. These efforts will lead to a much deeper understanding about the differences between cell types in the adult human brain and will facilitate future collaborations between researchers to compare cell types across species.
A multimodal platform to bridge the experimental gap between behavioral, neuronal, and molecular studies Cai, Dawen (contact) Cui, Meng University Of Michigan At Ann Arbor 2019 Active
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Despite the success in technology development in neuroscience, there currently lacks a method to directly link activity, connectivity, and molecular identity of individual neurons in a functional circuit at the single cell resolution. Here, Drs. Cai, Cui, and teams aim to use coMAAP, a method that combines Brainbow AAV labeling, calcium imaging, innovative sample preparation, and light-sheet microscopy, to acquire correlative optical mapping of activity, anatomy, and molecular identity of the same neurons in the same animal. After optimizing and validating the coMAAP experimental paradigm, they plan to utilize coMAAP to uncover the heterogenous neuronal populations that are activated in the mouse ventral tegmental area during arousal. Improved understanding of the cellular and circuitry components could accelerate the identification of specific neuronal targets in psychiatric disorders.

A new approach to biological recording of lineage hierarchy in primate brains Brivanlou, Ali H Rockefeller University 2019 Active
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Current genetic lineage recorders are limited to a finite number of recording events, making them unsuitable for the study of prolonged development. Here, Dr. Brivanlou’s lab plans to use a new approached called CHRONICLE to enable continuous, dynamic lineage-tracing in non-human primates. CHRONICLE (Cellular Hierarchy Recording in Organisms by Nucleotide Interconversion with Cas9 Linked Editors) combines base-editing with self-targeting guide RNA arrays to generate a large collection of sequence variants that can be used to trace cellular hierarchy lineages. The researchers aim to trace lineages in vitro human and marmoset cortical organoids, as well as in vivo marmoset early embryos, compare developmental lineage trees of the marmoset cortex in projection neurons, interneurons, and glia using single cell RNA analysis. Understanding novel lineage relationships of the primate brain may improve our ability to use developmental principles to restore function in diseased and damaged tissues.

A new strategy for cell-type specific gene disruption in flies and mice Clandinin, Thomas Robert (contact) Shah, Nirao Mahesh Stanford University 2015 Complete
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The ability to inactivate targeted genes only in relevant cell types is critical for understanding how specific genes contribute to circuit function and dysfunction. Clandinin's team will generate novel tools to inactivate genes in specific cell-types, and will validate these tools with imaging experiments and behavioral tests in live fruit flies. They will then adapt the tools for use in mice to directly manipulate genes controlling neuronal excitation and inhibition.
A Novel Approach for Cell-Type Classification and Connectivity in the Human Brain Sestan, Nenad Yale University 2014 Complete
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Dr. Sestan's group will substantially advance the profiling of cell types – their molecular identities and connections – made possible by a new method of better preserving brain tissue to maintain cell integrity.
A novel platform for the investigation of human microglia Blurton-jones, Mathew Mark Gandhi, Sunil (contact) Spitale, Robert C University Of California-irvine 2019 Active
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Recent work has revealed the need for a robust system to accurately model the dynamic nature of human microglia in the brain in health and disease. Dr. Gandhi and team aim to validate a novel mouse xenotransplantation platform, XMG, using human induced pluripotent stem cell-derived microglia as a promising model system which they intend to disseminate publicly. The group will compare the transcriptional landscape of XMG to endogenous microglia from mice and humans, as well as use cutting edge multiphoton imaging technique to measure calcium activity and insulin response of XMG following acute insult. Further, the group will query changes in the function of XMG in the context of a pathological state resembling Alzherimer’s disease in the mouse. Developing this novel XMG system may advance the ability to study human microglia in vivo and provide far-reaching insights into microglial biology.

A platform for high-throughput production of targeting systems for cell-type-specific transgene expression in wild-type animals Wickersham, Ian R Massachusetts Institute Of Technology 2016 Active
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In vivo genetic modification within a specific cell type generally requires production of transgenic or knockout animal models, a time- and resource-consuming process. Wickersham and colleagues will use high-throughput techniques to develop a novel set of viral vectors to allow selective transgene expression in targeted neuronal subpopulations in wild-type mammals. These tools will expand the possibility of optogenetic control, recording, and genomic modification of neural circuits to uncover their organization in healthy and dysfunctional brains, with potential therapeutic use in humans for mental and neurological disorders.
A Technology Resource for Polymer Microelectrode Arrays Meng, Ellis (contact); Song, Dong University Of Southern California 2019 Active
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Polymer microelectrode arrays are electrical recording devices made of flexible materials. These materials reduce tissue damage and improve the long-term stability of the recording setup. The Meng and Song labs aim to establish a service that will manufacture and test out arrays that are customized to researchers’ needs. The service may help researchers use the latest electrical recording devices for studying a variety of neurological disorders.

Accessible technologies for high-throughput, whole-brain reconstructions of molecularly characterized mammalian neurons Miller, Michael I Mueller, Ulrich (contact) Johns Hopkins University 2019 Active
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For a complete understanding of how the brain works, there is a need for a comprehensive parts list (all of the cells in the brain) along with knowledge of how those parts are connected. Current molecular technology has advanced the inventory of cell types in the brain, but detailed information about the circuits they form is limited. Dr. Mueller’s group will develop scalable and affordable cellular imaging and neuro-informatics tools, running preliminary experiments to connect the transcriptome to anatomy, in mice. Tools will be made available to researchers, to help accelerate the creation of detailed maps at cell resolution showing circuitry in whole brains.

Accurate and reliable computational dosimetry and targeting for transcranial magnetic stimulation Gomez, Luis Javier Duke University 2019 Active
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Transcranial magnetic stimulation (TMS) is a noninvasive technique used to study brain function and can be used to treat some brain disorders. Researchers use computational simulations of TMS electrical fields to gain a better understanding of how TMS affects the brain. Existing simulations, however, are inherently variable due to factors that impact the accuracy and precision of the technique, such as differences in experimental set-up and coil placement. Dr. Gomez proposes to use a novel computational framework to measure and address the uncertainty and variability of TMS electrical fields. The project will increase the fidelity and reliability of TMS simulations. The results will benefit researchers and clinicians by enabling more precise control of the technique and may help improve medical uses of TMS.

Achieving ethical integration in the development of novel neurotechnologies Chiong, Winston University Of California, San Francisco 2017 Active
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Novel neurotechnologies hold promise for treating neuropsychiatric disorders, but also raise profound neuroethics issues including self-ownership of our thoughts, emotions, and actions. Engaging patients and researchers in the early stages of neurotechnology research and clinical translation can help ensure ethical development of the field. This research study will be embedded in one of two projects funded by the DARPA BRAIN Initiative to develop implantable brain stimulation devices that both monitor and adaptively stimulate brain areas involved in mood and behavior regulation. Dr. Chiong and an interdisciplinary team with expertise in neuroscience, clinical care, law, philosophy, and social science will assess neuroethics issues associated with the DARPA-funded brain stimulation project. The overall goal is to enable acceptability and adoption of new treatments for neuropsychiatric disorders, by recognizing and incorporating the perspectives of patients, researchers, and other stakeholders into the design of these novel neurotechnological therapies.
Acoustically targeted molecular control of cell type specific neural circuits in non-human primates Shapiro, Mikhail (contact) Tsao, Doris Ying California Institute Of Technology 2019 Active
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Controlling specific neural circuits across large-scale areas is vital to improve our understanding of the nervous system. Drs. Shapiro, Tsao, and collaborators aim to further develop Acoustically Targeted Chemogenetics (ATAC) to modulate neural circuits non-invasively in non-human primates (NHPs) with spatiotemporal and cell-type specificity, starting in the visual cortex of macaques. The group will develop AAV viruses optimized for chemogenetic receptor delivery using in vivo evolution in mice and NHP, in addition to the development of ultrasound methods to target focused ultrasound-blood brain barrier opening in NHPs. ATAC will then be used to modulate face recognition neurons and sensorimotor circuits in NHPs.  Successful development of ATAC for NHPs will improve the study of neural circuits, and potentially help uncover new therapies for neuropsychiatric disease.

AN INDUCIBLE MOLECULAR MEMORY SYSTEM TO RECORD TRANSIENT STATES OF CNS CELLS Mitra, Robi D Washington University 2015 Complete
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Currently, methods that seek to link transient gene expression events to specific brain functions typically require genomic analysis of a population of cells, resulting in the destruction of those cells. This makes it difficult to directly connect molecular changes in a neuron with knowledge of subsequent biological outcomes, such as memory formation, brain development, or neurodegeneration. Mitra and his colleagues will develop a transformative technology called "Calling Cards" that provides a permanent genetic record of molecular events associated with gene expression, which can be read out by DNA sequencing at a later time after relevant biological outcomes have occurred. The data collected with this technique will deepen the understanding of processes such as brain development, memory formation and the progression of neurodegenerative disease.
An open software solution to integrate non-invasive brain stimulation with functional imaging data Opitz, Alexander University Of Minnesota 2019 Active
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Non-invasive brain stimulation methods, like transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS), modulate brain activity in a safe and painless manner. Several BRAIN Initiative projects are combining these non-invasive brain stimulation methods with neuroimaging methods. Dr. Opitz and team will develop a computational tool that integrates empirically validated finite element method (FEM) models with imaging data, by extending and scaling the SimNIBS (Simulation of Non-Invasive Brain Stimulation) software platform. The SimNIBS is the leading open source software platform for generating FEM-based models of the electric field distribution produced by TMS, tDCS, and tACS. The resultant analysis package will allow rapid visualization and analysis of non-invasive brain stimulation (NIBS) BRAIN Initiative data, which could be more broadly used by the general neuroscience community.

An optogenetic toolkit for the interrogation and control of single cells. Hannon, Gregory J Cold Spring Harbor Laboratory 2014 Complete
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Dr. Hannon's group will develop optogenetic techniques that use pulses of light to control genes and isolate proteins in specific cell types in the brain for molecular studies.
Anatomical characterization of neuronal cell types of the mouse brain Ascoli, Giorgio A Dong, Hong-wei (contact) Lim, Byungkook University Of Southern California 2017 Active
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Better anatomical characterization of neurons is needed if we want to identify and distinguish the different cell types in the brain. Dong and colleagues plan to classify neurons based on their spatial anatomy, connections with other neurons, and morphology using multiple neuronal retro- and anterograde tracing methods that will identify connected neurons. This team will first focus on 300 well-defined regions within the limbic system of the adult mouse, a circuit that is important for homeostasis and behavioral motivation, taking high-resolution images and creating high-throughput, three-dimensional reconstructions of these neurons. These data will provide a more complete anatomical picture of the limbic system, and this method can be applied in the future to study additional circuits throughout the brain.
Anion channelrhodopsin-based viral tools to manipulate brain networks in behaving animals Dragoi, Valentin (contact) Janz, Roger Spudich, John Lee University Of Texas Hlth Sci Ctr Houston 2015 Complete
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Examining neural circuits requires the ability to activate and silence individual neurons and subsequently assess the impact on circuit function and the circuit's overall influence on behavior. While genetically encoded molecular tools for selectively controlling the activity of neurons with light have been successfully implemented in mice, these tools have had limited success in non-human primates (NHPs). The researchers plan to modify a new class of recently discovered, light-activated molecular tools with superior light sensitivity to work well in NHPs. In addition, they will test a new, possibly more efficient, method of delivering these molecular tools via viral vectors into the neurons of awake, behaving NHPs.
Anterograde monosynaptic tracing Wickersham, Ian R Massachusetts Institute Of Technology 2015 Complete
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Using a modified rabies virus, neuroscientists can identify and manipulate neurons directly upstream from any targeted group of neurons in the brain. However, while this retrograde monosynaptic tracing system is now well established, an anterograde counterpart—one that would allow identification and manipulation of neurons directly downstream from a target cell group—has never been constructed. Wickersham and his team propose three different methods for creating an anterograde tracing system. Any one of the methods would greatly expand the types of anatomical and functional studies that can be performed in a large variety of animals, including primates.
Assessing the Effects of Deep Brain Stimulation on Agency Roskies, Adina L Dartmouth College 2018 Active
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Deep brain stimulation (DBS), a method of modulating brain circuit function, is FDA-approved for certain brain disorders such as Parkinson’s Disease. The NIH BRAIN Initiative aims to launch neurotechnological developments that include new ways of directly affecting brain circuit function. Use of these novel interventions warrants careful consideration about ways in which brain stimulation may affect personal identity, autonomy, authenticity and, more generally, agency. In this project, Dr. Roskies and her team will develop an assessment tool to measure changes in agency due to direct brain interventions, and establish a database to catalogue these changes in agency in various patient populations receiving DBS. These efforts have the potential to facilitate improvements in therapeutic approaches and informed consent and will be used to develop a framework for further neuroethical thought about brain interventions, allowing us to better identify, articulate, and measure effects on agency.

Automating whole brain connectomics: development, validation, and application of an open toolkit Bock, Davi University Of Vermont & St Agric College 2019 Active
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Advancements in 3D electron microscopy have provided a wealth of neuronal circuit data for the whole fruit fly brain, but current, manual analysis techniques are very slow and tedious. Dr. Bock and his team aim to disseminate their whole-brain EM data via the web-based circuit-mapping and analysis platform CATMAID, as well as develop new automated tools and software to investigate circuit structure. Fruitfly neurobiologists accessing CATMAID will be able to perform morphology-based neuron searches for segmentation-assisted circuit reconstructions, eventually using this software to guide additional infrastructure development. The proposed research should accelerate circuit mapping in the fruit fly brain, extend to other model systems, and allow individual labs to form and manage collaborations on a managed server.

Axonal connectomics: dense mapping of projection patterns between cortical areas Reid, R Clay Allen Institute 2019 Active
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Macroscale connectomics lacks cellular resolution, while microscale connectomics often lacks information about the source of inputs entering, or the targets of axons exiting the studied brain volume. Dr. Reid’s lab aims to tackle this problem through the development of a high-resolution 3D imaging technique to map antibody-stained axons over long distances. Using Dual Inverted Selective Plane Illumination Microscopy (diSPIM), the researchers propose to image and analyze visual cortical areas in macaque brain to create a dense axonal connectomics data set. The approach may allow whole-brain analysis of axonal projections with microscale connectomics, advancing our knowledge of how individual neurons communicate over long distances.

BCI2000: Software Resource for Adaptive Neurotechnology Research Brunner, Peter Schalk, Gerwin (contact) Wadsworth Center 2019 Active
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Changes occur to the central nervous system (CNS) throughout life due to activity-dependent plasticity as we learn new behaviors. Adaptive neurotechnologies are systems that can interact with the CNS in ways that produce beneficial neural plasticity. The group led by Schalk and Brunner has created a software platform, BCI2000, that can be used in a variety of adaptive neurotechnology applications. However, the current BCI2000 system requires considerable expertise in programming for successful implementation. This project will produce a configuration of BCI2000 that can be more easily used for adaptive neurotechnology experiments, as well as an introductory course and online training for scientists, engineers, and clinicians using the system. These new resources will allow deployed neurotechnologies to be more quickly used in the study, diagnosis, and treatment of brain disorders.

Behavioral readout of spatiotemporal codes dissected by holographic optogenetics Rinberg, Dmitry (contact) Shoham, Shy New York University School Of Medicine 2014 Complete
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Dr. Rinberg's team aims to understand how the brain turns odors into nerve signals by activating and recording neurons in the olfactory bulbs of mice as they detect a variety of odors.
BIDS-Derivatives: A data standard for derived data and models in the BRAIN Initiative Poldrack, Russell A Stanford University 2017 Active
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The proliferation and heterogeneity of magnetic resonance imaging (MRI) experiments, data analysis pipelines, and statistical modeling procedures presents a challenge for effective data sharing and collaboration. Russell Poldrack and colleagues propose expansion of the Brain Imaging Data Structure (BIDS), which standardizes the description and collection of imaging data/metadata for MRI, with development plans for other neuroimaging types as well. Under BIDS, the group will develop standards for pre-processing data pipelines, computational modeling results, and statistical modeling, using quick validation of any implemented standard so that researchers can assess whether their data fit within BIDS guidelines. These standardization goals will facilitate sharing of data, modeling, and results, ensuring their usability and engaging the greater research community in developing highly useable data standards.

Boss: A cloud-based data archive for electron microscopy and x-ray microtomography Wester, Brock A. Johns Hopkins University 2018 Active
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Technological advancements in high-resolution imaging of brain volumes permits the accumulation of huge quantities of data that requires solution for storage and archiving. Dr. Brock’s project develops an open, accessible, and cloud-based data archive for electron microscopy and X-ray microtomography data by leveraging the proven architecture of the existing BossDB database. Allowing for petabyte scale data storage, curation, sharing, visualization and analysis, the archive is scalable and allows for a fast in- memory spatial data store, seamless migration of data between low cost and durable object storage (i.e. S3), and rapid access to the enormous datasets. The system enables computing data quality metrics on large datasets and metadata stores through a standardized interface. The archive is developed through an agile process that actively folds in community stakeholders for regular reviews and continuous opportunities for design input.

Brain circuit mapping using light inducible recombinase systems Cetin, Ali Haydar Allen Institute 2017 Active
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Studying vast numbers of functioning neurons in the brain requires precise spatio-temporal tools. Toward this end, researchers are interested in genetically modifying specifically selected cells in vivo, for neuronal subtype-specific, single-cell-level analysis. Cetin and colleagues will modify current genomic manipulation enzymes, making them light inducible, to achieve high-throughput single-cell genomic modification in response to brief pulses of light in the brain. They will generate transgenic mouse lines with these recombinases, use light to trigger site-specific DNA modification, and study the connections, morphology, function, and genetic identity of individual neurons within the brain. This approach may break technical barriers and has a range of potential applications, enabling enhanced precision in analyzing mammalian brain circuitry.
BRAIN INITIATIVE RESOURCE: DEVELOPMENT OF A HUMAN NEUROELECTROMAGNETIC DATA ARCHIVE AND TOOLS RESOURCE (NEMAR) Delorme, Arnaud Majumdar, Amitava Makeig, Scott (contact) Poldrack, Russell A University Of California, San Diego 2019 Active
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Dr. Makeig et al. have identified the need for the creation of data archives and standards for specifying, identifying, and annotating the data deposited. Specifically, they aim to create a gateway from the OpenNeuro.org archive for human neuroelectromagnetic data such as EEG and MEG data. This gateway will also provide tools to users for quality evaluation and data visualization. This resource will further allow machine learning methods to be applied to human brain activity data.

BRAIN Initiative: Integrated Multimodal Analysis of Cell and Circuit-Specific Processes in Hippocampal Function Sweedler, Jonathan V. University Of Illinois At Urbana-champaign 2015 Complete
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Individual cell types contain specific combinations of chemical constituents that directly affect cell behavior. However, detailed knowledge of these constituents, as well as a precise method for identifying them, is currently lacking. Sweedler and colleagues will combine two methods for probing the chemical makeup of living tissue—mass spectrometry of individual cells, and stimulated Raman scattering microscopy (SRSM) from unlabeled tissue in brain slices. The combined analyses will be deployed in the dentate gyrus region of the hippocampus to identify the region’s many different cell types and chemical characteristics, and to investigate how this wealth of information relates to functions involved in memory formation.
BRAIN power: expanding reproducibility, quality control, and visualization in AFNI/SUMA COX, ROBERT WILLIAM (contact); NIELSON, DYLAN MILES U.S. NATIONAL INSTITUTE OF MENTAL HEALTH 2018 Active
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AFNI (Analysis of Functional NeuroImages) is an open-source software package for neuroimaging analysis and visualization of both functional and structural MRI as well as other modalities. Drs. Cox and Nielson propose to extend this widely used software package by offering containerization, cloud accessibility and web-accessible visualization. The software extension could support evolving BRAIN Initiative standards for human neuroimaging data organization and experiment specification. The project makes it possible for public integration testing of the software package, thus enabling end-user feedback and wider adoption and dissemination within the neuroimaging community.

Brain-wide correlation of single-cell firing properties to patterns of gene expression Cohen, Adam Ezra Harvard University 2018 Active
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Different neurons show widely varying patterns of gene expression and widely varying patterns of electrical spiking. It is not currently possible to predict the electrical spiking properties of a cell from its pattern of gene expression. Cohen’s team seeks to develop tools to record gene expression and spiking patterns in thousands of neurons by combining two novel technologies: all-optical electrophysiology and BRAIN Initiative-funded fluorescent in situ hybridization, MERFISH. They will create correlated brain-wide maps of gene expression and neuronal firing, first in rodent acute brain slices and then in the zebrafish spinal cord in vivo . These maps may ultimately help elucidate the roles of genes in governing neural function in health and disease.

Bridging structure, dynamics, and information processing in brain networks Choi, Hannah University Of Washington 2019 Active
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The mammalian brain has unique abilities to process various sensory inputs from the environment, based on efficient and complex brain network structures and dynamics. However, the precise connections between the brain’s intricate wiring and its rich network dynamics are unclear, as is our understanding of how the brain’s connectivity and dynamics relate to underlying neural coding principles. Leveraging the Allen Institute’s Mouse Brain Connectivity Atlas, Dr. Choi will explore these issues, ultimately aiming to help close the gap between brain biophysiology and neural coding principles, with a focus on predictive coding theory using data-driven mathematical models.

C-PAC: A configurable, compute-optimized, cloud-enabled neuroimaging analysis software for reproducible translational and comparative Craddock, Richard Cameron Milham, Michael Peter (contact) Child Mind Institute, Inc. 2018 Active
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Novel neuromodulation, recording, and imaging techniques applied to human and non- human primate brains generate datasets that require tools for organizing, processing and analyzing data that are widely available and easy to use. Drs. Milham and Craddock plan to extend C-PAC (Configurable Pipeline for the Analysis of Connectomes), building a configurable data analysis pipeline that incorporates various statistical analysis, machine learning, and network analytic techniques. In addition to adapting methods used in human imaging for non-human primate data, the project will implement a toolbox for alignment of electrophysiological data with brain imaging data. The resulting software enables high- throughput, semiautomated and end-to-end processing and analysis of structural and functional MRI data that are accessed locally or via the cloud.

Cell atlas of mouse brain-spinal cord connectome Dong, Hong-wei Tao, Huizhong Whit Zhang, Li I (contact) University Of Southern California 2018 Active
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Systematic studies on the brain-spinal cord connectome are lacking despite great efforts to characterize neuronal cell types in the brain. Zhang’s multi- laboratories project aims to systematically characterize neuronal types in the mouse spinal cord based on their anatomy, connectivity, neuronal morphologies, molecular identities, and electrophysiological properties. Via multiple newly-developed techniques, including an anterograde/retrograde trans-synaptic tagging method to label neurons, gene expression bard coding, and a fast 3D light sheet microscopy method, the team will establish a complete cell-type based brain-spinal cord connectome database, which will be made accessible to the neuroscience community.

Cell class- or type-specific viruses for brain-wide labeling and neural circuit examination Tasic, Bosiljka Allen Institute 2019 Active
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To gain a complete understanding of how certain cell types work, researchers must be able to access those specific cells. Despite advances in single-cell transcriptomics, commonly used genetic tools and methodologies have variable expression, can lack specificity, and often take a long time to create. Dr. Tasic’s group aims to develop a set of adeno-associated viruses containing enhancers to target specific cell types following administration via an injection behind the eye to access the whole brain, in mice. The enhancers will be defined via RNA and epigenetic sequencing, before being screened for their specificity. Once made publicly available, this toolkit could offer a more efficient method to access specific cell classes, facilitating investigations into their roles in circuit function.

Cell-Specific Visualization of Endogenous Proteins Mao, Tianyi Zhong, Haining (contact) Oregon Health & Science University 2019 Active
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Monitoring endogenous synaptic proteins in neuronal subtypes of behaving animals is needed to better understand neural circuits underlying behavior, but current visualization methods can produce altered protein function and off-target effects. Here, Dr. Zhong, Mao, and labs aim to develop a novel genetic strategy called endogenous labeling via exon duplication (ENABLED) to label endogenous synaptic proteins for in vivo imaging. Expanding on their success of labeling PSD-95 in neurons, the team will optimize the ENABLED method to label several additional synaptic proteins in mice, with the goal of generating ENABLED mice in which synaptic proteins are labeled with different colors for simultaneous imaging. This work could provide new tools for researchers to advance our understanding of synaptic connectivity and plasticity under physiological conditions in behaving animals.

Cellular mechanisms of hippocampal network neuroplasticity generated by brain stimulation Voss, Joel L (contact); Disterhoft, John F Northwestern University At Chicago 2019 Active
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Alzheimer’s disease, epilepsy and other neurological disorders can cause problems with how the brain learns. In this project, researchers in the Disterhoft and Voss labs will perform experiments on rodents and human subjects designed to understand the cellular effects of electrical stimulation on the hippocampus, a region known to be involved in learning and memory. As part of this project, they will examine the relationship between stimulation and hippocampal neuronal synchrony during theta activity rhythms. Their results may help researchers understand the underlying circuitry associated with the memory problems common in many brain disorders.

Cerebellar network mapping with a high-throughput TEM platform Lee, Wei-chung Allen Harvard Medical School 2017 Active
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Understanding cell type-specific neuronal connectivity may help indicate how the brain is altered in nervous system disorders. Lee’s team will use a high-throughput technology for electron microscopy volume image acquisition—capable of up to two orders of magnitude faster acquisition compared to current methods—and comprehensively characterize the cell types and connectivity within the cerebellum. They will reconstruct cerebellar network anatomy computationally and explore the organizational principles underlying cerebellar circuits. The tools and datasets will be released publicly, and may help uncover the role of specific circuit elements in nervous system function.
Chromatin Plasticity, Transcriptional Activity and Kinetics in Developing and Adult Human Astrocyte and Oligodendroglial Lineages Tsankova, Nadejda Mincheva Icahn School Of Medicine At Mount Sinai 2019 Active
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To better understand human-specific glial diversity, Dr. Tsankova’s lab has endeavored to improve isolation methods of glial cells from human brain tissue, via cell-specific immunotagging techniques to isolate nuclear RNA and chromatin from frozen brain. Building off this work, the team aims to profile the epigenetic and molecular features of developing and adult human astrocyte and oligodenroglial lineages. They will use high throughput technologies like Tn5-HiC, ChIP-, RNA-, and ATAC-seq to characterize the chromatin structure, transcriptional factor binding activity, and differentiation kinetics across different developmental stages of human astrocytes and oligodenroglial progenitors. These epigenetic and functional datasets should enable the creation of an integrated map of glial plasticity, providing a reference tool for comparative studies of human health and disease.

Circuit Dynamics for encoding and remembering sequence of events Jafarpour, Anna University Of Washington 2019 Active
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Typically, we experience the world as a continuous sequence of events; but when recalling memories, we remember segmented episodes. The hippocampus and prefrontal cortex (PFC) play a role in segmenting, linking, and retrieving memories of associated events, but the neural circuit mechanism of this process is not well understood. Dr. Jafarpour aims to use intracranial encephalography (iEEG) to identify the neural dynamics in the hippocampal-PFC circuit that support the encoding of sequences of words. By combining iEEG with advanced analytical techniques, natural language processing models, and research with patients with hippocampal lesions, this project will offer insights into the neural basis of speech encoding and memory formation. The work may inform the development of neural prosthetics for use by patients with memory impairments.

Circuit mechanisms of evidence accumulation during decision-making Luo, Zhihao Princeton University 2017 Active
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Dr. Luo will use optogenetic tools to inactivate specific brain structures while simultaneously recording neuronal activity across other brain areas in the rat during evidence accumulation tasks. This research could uncover the neural circuits that support the gradual accumulation of evidence during decision making.
Classification of Cortical Neurons by Single Cell Transcriptomics Ngai, John J. University Of California Berkeley 2014 Complete
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To understand what makes neurons distinct, Dr. Ngai's team will explore one major type of mouse brain cell, pinpointing genes responsible for differentiating them into subtypes and will also test whether each subtype has unique functions, using a new technique that labels them with tagged genes.
Classifying Cortical Neurons by Correlating Transcriptome with Function Scanziani, Massimo University Of California San Diego 2014 Complete
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Dr. Scanziani's team will record neuronal responses to different visual stimuli to discover how individual brain cell activity is linked to expression of specific genes.
Cognitive Restoration: Neuroethics and Disability Rights Fins, Joseph J. Weill Medical Coll Of Cornell Univ 2019 Active
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Many traumatic brain injury (TBI) patients often experience chronic cognitive impairments that disrupt functioning and can interfere with societal reentry – current efforts aim to rapidly restore cognitive function to TBI patients. In doing so, a thorough understanding of the opportunities and challenges posed by rapid cognitive restoration is critical. To address this need, Dr. Joseph Fins and his team will interview patients and family members before implantation of thalamic deep brain stimulation (DBS) devices. These interviews will collect perspectives on risks and benefits, expectations and fears, as well as factors that are weighed during decision making. After implantation, interviews will collect perspectives on the impact of cognitive impairment and restoration. The project aims to develop legal theory that supports social reentry for TBI subjects who have achieved cognitive restoration, paving the way for maximizing patient-centered benefits of any therapeutic advance.

Collaborative Standards for Brain Microscopy Hamilton, Carol M Research Triangle Institute 2018 Active
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Recent tissue-clearing techniques and advances in microscopy have made it possible to produce 3D images of intact brains. to help ensure consistency in data collection and analysis, Dr. Hamilton and her team will develop a set of standards for3D imaging of whole brains for the neuroscience research community.. Dr. Hamilton’s group will convene a Working Group of experts who will work through a consensus process to establish standards that will be distributed to the research community. These standards should help improve the efficiency of imaging research and allow comparisons across studies.

Collaboratory for atlasing cell type anatomy in the female and male mouse brain Osten, Pavel Cold Spring Harbor Laboratory 2017 Active
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Although neuronal properties have been studied for over a century, we still have an incomplete idea of how different cell types are distributed throughout the brain. Osten and colleagues will use the automated Cell Counting and Distribution Mapping (CCDM) pipeline that they developed to express specific neuronal markers in the brains of adult mice, take high-resolution images of the neurons, and then spatially map their location. They plan to identify the distribution patterns and somato-dendritic morphology of more than 80 molecularly defined cell types. These data will provide detailed anatomical information about cell circuits that can then be integrated with molecular data to better define cell types in the brain.
Combining genetics, genomics, and anatomy to classify cell types across mammals Bejerano, Gill Lois, Carlos Mitra, Partha Pratim Nelson, Sacha B (contact) Brandeis University 2014 Complete
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To gain a deeper understanding of how cells have evolved specialized features, Dr. Nelson and colleagues will create transgenic strains of rats and mice that carry identical genetic modifications in many different cell types and see how the properties of these cells diverge across species.
Comprehensive Classification Of Neuronal Subtypes By Single Cell Transcriptomics Regev, Aviv Sanes, Joshua R (contact) Schier, Alexander F Zhang, Yi Harvard University 2014 Complete
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Dr. Sanes and colleagues will use new methods of genetic screening to comprehensively catalog and distinguish different kinds of cells across species and brain regions.
Computational and circuit mechanisms for information transmission in the brain Eden, Uri Tzvi Frank, Loren M Ganguli, Surya Kepecs, Adam (contact) Kramer, Mark Alan Machens, Christian Tolosa, Vanessa Cold Spring Harbor Laboratory 2015 Complete
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Dr. Kepecs and colleagues are investigating how information is integrated into decision making, and then further transformed into behavior. This project focuses on understanding information flow across specific regions of the brain in trained rats. By performing parallel, large-scale, simultaneous electrical recordings of neural activity in these different brain regions while the animals perform two different types of decision-making tasks, these researchers hope to observe how activity in one area influences activity in a downstream area. In addition, there are plans to identify and manipulate the activity of neurons that connect these brain areas to understand the causal relationships governing information flow among these regions. Gaining such mechanistic insights into how the brain processes information will provide insights into how both the normal and disordered brain operates.
Cortical circuits and information flow during memory-guided perceptual decisions Sur, Mriganka Massachusetts Institute Of Technology 2014 Complete
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Dr. Sur and his team will combine a number of cutting-edge, large-scale imaging and computational techniques to determine the exact brain circuits involved in generating short term memories that influence decisions.
Cortical dynamics underlying visual working memory Resulaj, Arbora University Of California, San Francisco 2019 Active
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Working memory is crucial to many human functions, and a better understanding of its underlying mechanisms could improve our understanding of memory abnormalities in advanced age. Current hypotheses suggest that working memory is maintained by a hierarchy of interconnected cortical areas, but more work is needed to understand the unique role of each area. Dr. Resulaj aims to study visual working memory at the systems and cellular level in the mouse. Utilizing novel behavior assays, a laser scanning galvo system, and optogenetics, this work ultimately will develop a computational model of visual working memory in the mouse cortex.

Cortico-striatal representations of multisensory decision-making Sun, Xiaonan Feinstein Institute For Medical Research 2019 Active
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Activity in the striatum is known to be linked to perceptual decision-making processes orchestrated by the cortex. Dr. Sun proposes to use genetically-encoded calcium indicators to examine cortex-wide activity patterns in mice performing perceptual decision tasks. This will be combined with wide-field calcium imaging in order to correlate behavior with changes in neural activity. The research will enhance our understanding of how activity in the cortico-striatal pathway supports decision-making.

Crowd coding in the brain:3D imaging and control of collective neuronal dynamics Kanold, Patrick O (contact) Losert, Wolfgang Plenz, Dietmar Univ Of Maryland, College Park 2014 Complete
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Dr. Kanold and his team propose cutting edge methods to stimulate neurons at different depths in the auditory cortex, and will use new computational methods to understand complex interactions between neurons in mice while testing their ability to hear different sounds.
Crowdsourcing the Fly Connectome Murthy, Mala Seung, Hyunjune Sebastian (contact) Princeton University 2018 Active
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To fully map the fly brain, Seung and colleagues will develop “FlyWire,” a crowdsourcing platform designed to help scientists around the country analyze thousands of electron micrographs of brain circuits. The team will work with scientists at Janelia Research Campus, Ashburn VA, to acquire the pictures and then test the platform in their lab before making it available to the neuroscience community. The team will use this approach to study sensory circuits. Tools like “FlyWire” may one day be used to map the circuits underlying brain diseases in humans.

DANDI: Distributed Archives for Neurophysiology Data Integration Ghosh, Satrajit Sujit (contact) Halchenko, Yaroslav O Massachusetts Institute Of Technology 2019 Active
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Dr. Ghosh and colleagues propose to develop a new computer infrastructure for scientists to share, collaborate, and process neurophysiological data. The data will be open to both scientists and also be used to engage high school and college students. The team will also develop tools to facilitate data submission and access and to encourage adoption of the Neurodata Without Borders data standard.

DART2.0: comprehensive cell type-specific behavioral neuropharmacology Tadross, Michael R Duke University 2018 Active
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Neuropharmaceuticals provide relief to millions suffering from an array of neurological and neuropsychiatric disorders. However, a barrier to identifying novel therapeutic targets can be attributed to a poor understanding of how the behavioral effects of drugs are mediated by specific neural cell types in the brain. Tadross’ team recently developed DART (Drugs Acutely Restricted by Tethering), the first and only method to date that can map the behavioral effects of clinical drugs by cell type. These tools would reveal circuit origins of desired vs harmful drug effects, explain why some drugs have higher efficacy than others, and potentially empower future rational efficacy advances. This project aims to expand the catalog of available DARTs, increase their subcellular specificity, and improve ease of use – particularly in combination with recording devices across larger brain areas. If successful, these tools will maximize utility to the neuroscience community, enabling previously intractable questions to be addressed.

Data Archive for the Brain Initiative (DABI) Duncan, Dominique Pouratian, Nader Toga, Arthur W (contact) University Of Southern California 2018 Active
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This project develops DABI (Data Archive for the Brain Initiative) to aid the dissemination of human neurophysiological data generated through the BRAIN Initiative. Incorporating infrastructure from a pre- existing hub for delivering effective informatics and analytics solutions for major projects in the study of neurological diseases, Drs. Toga, Duncan, and Pouratian will aggregate data related to human electrophysiology, making the data broadly available and accessible to the research community. The group plans to incorporate analysis tools with user interfaces, implement tools for data management and use, and link metadata across different data modalities. The overarching goal of this project is to secure, link, and disseminate BRAIN Initiative data with all pertinent recording and imaging parameters coming from participating sites

Data interface and apps for systems neurophysiology and imaging Van Hooser, Stephen D Brandeis University 2018 Active
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Many labs develop unique software to manage and interpret their findings, but those programs are often specific for certain types of datasets, making them difficult to share among researchers. Dr. Van Hooser’s team plans to create an interface standard that establishes a common set of processes for accessing neurophysiological and imaging data. The standard will be tested, and revised accordingly, based on feedback from graduate students and postdoctoral researchers during data access events, or “hack-a-thons.” The interface standard will help increase the speed of research and make data widely available, allowing individuals outside of the neuroscience and research communities to make discoveries.

Defining cell types, lineage, and connectivity in developing human fetal cortex Geschwind, Daniel H University Of California Los Angeles 2014 Complete
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Dr. Geschwind's group will explore the diversity of cell types in the developing human brain, and will bring to bear state-of-the-art genetic and cellular visualization technology to map and trace the relationship between cell types across the cortex.
Dendritome mapping of genetically-defined and sparsely-labeled cortical and striatal projection neurons Dong, Hong-wei Yang, Xiangdong William (contact) University Of California Los Angeles 2018 Active
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The precise number of neuronal cell types of about one hundred million highly-interconnected neurons in the mouse brain is unknown. Ultimately, the classification of neuronal cell types in the mammalian brain will require integrating molecular, morphological, and connectomic properties. Yang and colleagues propose to classify neuronal cell types via brain-wide comprehensive profiling of the dendritic morphology of neurons with subsequent digital reconstruction. Their transgenic mouse lines, MORF, enable sparse labeling of genetically-defined neurons in mice, which allow for the resolution and reconstruction of individual cells’ dendritic morphologies within densely populated neuronal networks. This project will help contribute to the BICCN effort to generate a reference mouse brain cell atlas, and data will be shared publicly through the BRAIN Cell Data Center.

Determination of olfactory bulb cell identity through the integration of single cell epigenomic and transcriptomic data Doyle, Wayne University Of California, San Diego 2019 Active
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Olfaction is an extremely important sensory modality across species, and it is one of the first to be disrupted in many neurodegenerative diseases. Dr. Doyle will conduct a full census of all cell types in the mouse olfactory bulb, to better understand information integration and processing in the olfactory system. This approach will utilize transcriptomic (single cell RNA-sequencing) and epigenomic (single nucleus methylome- and single nucleus ATAC-sequencing) data generated by members of the BRAIN Initiative Cell Census Network (BICCN). Overall, this will allow for a fuller understanding of the roles of cell diversity, regulatory elements, and transcription factors in the mouse olfactory system.

Determining the role of muscle afferent signals in cortical proprioceptive representation Blum, Kyle Northwestern University At Chicago 2019 Active
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While it is known that proprioception plays an important role in movement, how the brain translates proprioceptive information into information for movement in the somatosensory cortex (S1) is poorly understood. Dr. Blum aims to study how active and passive movements of limbs elicit different responses from muscle spindles and Golgi tendon organs, especially as reflected in area 3a of S1. Using electrophysiological data, arm kinematic measurements, and EMGs in monkeys trained to perform an arm-reaching task, this research aims to model afferent proprioceptive signals and motor outputs in a neural network model. These results will improve our understand of the neural control of movement.

Develop and validate novel chemogenetic tools to modulate synaptic transmission Tomita, Susumu Yale University 2017 Active
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Neuronal activity modulates the strength of synaptic connections, a phenomenon known as synaptic plasticity, which is critical for forming and maintaining memories, for behavioral adaptations, and is disrupted in a variety of nervous system disorders. Tomita and colleagues will develop tools to chemically modulate excitatory synaptic transmission in vivo, mimicking synaptic plasticity. They will engineer a protein that transiently modulates synaptic activity upon addition of small chemical compounds. They will validate the protein module using a mouse fear conditioning behavioral paradigm and electrophysiology. This approach may help identify precise circuits/mechanisms underlying brain functions like learning and memory.
Developing a noninvasive method to manipulate specific cell types within the mammalian brain Chalasani, Sreekanth H. Salk Institute For Biological Studies 2016 Active
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Current optogenetic techniques to manipulate cellular activity rely on an invasive light delivery method which makes control of cells deep in the brain difficult. Chalasani and colleages are developing a non-invasive method of cellular control using mechanosensitive channels that are responsive to low-intensity ultrasound - a novel technique deemed “sonogenetics.” The group can control neuronal activity in vitro by expressing these channels in target cells, and plan to test similar channels to fine-tune responsiveness to ultrasound pulses. Further, the group will develop a head device to deliver ultrasound pulses in mice, test efficacy in vivo via electrophysiological and behavioral analyses. Following development in rodents, this tool could be broadly applicable across multiple species to manipulate specific neuronal and non-neuronal cell types.
Developing drivers for neuron type-specific gene expression Hobert, Oliver Columbia University Health Sciences 2014 Complete
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Dr. Hobert and colleagues will create a highly selective technology for experimentally manipulating genes in neurons, by tapping into the regulatory machinery of individual cell types.

Developing genetically-encoded detectors for neuropeptide release based on class B G-protein coupled peptide receptors Pang, Zhiping P. Rbhs-robert Wood Johnson Medical School 2019 Active
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Due to their chemically inert nature and delayed signaling pathways, neuropeptides have been difficult to study by conventional electrophysiology or with oxidizable probes. To overcome this, Dr. Pang’s group aims to develop genetically encoded optical sensors for neuropeptides, named Chimeric Detectors for Neuropeptide Release (CDNRs), using unique structural features of neuropeptide-recognizing receptors. To validate the new probes, the researchers will express CDNRs in defined glucagon-like peptide-1 (GLP-1) and corticotropin-releasing hormone/factor (CRF) circuitry using viral transduction in mice and perform high-resolution optical recording to detect the release of endogenous GLP-1 and CRF, ex vivo and in vivo. This work may lay a foundation for the development of other neuropeptides detectors to advance our understanding of neuropeptide functional connectivity in the brain.

Developing new tools for high throughput analysis of microcircuits and synapse ultrastructure using tagged vesicular transporters and deep learning. Boassa, Daniela Hnasko, Thomas (contact) University Of California, San Diego 2019 Active
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Understanding neuropsychiatric illness, many of which trace to synaptic dysfunction, requires uncovering the synapse connectome. Utilizing advancements in optics, genetics, computing, and engineering, Dr. Hnasko and his team aim to develop new imaging and analysis methods to better understand microcircuits and synapse structure. The team will use CRISPR/Cas9 to insert electron microscopy-compatible tags into endogenous vesicular transporters to image neurotransmitter-defined synaptic connections in 3D ultrastructure. In addition, the researchers will develop computational tools for automated segmentation and quantification of pre- and post-synaptic features. This toolkit may allow researchers to map and analyze neurotransmitter-defined circuit connections in defined cell types in 3D, improving understanding of synapse structure and function.

Developing novel chemo-optogenetic tools for in vivo applications Lam, Pui Ying University Of Utah 2019 Active
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Optogenetics and chemo-optogenetics are emerging tools for neuroscience research, providing ways to modulate cell function with light. However, current limitations for these tools include limited ability to target cells deep in the brain, the relatively small effects they elicit, and safety concerns over long-term use. Dr. Lam proposes to develop new chemo-optogenetic tools to address these issues, based on the TRPA1 and TRPV1 receptor channels. Further, she will develop this technology for in vivo use, testing its utility in behavioral assays of zebrafish. The work will improve our ability to understand brain circuit function, and will create a platform for the discovery of other novel chemo-optogenetic approaches that mimic natural cell activity.

Development and validation of AAV vectors to manipulate specific neuronal subtypes and circuits involved in epilepsy and psychiatric disorders across mammalian species. Deverman, Benjamin E Dimidschstein, Jordane Fishell, Gordon J (contact) Broad Institute, Inc. 2019 Active
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The ability to genetically target specific neuron populations in non-human primates (NHPs) and humans is needed to understand neural circuits in epilepsy and psychiatric disorders. Here, Drs. Fishell, Dimidschstein, and Deverman and collaborators aim to develop a Cre-based, high-throughput screening platform to identify AAV-enhancer vectors that could target specific disease-relevant neuronal populations. The team plans to evaluate the performance of promising AAV vectors across model systems (mice, NHPs, and human cell-derived organoids), before mapping the functional connectivity of inhibitory and disinhibitory interneurons in prefrontal cortex of NHPs. This work may provide a validated toolkit of AAV vectors to investigate the brain activity of specific neuronal cell populations to further our understanding of disease-relevant circuits.

Development of Line-Scan Temporal Focusing for fast structural imaging of synapse assembly/disassembly in vivo Boivin, Josiah R Massachusetts Institute Of Technology 2017 Active
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Dr. Boivin will contribute to the development of high-resolution, high-throughput Temporal Focusing (TF) two-photon microscopy to achieve real-time monitoring of synapse assembly/disassembly in developing neural circuits in vivo in the mouse brain.
Development of tools for cell-type specific labeling of human and mouse neocortical neurons Lein, Ed Levi, Boaz Pirie (contact) Ting, Jonathan T Allen Institute 2017 Active
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An important strategy for understanding the neural circuits is to identify the component cell types, then determine each cell type’s function. Currently, the characteristics of mammalian neocortical cell types are incompletely characterized, and the necessary investigative tools are lacking. Levi and colleagues will develop cross-species, cell-class-specific viral vector libraries for tagging different cell types in mouse and post-mortem human neocortex, which will be validated using single-cell RNA sequencing and electrophysiology. If successful, this project will achieve novel cell type-specific genetic tools to investigate and compare cross-species neocortical cell types.
DREADD2.0: AN ENHANCED CHEMOGENETIC TOOLKIT Jin, Jian Kash, Thomas L. Roth, Bryan L. (contact) Univ Of North Carolina Chapel Hill 2014 Complete
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Dr. Roth and colleagues will build second generation technology that uses artificial neurotransmitters and receptors to manipulate brain activity simultaneously across select cells and pathways to understand their functions and potentially treat brain disorders.
Dynamic network computations for foraging in an uncertain environment Angelaki, Dora (contact) Dragoi, Valentin Pitkow, Zachary Samuel Schrater, Paul R Baylor College Of Medicine 2015 Complete
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The computational strategies and underlying mechanisms the brain uses to enable animals to interact flexibly with their environment are poorly understood. These researchers will use large-scale, wireless, electrical recordings from six relevant, interconnected brain regions in freely-behaving monkeys to record neuronal activity while the animals engage in foraging behavior-a natural task that involves sensory integration, spatial navigation, memory, and complex decision-making. The research team will use theoretical models of decision-making to interpret the neural activity data gathered as the animals interact with their environment, with the ambitious goal of understanding how brains create and use internal models of the world.
Effects of standard fMRI calibrations on the diverse microvascular blood flow and oxygenation responses in cortical layers Sencan, Ikbal Massachusetts General Hospital 2019 Active
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Various improvements are being considered to create next generation biophysical models of blood oxygenation and fMRI measurements in brain. Dr. Sencan plans to quantify spatial and temporal diversity in cortical metabolism in order to inform these scientific advancements. By measuring processes of cortical oxygenation, metabolic rate, and blood flow responses at microvascular scales, she aims to understand how these processes contribute to brain function and vary across age, region, and depth in the awake, mouse brain. To achieve these goals, she will use novel experimental techniques, related to faster, deeper, and more realistic imaging of oxygen concentration. This work may support better interpretation of clinical results derived through imaging technologies like fMRI.

Efficiency and Safety of Microstimulation Via Different Electrode Materials Cui, Xinyan Tracy University Of Pittsburgh At Pittsburgh 2019 Active
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Microstimulation electrodes help neurologists examine the brains of patients suffering from epileptic seizures and other neural circuit problems. The Cui team aims to develop standardized in vivo and in vitro model systems for testing the safety and efficiency of novel microstimulation devices made with newly designed t materials. Experiments in mice and cultured neurons will examine the short- and long-term effects of stimulation on the health of the tissue and the integrity of the electrodes. This system may help researchers develop better microstimulation devices for treating a variety of neurological disorders.

Enabling ethical participation in innovative neuroscience on mental illness and addiction: towards a new screening tool enhancing informed consent for transformative research on the human brain Roberts, Laura W Stanford University 2017 Active
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The NIH BRAIN Initiative aims to accelerate the development of innovative neurotechnologies and their application to reduce the burden of brain disorders, including mental illnesses and substance use disorders. However, because the brain is central to our humanity, this kind of research raises profound neuroethics issues, including questions about personal identity, and socially acceptable limits on novel neurotechnologies. Further, research involving participants with brain disorders is complex because these disorders can affect cognition, emotion, behavior, and decision-making capacity. In this project, Dr. Roberts and colleagues will assess the neuroethics issues encountered in neuroscience research related to mental illness and addiction through interviews with neuroscientists, neuroethicists, and institutional review board members. They will also study factors that influence research decision-making by people with mental illness and addiction, as compared with healthy controls and people with diabetes. Finally, they will develop a screening tool to enhance informed consent, as an evidence-informed practice to facilitate ethically sound cutting-edge human neuroscience research.
Engineered viral tropism for cell-type specific manipulation of neuronal circuits Schmidt, Daniel (contact) Thomas, Mark John University Of Minnesota 2015 Complete
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Revealing how specific cell types contribute to different neural circuits that underlie cognition, behavior, and disease pathology remains a longstanding goal in neuroscience. Current methods for investigating cell-types are limited, and typically require genetically engineered animal models. Schmidt and his team propose a completely different approach that relies on natural toxins from venomous organisms, which have evolved to bind to specific receptors and ion channels residing on neuronal cell surfaces. The toxin binding domains will be attached to the surface of viruses as a means for them to gain entry into specific cell-types. This method will make it possible to study specific cell types in a wider range of animals than is currently possible.
Engineering optogenetic tools for studying neuropeptide activity French, Alexander Robert Purdue University 2017 Active
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Dr. French will develop a high throughput screening platform to identify peptides that activate opioid receptors in response to light, creating high-resolution tools to study the function of specific opioid neural circuits in the brain.
Epigenetic tools and resources for cell-type and spatial analysis of individual mammalian non-neuronal cells Adey, Andrew OREGON HEALTH & SCIENCE UNIVERSITY 2018 Active
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Dr. Adey’s team will use advanced single cell analysis techniques to explore the epigenetic properties of non-neuronal brain cells. Techniques will include performing chromatin access assays and genome-wide profiling of DNA methylation, along with studying how a cell’s chromatin folds. Some of their methods will be used to profile and compare glial and vascular cells across brain regions in both rodents and humans. To help further understand the role of non-neuronal cells in the brain, the group plans to make these tools and data available to the research community for additional analyses.

Epigenomic cell-type classification and regulatory element identification in the human brain Behrens, M Margarita Ecker, Joseph R (contact) Salk Institute For Biological Studies 2019 Active
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Although major categories of cell types have been identified in the human brain, less is known about the different subtypes or their locations. Drs. Ecker and Behrens’ groups will create an epigenetic atlas of the human brain focusing on DNA methylation, open chromatic patterns, and transcriptomic signatures at the single-cell level. In addition to defining new cell types and their markers, this analysis may uncover new information on genetic variants associated with psychiatric and neurological disorders.

Epigenomic mapping approaches for cell-type classification in the brain Behrens, M Margarita Ecker, Joseph R (contact) Salk Institute For Biological Studies 2014 Complete
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Dr. Ecker's group will use signatures of epigenetics, the switching on-and-off of genes in response to experience, in mouse frontal cortex to help identify different classes of cells and understand their function.
Establishing a Comprehensive and Standardized Cell Type Characterization Platform Anderson, David J Zeng, Hongkui (contact) Allen Institute 2014 Complete
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Dr. Zeng's group will characterize cell types in brain circuits controlling sensations, such as vision and emotions, as a first step to better understand information processing across circuits. The data generated will be posted as a public online resource for the scientific community.
Ethical Safeguards for Exit and Withdrawal from Implanted Neurotechnology Research Sankary, Lauren Cleveland Clinic Lerner Com-cwru 2017 Active
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Dr. Sankary will combine an assessment of the experience of research participants exiting from research studies involving implanted neurological devices with a critical evaluation of existing research practices and regulations that protect these subjects. The goal of this research is to determine the responsiveness of these safeguards to patient concerns and lay the groundwork for development of evidence-based guidelines for the ethical conduct of this research.
Ethics of Patients and Care Partners Perspectives on Personality Change in Parkinsons disease and Deep Brain Stimulation Kubu, Cynthia M. S. Cleveland Clinic Lerner Com-cwru 2017 Active
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The nature and extent of personality changes following deep brain stimulation (DBS) for the treatment of Parkinson's disease (PD) are unclear. Dr. Kubu and colleagues will analyze patients’ and caregivers’ perspectives on personality characteristics (e.g., extroversion, humility) at different stages of PD and over the course of DBS (patients within one year of diagnosis, within 5 -7 years of diagnosis, and those undergoing DBS). This study will shed light on participant's most valued personality characteristics, and whether those characteristics are captured in the existing informed consent process; the influence of PD and/or DBS on personality; and the extent of agreement between patients’ and caregivers’ perceptions of personality change. These data will facilitate an enhanced, iterative informed consent process that includes systematic assessment of patients’ perceived personality changes, values, and goals; will inform understanding of identity and autonomy in the context of DBS; and may allow clinicians to ease the fears of patients receiving DBS.
Expanding access to open-source data acquisition software for next-generation silicon probes Siegle, Joshua H Allen Institute 2019 Active
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Determining how brain cells communicate with each other bolsters understanding of the causes of disorders. The new Neuropixels probe allows for highly detailed recordings of neurons communicating; however, sophisticated software is required to use this tool and to understand the data it generates, which include nearly 1000 recording sites from a single probe. For other labs to use this system, a support network is needed to address user requests, maintain the software code, and improve documentation. Through this project, Dr. Siegle and colleagues will support other labs that wish to use Neuropixel probes to better understand the underpinnings of neurological and mental disorders.

Exploring the role of reactive astrocytes in brain inflammation using a novel combinatorial strategy Fiacco, Todd A (contact) Riccomagno, Martin Miguel Wilson, Emma Harriet University Of California Riverside 2019 Active
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From Electron Microscopy to Neural Circuit Hypotheses: Bridging the Gap Fee, Michale S Massachusetts Institute Of Technology 2018 Active
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The Fee lab will develop tools to help scientists make highly detailed maps of neural circuits from images of brain tissue taken with an electron microscope- (EM). Specifically, they will acquire and automatically segment millimeter scale EM data, identify cell types from ultrastructural fingerprints and perform virtual experiments with the dataset. They will use these tools to test theories about how songbirds learn to sing and move. Their hope is that scientists can use these tools to fully understand circuit problems behind a variety of brain disorders.
Functional implications of a patch/matrix-like compartmental organization in the mouse inferior colliculus Lesicko, Alexandria Marie University Of Pennsylvania 2019 Active
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The brain’s inferior colliculus is described to have a patch- or matrix-like “modular” anatomical organization, with various nuclei and distinct chemical boundaries. However, the functional implications of this organization are unknown. Dr. Lesicko’s experiments aim to determine whether this modularity underlies distinct streams of information processing in the inferior colliculus. Using a combination of two-photon calcium imaging, clustering analysis, optogenetics, and behavioral assays in mice performing a behavioral task, the work will examine distinctions in neural activity and mechanisms for auditory and somatosensory signaling in the inferior colliculus.

Generating a formal set of collaborative standards for sharing behavioral data and task designs to enable reproducibility in neuroscience Edwards, Stephen Anthony; Kepecs, Adam (contact) Cold Spring Harbor Laboratory 2019 Active
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Different laboratories use different behavioral systems, hardware, and software, which makes it difficult to standardize, communicate, and replicate experiments. Dr. Kepecs et al. have led the creation of a laboratory consortium to address this problem by developing requirements for behavioral data formats and an open source software suite for editing, executing, and visualizing behavioral tasks. They will also engage the scientific community to promote the adoption of these standards and tools.

Generating Multiple Circuit and Neuron Type Specific AAV Vectors With Cross-Species Applicability He, Zhigang Boston Children's Hospital 2015 Complete
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Tools to investigate and manipulate brain functions in a cell-type or circuit-specific manner are critical for understanding how different neurons and circuits underlie cognition and behavior. So far, this capability has primarily been available only for the mouse, and only for a limited number of cell types. Dr. He and his team will screen DNA sequences from ultra-conserved regions of the genome known as "enhancer elements," and test their ability to control region- and cell-type specific gene expression in the brain, as well as for expression that is dependent on neurons' electrical activity. The goal is to produce an expanded, universal tool set consisting of vectors for cell- and circuit-specific gene expression that can be used across a wide variety of species.
Genetic analyses of complete circuit formation in Caenorhabditis elegans Cook, Steven Jay Columbia Univ New York Morningside 2017 Active
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Using the model system C. elegans, which has a simple, well characterized nervous system, Dr. Cook will develop new tools to create an exquisitely detailed map of a circuit in live animals and reveal the genetic factors that orchestrate assembly of a complete neural circuit.
Genetic tools and imaging technology for mapping cholinergic engrams of anxiety Role, Lorna W State University New York Stony Brook 2015 Complete
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Neuronal circuits are widely modulated by neurotransmitters such as acetylcholine. To explore in detail how acetylcholine impacts neural circuits, Role's team will use gene-activity mapping of neurons involved in a specific cognitive function in mice - recall of anxiety-provoking experiences. During recall, the team's mapping technique will track activity-related gene expression in basal forebrain neurons expressing acetylcholine and the neurons they project to in the hippocampus, amygdala, and cortex. In addition the team will make improvements to an imaging system called 3D SPIM that can be used to track neuronal activity. These improvements have the potential to reduce the time it takes to collect and analyze the imaging data by a factor of 50.
Genetically engineered anterograde monosynaptic viral tracers for multi-species neural circuit analysis Horwitz, Gregory D Luo, Min-hua Sandri-goldin, Rozanne M. Xu, Xiangmin (contact) University Of California-irvine 2019 Active
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Due to the relatively poor performance of current anterograde viral tracers, Drs. Xu, Horwitz, Luo, Sandri-Goldin and teams aim to engineer improved anterograde monosynaptic tracers with increased labeling efficacy and reduced toxicity for the analysis of neural circuits. Using a bacterial artificial chromosome-based engineering system, the team will generate recombinant Herpes simplex virus type 1 strain 129 (H129) vectors for targeted expression in multiple neural circuits. The researchers will then validate their anterograde tracers in the visual system, hippocampus, and stress-relevant hypothalamus circuits of rodents and non-human primates. The tools developed here will be disseminated through a service platform with the goal of improving the ability to study neuronal projection networks.

High Throughput Approaches for Cell-Specific Synapse Characterization Barth, Alison L Bruchez, Marcel P (contact) Carnegie-mellon University 2017 Active
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Understanding the wiring principles within the cerebral cortex will benefit understanding of cognitive function, and how experiences are encoded into long-term memory. Bruchez and colleagues will develop molecular genetic tools using fluorogen activating proteins (FAPs), a system enabling fluorescence identification of synapses and cell-type specific connectivity, in mice. They will perform pre- and post-synaptic targeting of fluorescent and FAP proteins, respectively, allowing selective detection of connections between genetically selected cell populations. Through cell-type-specific synapse detection via high-throughput 3D imaging and analysis, this project may transform researchers’ ability to study synaptic connectivity.
High throughput mapping of neuronal circuitry using DNA sequencing Zador, Anthony M Cold Spring Harbor Laboratory 2017 Active
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Neurons transmit information to distant brain regions via axonal projections. Current neuroanatomical techniques for tracing these projections are expensive and labor intensive. Zador and his team will use high-throughput DNA sequencing to map neuronal circuitry cheaply and efficiently. Their goal is to tag each neuron in the mouse neocortex with many copies of a unique RNA barcode. Because the barcode will be present throughout the neuron, projections can be mapped across brain regions. By converting circuit mapping into a DNA sequencing task, this model will leverage the remarkable advances in high-throughput sequencing. This project could provide a new method for understanding normal neuronal circuitry and a new tool for studying animal models of neural circuit disorders.
High-density microgrid development for human neural interface devices Cleary, Daniel R University Of California, San Diego 2019 Active
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Brain-computer interfaces (BCI) show promising potential in treating symptoms of various brain diseases. A collaborative group at the University of California, San Diego, has developed a high-density array of microgrid electrodes that are thin, non-destructive, and sit lightly on the surface of the brain, for improved decoding and resolution of neural activity. This study will implement this technology to study cortical physiology and organization in the rat somatosensory cortex. Dr. Cleary aims to test the capabilities of these surface microgrids for discriminating cortical columns in the rat “barrel cortex,” representing innervation of the whiskers. He also will study how surface stimulation of the cortex affects neural activity in different layers of the cortex, initially in rats and subsequently in human neurosurgical patients. This work may improve BCI technology, providing additional treatment strategies for various brain diseases.

High-throughput Physiological Micro-connectivity Mapping in Vivo Adesnik, Hillel University Of California Berkeley 2019 Active
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New approaches to probe the dynamics of structural and functional synaptic connectivity may improve understanding of the neural basis for behavior and learning. Through a collaborative team effort, Dr. Adesnik, Ji, and Paninski’s groups aim to develop two new methods to uncover physiological connectivity of single neurons across cortical networks over time. The first technology combines multiphoton photo-stimulation in vivo with single cell electrophysiology and statistical algorithms for high-throughput mapping of the presynaptic connectome in mice. The second tool employs this photo-stimulation with optical reporters of single synapse activity to measure synaptic connectivity over time in the same animal. These approaches should enable measurements of synaptic strength and dynamics of discrete synaptic connections, as well as tracking changes in the micro-connectivity of cortical networks during development, learning or disease progression.

Highly specific, renewable, and cost-effective antibody toolbox for 3D proteomic phenotyping of the brain Chung, Kwanghun (contact) Eichinger, Daniel J Pino, Ignacio Zhu, Heng Massachusetts Institute Of Technology 2019 Active
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Recent tools have led to advances in 3-D imaging of whole brains, opening the door for proteomic imaging that can increase our understanding of how the structure and activity in cells lead to brain functions. Unfortunately, proteomic imaging is limited by antibodies currently available for this type of research. Dr. Chung’s team aims to develop a comprehensive, open-source toolbox of antibodies generated against 300 proteins that are critical for understanding how the brain works. These antibodies should be more cost-effective, targeted, and compatible with a variety of tissue processing techniques.

Human Agency and Brain-Computer Interfaces: Understanding users? experiences and developing a tool for improved consent Goering, Sara (contact) Klein, Eran University Of Washington 2018 Active
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Agency, our ability to act and experience a sense of responsibility for our actions, is central to individual identity and societal conceptions of moral responsibility. Neural devices are currently used to treat some brain disorders, such as Parkinson’s disease, and are being developed to treat others such as depression and obsessive-compulsive disorder, yet their use raises important ethical concerns about potential effects on agency. Dr. Goering, Dr. Klein and their team will investigate agency in individuals receiving brain computer interface devices for sensory, motor, communication, and psychiatric indications. They aim to build a user-centered neural agency framework, and, ultimately, to enhance the informed consent process by developing a communication tool that patient participants might use to better understand and discuss potential changes in agency associated with use of neural devices.

Identification of enhancers whose activity defines cortical interneuron types Rubenstein, John L. R. (contact) Sohal, Vikaas Singh University Of California, San Francisco 2014 Complete
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Dr. Rubenstein and colleagues plan to identify enhancer molecules specific to particular types of interneurons – that relay neural signals – and use this information to profile distinct cell types and new ways to manipulate genes.
Illuminating Neurodevelopment through Integrated Analysis and Vizualization of Multi-Omic Data Hertzano, Ronna (contact) White, Owen R University Of Maryland Baltimore 2018 Active
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Molecular and cellular neuroscientists often lack the training in computer programming to fully explore “-omics” data common in the BRAIN Initiative. Drs. Hertzano and White will implement analytic software for visualization and interactive genome browsing of gene expression and RNA-seq data, including simple and complex cross-dataset analysis. These tools will be made available in the BRAIN Initiative funded Neuroscience Multi-Omic Data Archive (NeMO) which hosts multi-omic data. The software will provide an easy-to-use web-based work environment for visualization and analysis of multi-modality and multi- omic data, interrogation of relationships between epigenomic signatures and gene expression, and integration of analytical techniques for multivariate analysis, gene co- expression and other analyses.

Imaging and Analysis Techniques to Construct a Cell Census Atlas of the Human Brain Boas, David A Fischl, Bruce (contact) Massachusetts General Hospital 2018 Active
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Three-dimensional human brain atlases are increasingly important for integrating complex datasets into useful community resources. Fischl’s team proposes to create a multi-scale atlas—akin to Google Earth™ for the human brain—to map hemisphere-wide networks and also zoom in to see individual, labeled cells at micron resolution. This advance will be made possible through multiple imaging technologies, including light-sheet microscopy, tissue clearing, immunohistochemistry, magnetic resonance imaging, and newly-developed techniques in Optical Coherence Tomography. The ability to probe the cellular properties and multi-scale networks of specific areas in the human brain could evolve to an automated system for visualizing across the entire human brain in health and disease.

In situ transcriptional analysis of brain circuits at single cell resolution Dulac, Catherine G (contact) Regev, Aviv Zhuang, Xiaowei Harvard University 2016 Active
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A fundamental challenge to achieving a mechanistic understanding of how the brain works is obtaining a systematic characterization of diverse cell types at single-cell resolution. Dulac, Regev, and Zhuang, will use Multiplexed Error Robust Fluorescent in situ Hybridization (MERFISH) to measure the transcriptome of single cells from intact brain tissue, creating a spatially informed cellular inventory of neural circuits in mouse. By expanding this method into the marmoset and coupling it with behavioral tasks, they will validate a new, unbiased imaging platform and computational toolkit that uses gene expression profiles to classify cells in the functional context of behaviorally relevant circuits.
In Vivo Imaging of Local Synaptic Neuromodulation by Dopamine Evans, Paul Robert Max Planck Florida Corporation 2018 Active
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Dopamine is a powerful neurotransmitter that facilitates memory formation and underlies reward-related behaviors, but current techniques to assess dopamine signaling in vivo lack sufficient specificity and spatiotemporal resolution. Evans will develop new fluorescent sensors for dopamine receptors and apply them to investigate the molecular mechanisms that underlie learning in mice in vivo. The biosensors will be used to visualize the dynamic activity of specific dopamine receptors in vitro, before they are virally expressed in the motor cortex in behaving mice. Employed during motor learning, these sensors should generate a sub-micron scale map of how dopamine receptor subtypes modulate long-term structural plasticity of cortical dendritic spines. The results could help shed light on how dopaminergic modulation correlates with structural and functional plasticity.
In-vivo circuit activity measurement at single cell, sub-threshold resolution Forest, Craig (contact) Stanley, Garrett B. Georgia Institute Of Technology 2014 Complete
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Dr. Forest's team will use a newly developed robot guided technique to measure precise changes in electrical activity from individual neurons that are connected over long distances across the brain, to understand how these connections change when our brains go into different states, such as sleeping and waking.
Informing Choice for Neurotechnological Innovation in Pediatric Epilepsy Surgery Illes, Judy (contact) Mcdonald, Patrick University Of British Columbia 2018 Active
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More than 500,000 children in the US and Canada suffer from epilepsy and 30% of these children continue to experience seizures despite being treated with anti-seizure medication. Unmanaged, epilepsy can result in cognitive decline, social isolation, and poor quality of life, and has substantial economic impact on families and society. Novel approaches for treating epilepsy such as vagal nerve stimulation and responsive neurostimulation are being developed, but this work has been conducted predominately in adults and the outcomes of these trials are often not clearly generalizable to children. In this project, Drs. Illes and McDonald will explore ethical issues confronting families and clinicians when considering new treatment options for drug-resistant epilepsy in children. They aim to develop, evaluate, and deliver patient-directed resources in the form of infographics and informational materials and videos, and clinician resources for family decision-making, clinician counseling, and care.

Input-specific imaging and manipulation of synaptic plasticity underlying social memory Phillips, Mary L Max Planck Florida Corporation 2019 Active
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In an effort to improve our understanding of how synaptic plasticity contributes to social memory, Dr. Phillips aim to create a tool to modulate synaptic plasticity in specific circuits during behavior. Using advanced imaging techniques and various innovative biochemical assays, she plans to create a photo-activatable inhibitor of presynaptic plasticity and will use this tool to understand the circuitry of social memory. The researcher will develop constructs of a photo-activatable PKA inhibitor and screen the constructs using 2-photon fluorescence lifetime imaging in HeLa cells. The optimized inhibitor constructs will then be expressed in the dCA2-vCA1, vCA1-PL, and PL-dPAG projections in mice and used to block presynaptic plasticity during social learning in either aggressive or neutral contexts.  Successful development of these tools will enable investigation of neural circuitry to better our understanding of behavior and neuropsychiatric diseases.

Integrated Biophysical and Neural Model of Electrical Stimulation Effects Bazhenov, Maksim V Halgren, Eric (contact) University Of California, San Diego 2019 Active
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Electrical stimulation devices are used for neuroscience research and the treatment of brain disorders. To make the procedures more predictable, researchers in the Halgren and Bazhenov labs aim to develop a novel computational approach for predicting which neuron type will be activated by stimulation. Models will be based on neuron type, shape, brain location, and connectivity. The validity of these models will be tested in mice and humans using advanced imaging and microscopic techniques that will help the researchers observe neuronal responses.

Integrative approach to classifying neuronal cell types of the mouse hippocampus Dong, Hong-wei (contact) Zhang, Li I University Of Southern California 2017 Active
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Identifying the diversity of nervous system cell types may enable their selective manipulation and reveal their functions in health and disease. Dong and his team propose state-of-the-art techniques in viral circuit tracing and molecular and electrophysiological profiling, to classify neuronal cell types of the mouse hippocampus and subiculum. Combined with CLARITY (a tissue-clearing technique), expansion microscopy, and multiphoton imaging, their approach will report the anatomical location, connectivity, morphology, molecular profile, and electrophysiological characteristics of each cell type. Raw and analyzed data will be publicly shared on the Mouse Connectome Project website. If successful, this work can be applied toward characterizing neuronal cell types of the entire brain.
Integrative Functional Mapping of Sensory-Motor Pathways Dickinson, Michael H (contact) Holmes, Philip J Mann, Richard S Wilson, Rachel California Institute Of Technology 2014 Complete
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Dr. Dickinson will lead an interdisciplinary team to study how the brain uses sensory information to guide movements, by recording the activity of individual neurons from across the brain in fruit flies, as they walk on a treadmill and see and smell a variety of sights and odors.
Intercellular TWEAK/Fn14 Cytokine Signaling in Sensory-Dependent Circuit Refinement Cheadle, Lucas M Harvard Medical School 2019 Active
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Neurodevelopmental disorders can arise from impairments in sensory-dependent refinement or strengthening of synapses during postnatal brain development. However, treatment strategies focused on addressing such impairments lack an advanced understanding of the cellular and molecular mechanisms of this process. Building on prior results showing that expression of the gene Fn14 is driven by visual experience and encodes a receptor required for synaptic refinement, Dr. Cheadle aims to use slice electrophysiology and bioinformatics to study how microglia-to-neuron signaling is involved in refinement via examining the role of TWEAK, an Fn14 receptor ligand, in healthy and neurodevelopmentally-impaired mice. The results may offer insights into the development of treatments for neurodevelopmental disorders.

Interneurons differentially regulate discrete pathways from ventral hippocampus Donegan, Jennifer University Of Texas Hlth Science Center 2019 Active
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Hippocampal microcircuits include excitatory pyramidal cells, which integrate information and signal to downstream brain regions, and inhibitory interneurons, which function locally to regulate pyramidal cell activity. Circuit dysfunction in the ventral hippocampus (vHipp) has been associated with various brain disorders. Dr. Donegan will use techniques including mammalian GFP reconstitution across synaptic partners (mGRASP), fiber photometry, in vivo electrophysiology, and optogenetics, to test the hypothesis that different types of interneurons in the vHipp differentially regulate the function of ventral hippocampus pyramidal cells depending on their projection target. She will also test whether vHipp microcircuit anatomy and function are altered by chronic stress, shedding light on the potential link between circuit dysfunction in the hippocampus and brain disorders.

Interrogating Biophysical Mechanisms of Magnetogenetic Cell Stimulation at Radio Frequencies Liu, Chunlei University Of California Berkeley 2019 Active
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Magnetogenetics refers to a promising new method for wirelessly stimulating brain circuits. Initial reports suggest that neurons can be genetically modified to express magnetically sensitive ion channels, allowing the neurons to be activated by exposure to electromagnetic fields. The Liu group aims to systematically explore the full potential and limitations of this technology. Their results may help neuroscientists noninvasively examine the role of brain circuits in a variety of behaviors and disorders.

Intrabody-dependent activation of cell-specific gene expression in CNS Blackshaw, Seth Johns Hopkins University 2015 Complete
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Techniques for inducing specific cell types to express certain proteins typically require using genetically engineered animals, which are limited primarily to rodents and can take years to develop. Blackshaw and colleagues are developing tools that will allow specific cells to be labeled and manipulated without complex genetic approaches. If successful, this technology would enable the labeling and modification of multiple types of specific neurons in nearly any animal, at a fraction of the cost and time of current techniques.
Investigating the hypocretin to VTA circuit in memory consolidation during sleep Borniger, Jeremy Stanford University 2018 Active
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Brain-computer interfaces and neuroprosthetics have provided a significant benefit to patients with cervical spinal cord injuries. However, current technology is limited in its abilities to allow the user to control how much force is exerted by the prosthesis and to provide sensory feedback from the prosthetic hand. In a public-private collaboration with Blackrock Microsystems, Dr. Boninger and colleagues are looking to improve the dexterity of neuroprostheses by incorporating microstimulation of the somatosensory cortex. This stimulation could provide tactile feedback to the user and hopefully allow the user to better control the force applied. Ultimately, this approach will improve the dexterity and control of prosthetic limbs used by patients with spinal cord injuries.

Investigating the molecular, cellular and circuit effects of transcranial magnetic stimulation Falchier, Arnaud Y Opitz, Alexander (contact) Vlachos, Andreas University Of Minnesota 2019 Active
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Transcranial magnetic stimulation (TMS) has the potential to non-invasively treat brain circuit disorders. Nevertheless, scientists do not completely understand how it may work. Researchers in the Falchier, Opitz, and Vlachos labs plan to use electrical and optical recording techniques to examine the molecular and cellular effects of TMS on neurons in brain slices from rodents and nonhuman primates. Their goal is to develop computational models that will help researchers understand and predict the effects of TMS. Ultimately, the results may help researchers devise improved TMS based treatments for a variety of neurological disorders.

Investigating the response of CNS neurons to electric and magnetic stimulation Fried, Shelley Massachusetts General Hospital 2019 Active
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To help improve nerve stimulation devices, the Fried team will explore the fundamental neurophysiological principles that guide how retinal and cortical neurons respond to artificial electrical and magnetic stimulation. Neural responses to stimulation will be recorded in individual retinal ganglion cells from rodents or nonhuman primates. The scientists will then map the sensitivity of different parts of each neuron. The results may be used to create models of neuronal activity that may inform the development of more efficient nerve stimulation devices for treating neurological disorders.

Investigating the Role of Neurotensin on Valence Assignment During Associative Learning in the Basolateral Amygdala Olson, Jacob Michael Massachusetts Institute Of Technology 2017 Active
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Dr. Olson will systematically identify, manipulate, and characterize the neural projections that release the neuropeptide neurotensin to the basolateral amygdala during behavior conditioning tests in mice to identify a new circuit that regulates associative learning.
Is the Treatment Perceived to be Worse than the Disease?: Ethical Concerns and Attitudes towards Psychiatric Electroceutical Interventions Cabrera Trujillo, Laura Yenisa Michigan State University 2018 Active
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The NIH BRAIN Initiative aims to catalyze novel tools and technologies to modulate brain circuit function, paving the way for new treatment options for brain disorders. However, such interventions also have the potential to cause unintended changes in aspects of cognition, behavior, and emotion. These changes, in turn, raise concerns regarding autonomy, personal identity, and capacity for informed consent. In this study, Dr. Cabrera Trujillo and her team will study ethical concerns, beliefs, and attitudes about the use of novel bioelectric approaches among clinicians, patients, and the broader public. The work will provide stakeholder perspectives that will be valuable for informing the responsible development and use of these novel neurotechnologies.

Lagging or Leading? Linking Substantia Nigra Activity to Spontaneous Motor Sequences Adams, Ryan Prescott Datta, Sandeep R Sabatini, Bernardo L (contact) Harvard Medical School 2015 Complete
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One of the goals of the BRAIN Initiative is to understand how the brain generates behaviors. These researchers are utilizing a novel 3D machine vision technology to automate classification of spontaneous behavior when freely-moving mice are confronted with stimuli; they are then correlating that information with dense recordings of neural activity in key regions of the brain implicated in movement disorders. Researchers are then manipulating the activity of specific neurons in this brain region with light to test their role in the animal’s behavior. Dr. Sabatini and colleagues offer an innovative ‘grammatical’ structure to understanding how the brain produces complex, systematic behavior.
Large-scale monitoring of sensory transformations in the mammalian olfactory system Burton, Shawn Denver University Of Utah 2017 Active
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Dr. Burton will leverage recent enhancements in calcium indicators to image pre- and post-synaptic neural activity simultaneously in the mammalian olfactory system, gaining insight into how sensory information is transformed as it moves through a neural circuit.
Leveraging ethical dissension among capacity, beneficence and justice in clinical trials of neurotherapeutics in the severely disabled: lessons from schizophrenia Davis, Rachel A Gault, Judith Morse (contact) Saks, Elyn R. University Of Colorado Denver 2019 Active
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Individuals with severe, disabling, chronic mental illness, such as treatment-refractory schizophrenia/schizoaffective disorder (TRS), have often been excluded from research, leading to challenges in developing treatment for their illnesses as well as access to that treatment. Here, Dr. Judith Gault will examine the ethical issues that will lay a foundation for conducting clinical research in TRS patients who have traditionally been excluded in studies. These ethical principles will include transparency, accessibility and safety of clinical trials testing neurosurgical intervention in TRS patients who are in urgent need of effective novel interventions. The team will explore the ethical implications of excluding individuals based on their capacity to consent, surgical risks, and severity of symptoms for a planned clinical trial to treat TRS. Successful completion of the project could revolutionize our understanding of how to overcome research disparities among severely disabled individuals by improving transparency, accessibility, and safety of clinical trials.

LIPS: A novel technology for spatial and temporal control of protein synthesis in dendritic spines Gan, Wenbiao Jaffrey, Samie R (contact) Weill Medical Coll Of Cornell Univ 2015 Complete
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Synaptic plasticity involves changes in protein expression that are precisely localized to dendrites and synaptic spines, but current techniques for manipulating gene expression are not able to approach these small scales. Jaffrey and colleagues propose a method called light-induced protein synthesis (LIPS), using RNA transcripts under control of plant-derived phytochrome proteins that can be activated by microscopic laser spots. The ability to directly manipulate the protein content at specific synapses and spines may greatly enhance efforts to decipher the roles of synaptic proteins in learning, memory, behavior, and disease.
Mapping and controlling gene expression in inhibitory interneurons mammals Fishell, Gordon J New York University School Of Medicine 2016 Complete
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In order to better understand what influences normal brain development, it is necessary to track changes in gene expression over time and in different contexts, including learning and development. Fishell and colleagues modified DNA Adenine Methyltransferase Identification technology (DamID) to make it inducible in forebrain interneurons at particular developmental time points to measure gene activation. The new DamID will provide a transcriptome timestamp in a diverse cell population without requiring transgenic tools. The group intends to use transcriptome data and computational programming to expand into viral vectors to modulate interneuron subgroups in mice and non-human primates.
Mapping cerebellar granule cell function with novel genetic and optical tools Broussard, Gerard Joey Princeton University 2019 Active
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Small, tightly-packed granule cells (GrCs) in the cerebellum have been associated with sensory and motor events, but their specific roles remain unclear due to their close packing.  Dr. Broussard aims to precisely record from and perturb GrCs and measure the resulting effects on neural firing patterns and activity in mice. The researcher will develop a spike-counting method for genetically encoded indicators by optimizing the kinetics of the calcium sensor GCaMP. After developing a cleared skull preparation to access the full posterior cerebellum in mice, the new indicator will be used to map the neocortical drivers of GrC activity across the cerebellum, and rodent behavioral tasks will be used to disambiguate sensory, motor and internal-state contributions to granule cell activity patterns. Better knowledge of GrCs activity will further our understanding of neural circuits that guide sensory processing and plays roles in neurological disorders.

Mapping Developmental Lineage Relationships in the Cerebral Cortex Nowakowski, Tomasz University Of California, San Francisco 2019 Active
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A variety of cell types across the cerebral cortex develop from a small number of radial glia neural stem cells, though current tools lack the ability to connect this lineage to genetic mutations underlying developmental perturbations in a scalable manner. Dr. Nowakowski’s team will combine developmental lineage tracing and spatial transcriptomic technologies into molecular barcodes that trace the origin of cortical cells in mice. In addition to potentially increasing understanding of brain development, these studies may introduce a scalable framework to integrate lineage tracing technologies with spatial tissue mapping.

Mapping neuronal chloride microdomains Staley, Kevin J. Massachusetts General Hospital 2014 Complete
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Using protein engineering technology to monitor the movement of chloride through inhibitory neurotransmitter receptor channels, Dr. Staley's group aims to understand the role of chloride microdomains in memory.
Mapping neurotransmitter receptors onto the connectome Zipursky, S. Lawrence University Of California Los Angeles 2018 Active
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The Zipursky team plans to develop a system for finding postsynaptic neurotransmitter receptors on high-resolution pictures of synapses. By combing expansion microscopy with CRISPR-based and stochastic single-cell labeling techniques the team aims to tag receptors found at the synapses of Drosophila visual system circuits. With minor adjustments, these techniques may one day be used to map receptors in the human brain.

Mapping the Developing Human Neocortex by Massively Parallel Single Cell Analysis Kriegstein, Arnold University Of California, San Francisco 2014 Complete
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By combining genetic, molecular and physiological techniques at the single cell level, Dr. Kriegstein and colleagues will classify diverse cell types in the prefrontal cortex of developing human brain tissue.
Mechanism underlying Nerve Conduction Block by High Frequency (kHz) Biphasic Stimulation Tai, Changfeng University Of Pittsburgh At Pittsburgh 2019 Active
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High frequency biphasic stimulation (HFBS) of the spinal cord is a new and highly effective method for treating lower back pain, but little is known about why it works. Here the Tai group will perform experiments in animals to explore how HFBS blocks nerve signal conduction along spinal cord axons. They will focus on changes in axonal ion gradients, ion channels, and ion pumps in response to stimulation. Their results may help researchers not only understand how HFBS works but also refine the way it is used to treat pain.

Mechanisms of Active Sensing in Drosophila Suver, Marie New York University School Of Medicine 2019 Active
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To process information about the world, the nervous system must distinguish external stimuli from internally generated sensory stimuli, but the mechanisms underlying the cellular basis of internally generated sensation and movement are not well understood. Here, Dr. Suver plans to develop a small circuit model of this process using the antennae of the fruit fly as a model system. Using electrophysiological recordings, optogenetics, and immunohistochemistry, she will develop the neural circuits controlling and sensing antennal movement as a cellular model for studying principles of active sensing. The insights gained from a tractable genetic circuit model may improve understanding of active sensation, as well as how these mechanisms might fail in disease.

Mechanisms of electrical stimulation of a canonical motor microcircuit Heckman, Charles NORTHWESTERN UNIVERSITY AT CHICAGO 2018 Active
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A central goal of the NIH BRAIN Initiative is to develop new and improved methods for modulating the activity of specific neural cells and circuits, including those of the spinal cord. Dr. Heckman and his team will study the effect of dorsal electrical stimulation (DES) on motor circuits of the lumbar spinal cord. Specifically, they will investigate how DES affects two functions of descending inputs from the brain to the spinal cord – the generation of movements and the control of spinal neuron excitability. This work will help define the potential of DES for selective control of spinal motor circuits and may inform efforts to restore movement after spinal cord injury via DES.

Mechanisms of neural circuit dynamics in working memory Bialek, William Brody, Carlos D (contact) Seung, Hyunjune Sebastian Tank, David W Wang, Samuel Sheng-hung Witten, Ilana Princeton University 2014 Complete
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Dr. Brody and his colleagues will study the underlying neuronal circuitry that contributes to short-term "working" memory, using tools to record circuit activity across many brain areas simultaneously while rodents run on a track-ball through virtual mazes projected onto a screen.
Mechanisms underlying large-scale coordination of cortical activity during perceptual decisions Pinto, Lucas Princeton University 2019 Active
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Evidence suggests that both spontaneous and learned behaviors engage activity in various regions of the cortex. However, for perceptual decision-making, more complex and demanding tasks involve decorrelated cortical activity as a more distributed, widespread process throughout the cortex. Dr. Pinto aims to understand this phenomenon, using cutting-edge technology to study how distributed cortical acitivity mediates complex decision-making and the mechanisms of task-induced changes in large-scale cortical dynamics. The research will utilize two-photon calcium imaging, virtual reality behavioral tasks, pharmacogenetics, optogenetics, and modelling, increasing our understanding of the neural basis of decision-making.

Model behavior in zebrafish: characterization of the startle response Meserve, Joy Hart University Of Pennsylvania 2018 Active
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The startle response is disrupted (i.e., uncoordinated or weak) in several neurological and psychiatric disorders. Meserve will investigate the startle response using live imaging of neural activity in transparent larval zebrafish. The slc5a7 gene (required for acetylcholine synthesis) modulates the startle response in zebrafish, and human slc5a7 mutations are implicated in attention deficit disorder and major depression. This project will study slc5a7a’s role in neural circuit development and/or startle response. Circuit defects in slc5a7a mutants will be investigated via calcium imaging and whole-brain activity mapping of neurons known to be required for the startle response. Integrated studies on gene function, neural circuitry, and behavior will uncover the developmental stage and anatomical region where slc5a7a is required. These experiments may determine how slc5a7a promotes normal startle response, and contribute knowledge about how acetylcholine regulates behavior.
Motion Sequencing for All: pipelining, distribution and training to enable broad adoption of a next-generation platform for behavioral and neurobehavioral analysis Datta, Sandeep R Harvard Medical School 2019 Active
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Despite the ability of scientists to record from and modulate the activity of individual neurons and neuronal circuits, it has been difficult to translate those observations into a readout of behavior. Dr. Datta and colleagues have developed a technology called Motion Sequencing (MoSeq) that captures, in three dimensions, the behavior of a freely moving mouse and then, using machine learning, turns that data into standard “syllables” of behavior. While MoSeq could have broad applications for several research projects, the complex math makes it difficult for non-expert users to implement. This project will adapt the MoSeq system to make it more accessible for researchers and will provide a training course on how to set up and use MoSeq. This will enable a wider range of research projects to use the technology, which could improve our ability to study the effects of drugs or genetic and neuronal changes on behavior.

Multi-context software for robust and reproducible neuroscience image analysis Papademetris, Xenophon (contact) Scheinost, Dustin Yale University 2017 Active
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A thorough understanding of brain function requires the integration of neuroscience data across species and scales. While current software can verify data quality within one or a handful of data sources, reproducibility across multiple data sources is limited. Xenophon Papademetris and colleagues are developing software tools with cross-scale, cross-species reproducibility analysis in mind. By leveraging data created by two other BRAIN Initiative projects at Yale University, Papademetris will extend current software algorithms to incorporate data from multiple sources, design the software to be cross-platform compatible, validate the software through rigorous testing, and finally, distribute it to the community. The potential for a set of software tools to reliably and reproducibly analyze multiple heterogeneous neuroscience data types will help to break down data barriers for the greater neuroscience community.

Multiparametric Biosensor Imaging in Brain Slices Blanpied, Thomas A Meredith, Andrea L Rizzo, Mark A (contact) University Of Maryland Baltimore 2016 Active
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The coordinated observation of spatial and temporal interactions of multiple signaling pathways within individual cells and across intact circuits is limited by an inability to simultaneously track dynamic molecular activity. Rizzo and colleagues will validate and further develop a new methodology, Fluorescent Anisotropy Reporters (FLAREs), for simultaneous optical imaging of multiple biosensors within single neurons of mouse brain slices during neural coding. The group will improve the optical sectioning microscopy methodology and increase the range of signaling molecules measurable with FLAREs. This technique may enhance subcellular spatial resolution and cellular temporal resolution of signaling pathways, and could scale to visualize coordinated cellular activities and neural coding in intact brain circuits.
Multiplex in vivo imaging of cell-specific and circuit-specific signaling pathways during synaptic plasticity Huganir, Richard L (contact) Zhang, Jin Johns Hopkins University 2016 Active
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Kinase signaling pathways that regulate synaptic plasticity help integrate multiple types of synaptic inputs to control neuronal circuit adaptation during behavior. However, monitoring more than one of these pathways simultaneously in awake behaving animals remains a challenge. Huganir and Zhang plan to develop and validate new genetically encoded fluorescent biosensors and use two-photon microscopy to image activity of multiple kinase signaling pathways in awake, behaving mice. This tool will improve rapid (seconds to minutes) detection of dynamic signaling pathways during physiologically relevant sensory experiences and learning tasks, greatly improving our ability to visualize cell-specific and circuit-specific signaling pathways.
MULTISCALE ANALYSIS OF SENSORY-MOTOR CORTICAL GATING IN BEHAVING MICE Jaeger, Dieter (contact) Stanley, Garrett B. Emory University 2015 Complete
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The neural circuitry underlying how animals make motor decisions, especially in response to sensory or environmental cues, is not well understood. Many motor disorders, including Parkinson’s and Huntington’s disease, are linked to faulty circuits in a region of the brain called the basal ganglia. Researchers will use a variety of advanced methods to image, record, and manipulate the activity of neurons in this area as well as in the areas of the brain involved in sensory perception and movement. By employing these methods at multiple scales – from the individual neuron to neuronal networks – and then correlating these data with the behavior of awake, behaving mice, researchers hope to reveal how sensory information is integrated with input from the basal ganglia to result in the decision to initiate or suppress movement.
Multiscale Imaging of Spontaneous Activity in Cortex: Mechanisms, Development and Function Constable, R. Todd Crair, Michael (contact) Yale University 2015 Complete
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Being able to observe the activity of a single neuron while simultaneously observing the activity of entire brain regions is a critical step in bridging the gap in understanding of how a collection of nerve cells ultimately generates an organized behavior. Dr. Crair and colleagues will develop and use two different imaging techniques to measure the activity of individual neurons, regions of the brain, and the whole brain, during different behavior states, such as REM and non-REM sleep, in developing mice. Bridging their analyses and insights between and within scales will allow these researchers to examine neural circuits and networks in different brain states and determine how they are modulated through development.
Nano-switches for optogenetic control of neuronal proteins with ultra-specificity Wang, Lei University Of California, San Francisco 2017 Active
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Optogenetics is a powerful tool for controlling the activity of neurons with light, but it currently cannot be readily applied on any protein of choice, and lacks specificity. Wang and his team propose a nano-switch technology, in which unnatural amino acids (UAA) will be incorporated into neuronal proteins at single sites, achieving reversible optical control of the protein. Compared with existing methods using large, light-sensitive proteins, this method uses only a single UAA for light sensitivity, and can photo-modulate a protein without knowing its function in advance. This project’s success in model organisms will introduce vast opportunities for investigating previously-inaccessible neuronal processes at the molecular level.
Network basis of action selection Komiyama, Takaki Kreitzer, Anatol (contact) Lim, Byungkook J. David Gladstone Institutes 2015 Complete
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Three separate research groups are collaborating to understand in detail how three distinct areas of the brain function and work together to enable learning and decision-making behaviors. Drs. Kreitzer, Komiyama, and Lim are leveraging an impressive set of technologies to monitor and perturb different cell types in each brain region while the mice perform learning and decision-making tasks. By applying multiple recording methods across these brain regions at both the level of a single neuron and entire subpopulations of neurons, while the animals perform the same set of tasks, researchers hope to develop a single model of how vertebrate animals make choices about what to do next.

Neural circuits in zebrafish: form, function and plasticity Cepko, Constance L Engert, Florian (contact) Lichtman, Jeff W Sompolinsky, Haim Harvard University 2014 Complete
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Dr. Engert's team will combine a wide array of cutting-edge neuroscience techniques to watch the entire brain activity of a see-through fish while it swims, and to make detailed maps of its brain circuitry.
Neural ensembles underlying natural tracking behavior Fiete, Ila R. Huk, Alexander C Priebe, Nicholas J. (contact) University Of Texas, Austin 2015 Complete
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Animals move their eyes to track the movement of objects around them. These researchers will measure and manipulate the activity of populations of identified neurons in marmosets during pursuit eye movements. This work will allow a detailed understanding of how the pursuit circuit integrates information from a large number regions is a critical step in bridging the gap in understanding of how a collection of nerve cells ultimately generates an organized behavior. Dr. Crair and colleagues will develop and use two different imaging techniques to measure the activity of individual neurons, regions of the brain, and the whole brain, during different behavior states, such as REM and non-REM sleep, in developing mice. Bridging their analyses and insights between and within scales will allow these researchers to examine neural circuits and networks in different brain states and determine how they are modulated through development.
Neural signatures of learning complex environments in the amygdala-prefrontal network Barack, David Columbia University Health Sciences 2019 Active
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The ability to learn, think, and make decisions in complex environments is extremely important to critical life functions across species, but the neural correlates of external and internal representative states are largely unstudied. Recent studies suggest activity in the amygdala and orbitofrontal cortex correlate to state representation, but their exact roles are unknown. Dr. Barack aims to investigate how monkeys learn these state representations, using a complex, sequential decision-making task. During this novel behavioral task, similar to the boardgame “Battleship,” the team with elucidate learning in a complex environment, measuring associated neural mechanisms of circuits in the amygdala and orbitofrontal cortex activated in learning and decision-making. These results could promote the creation of computational models that may provide insights about animal and human interactions with the world.

Neuro-glio-vascular interactions in vivo probed with optical imaging Du, Congwu Pan, Yingtian (contact) State University New York Stony Brook 2019 Active
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With the goal of understanding the interplay between astrocyte, neuronal activities, and regional neurovascular response, Dr. Pan and his team aim to develop an optical platform to image synchronized activity, via genetically encoded calcium indicators, alongside local cerebral blood flow dynamics. The team plans to develop multimodality fluorescence – swept-source optical Doppler microscopy (fl-ssODM) to image large-scale astrocyte/neuronal calcium fluorescence and cerebral blood flow velocities in the cortex of mice. fl-ssODM will provide real-time spatiotemporal dynamics of astrocyte/neural calcium activity and vascular responses at rest and during activation of the cortex. The researchers will employ inhibition of astrocyte signaling using designer receptor exclusively activated by designer drugs to further validate fl-ssODM as a useful tool to investigate the interactions of astrocytic and neuronal activities and local cerebral blood flow in the brain.

Neuroethics of aDBS Systems Targeting Neuropsychiatric and Movement Disorders Goodman, Wayne K Lazaro-munoz, Gabriel (contact) Mcguire, Amy Lynn Baylor College Of Medicine 2017 Active
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A technological advance beyond traditional, open-loop DBS devices, adaptive deep brain stimulation (aDBS) devices monitor local neural activity to adjust stimulation in real time when treating certain movement and neuropsychiatric disorders. However, because aDBS devices autonomously record neural data and provide neuromodulation to affect motor function and mood, these systems raise important neuroethics issues, including changes in perception of autonomy and personal identity; risk-taking propensity; and privacy, use, and ownership of neural data. In this project, Dr. Lazaro-Munoz and colleagues will gather data from participants in existing aDBS clinical trials, their caregivers, people who declined to receive aDBS, and the aDBS researchers, to identify and assess the most pressing neuroethics issues related to aDBS research and translation. The long-term goal of this research program is to develop an empirically-informed and ethically-justified framework for the responsible development and clinical translation of aDBS systems, which will help maximize the social utility of this type of novel neurotechnology.
Neuromodulation approaches for restoring dexterous control following cortical stroke. Khanna, Preeya University Of California, San Francisco 2019 Active
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Despite physical therapy, about 50% of stroke survivors must live with impaired hand function, impacting daily activities for the remainder of their life. However, recent studies in rats have suggested that low-frequency cortical stimulation may help alleviate such symptoms. In order to translate this work to humans, Dr. Khanna aims to use a multiscale model of electrophysiological recording to monitor motor and somatosensory activity during dexterous control, comparing affected and unaffected hemispheres in non-human primates (NHP) recovering from a stroke. The results may inform development of therapeutic techniques for stroke-related motor dysfunction, while improving our understanding of neuromodulation.

Neuronal and Dopaminergic Contributions to Dissimilar Evoked Hemodynamic Responses in the Striatum Walton, Lindsay Univ Of North Carolina Chapel Hill 2018 Active
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Blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI) is a non-invasive imaging technique that infers increased brain activity from observed increases in cerebral blood flow. A notable exception to this relationship occurs in the striatum. Walton will investigate the activity of dopamine neurons, medium spiny neurons, and dopamine receptors, under conditions that evoke either blood vessel dilatation or constriction in the striatum. She will utilize optogenetic stimulation, synthetically-derived receptors, and receptor antagonist drugs to reveal the mechanisms underlying striatal positive and negative fMRI responses. These studies are important for the accurate interpretation of BOLD fMRI signals from brain regions with atypical hemodynamic responses.
New approaches for single cell tagging, editing and profiling of glial cells in vivo Hong, Weizhe University Of California Los Angeles 2019 Active
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Despite their vital roles in the brain, glial cells have been understudied in the past due to a lack of tools to precisely target and manipulate these cells. Drs. Hong and Chen plan to combine a new single-cell RNA sequencing tool, Act-seq with novel AAV-based CRISPR techniques to build a toolbox for profiling and manipulating specific mouse glial populations in vivo. Act-seq will permit transcriptional profiling of diverse glial cells, as well tracking of changes following perturbation. AAV-based CRISPR will enable tagging, labeling, and functional manipulations. By combining their expertise, the groups hope to open new avenues to study glial cell composition, function and interaction with neurons for better understanding of myriad neural circuits and complex behaviors.

New Proteomic and Genome Engineering Approaches to Decipher Astrocyte Function at Synapses SODERLING, SCOTT DUKE UNIVERSITY 2018 Active
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Star-shaped astrocytes are the most abundant non-neuronal cells of the brain. Their thin processes envelop neuronal synapses and critically shape their formation and function. In this project, BRAIN Initiative-funded researchers, Drs. Eroglu and Soderling, will develop and use a novel chemicogenetic approach called iBioID enabling the capture of astrocyte processes and the identification of the key proteins that form the interface between neurons and astrocytes. The team will use this technique in combination with gene editing to study how these proteins regulate the growth and maintenance of synapses in the healthy brain and explore what role they may play in neurological disorders.

New tools to target, identify and characterize astrocytes in the adult nervous system Gradinaru, Viviana Khakh, Baljit (contact) University Of California Los Angeles 2018 Active
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Nearly 40 percent of the central nervous system is made up of astrocytes, star-shaped cells thought to provide synaptic support and facilitate neuronal signaling. For this project Drs. Khakh and Gradinaru plan to accelerate the development of tools for studying astrocytes. These tools include advanced methods for studying RNA and proteins, ATP biosensors for monitoring astrocyte communication, and viruses for delivering genes to astrocytes in different parts of the brain. A complement of such tools could help advance our understanding of the role of astrocytes in the healthy and diseased brain.
Next Generation Cell-Type-Specific Viral Vectors for Non-Neuronal Brain Cell Types Greenberg, Michael E Harvard Medical School 2019 Active
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Our ability to genetically target diverse non-neuronal cell types in research and therapeutics has remained quite limited due to a lack of specific genetic tools. Dr. Greenberg and his team aim to advance the development of cell type-specific adeno-associated viral (AAV) drivers for non-neuronal cell populations and their distinct subtypes in mice. This group will use single-cell profiling, high-throughput screening, and validation with in vivo characterization to develop AAVs that expand genetic access to astrocytes, oligodendrocytes, microglia, and endothelial cells. The AAV drivers should retain utility across species for future experimental studies.

Next-gen Opto-GPCRs: spatiotemporal simulation of neuromodulator signaling Bruchas, Michael R (contact) Sunahara, Roger K Washington University 2016 Active
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Current tools for controlling neural activity in awake behaving animals, like optogenetics and designer receptors, are still limited in spatial and temporal control of diverse, discrete cell types. Bruchas, Sunahara, and their team will address these limitations by developing and validating a broader array of optically controlled G-protein coupled receptors with enhanced signaling dynamics and greater sensitivity and efficacy across myriad pathways. These Opto-XRs can be used in both neurons and glia, expanding the scope of experimentation in mapping brain circuitry in freely behaving animals, allowing discrete control and optodynamic stimulation of neuromodulatory signaling in brain tissues.
Noninvasive Gene Delivery for Monitoring and Perturbing Cell Types and Circuits in Transgenic and Non-Transgenic Animals Gradinaru, Viviana California Institute Of Technology 2018 Active
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When used in conjunction with transgenic animals to restrict expression to cell populations of interest, adeno-associated viruses (AAVs) can provide well-tolerated, targeted transgene expression enabling long-term behavioral, in vivo imaging, and physiological experiments. From previous BRAIN Initiative funding, Gradinaru’s team developed a method that allows systemic delivery of viral vectors capable of crossing the blood brain barrier, circumventing the need for transgenic animals. Here the team proposes to improve on this methodology by enabling select AAV variants to anterogradely cross synapses. This will be achieved through targeted evolution of AAVs. This ability to cross synapses with cell-specificity will also provide neural connectivity information. One could envision eventually being able to deliver therapeutics systemically that target disrupted circuitry with cell-specificity.

Novel Genetic Strategy for Sparse Labeling and Manipulation of Mammalian Neurons Yang, Xiangdong William University Of California Los Angeles 2014 Complete
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Dr. Yang's team will develop a new way to genetically target specific neurons, incorporating streamlined imaging and mapping methods that will enable the detection of sparse populations of cells that often elude existing methods.
Novel technologies for nontoxic transsynaptic tracing Wickersham, Ian R Massachusetts Institute Of Technology 2014 Complete
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Dr. Wickersham and colleagues will develop nontoxic viral tracers to assist in the study of neural circuitry underlying complex behaviors.
Novel tools for cell-specific imaging of functional connectivity and circuit operations Isacoff, Ehud University Of California Berkeley 2015 Complete
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Fundamental to understanding brain function in health and disease is the ability to relate the firing patterns of specific brain neurons to the synaptic connections they share with other neurons, and determine the strength of those connections. Isacoff and colleagues will develop novel, genetically encoded light-activated indicators in zebrafish, fruit fly, and mouse, which can selectively image neural activity in highly detailed structures of single neurons. Additional light-activated indicators will be targeted to synapses to quantify the release of neurotransmitters simultaneously at hundreds to thousands of synapses associated with a single neuron. This information can be used for tracking the strength of synapses over time in order to explore mechanisms of learning and brain adaptation.
Novel tools for spatiotemporal modulation of astrocytes in neuronal circuits Sur, Mriganka Massachusetts Institute Of Technology 2019 Active
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Dr Sur’s lab plans to develop innovative tools to probe astrocyte gene expression, intracellular signal transduction, and glutamate uptake with enhanced spatiotemporal regulation. The team will use CRISPR/Cas9 to target multiple genes using a single virus Multi-gRNA, Cys4-mediated, Universal Targeting System (MRCUTS) in cultured astrocytes, comparing its efficacy to CRE-LoxP methods. The team will also develop optogenetically activated G-protein receptors to probe astrocyte signal transduction in vitro and in vivo.  In addition, the researchers will develop an in vivo method to optogenetically disrupt astrocytic glutamate uptake using a light-gated ion channel, ChromeQ in mouse brain slices. The tools developed may further our ability to investigate and understand astrocyte-neuron crosstalk with enhanced spatial and temporal precision.

NWB:N: A Data Standard and Software Ecosystem for Neurophysiology Ng, Lydia Lup-ming Ruebel, Oliver (contact) University Of Calif-lawrenc Berkeley Lab 2018 Active
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Neurophysiology research, which focuses on recording brain cell activity, produces enormous amounts of complex data that are difficult to manage. Drs. Rubel and Ng will build upon the Neurodata Without Borders: Neurophysiology project to create a system that will allow for standardizing, sharing, and reusing neurophysiological data. The team will design an open source software system; develop methods to establish a consistent vocabulary for defining cell types, measurements, and behavioral tasks; and create tools to help the community adopt these new resources and standards. The proposed system will help accelerate neurophysiological discoveries as well as reproducibility studies.

OpenNeuro: An open archive for analysis and sharing of BRAIN Initiative data Poldrack, Russell A Stanford University 2018 Active
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To leverage the public investment in the BRAIN Initiative, the sharing of data produced by its myriad projects is paramount. Dr. Podrack’s project extends the recently released OpenNeuro, which was developed based on the well-established and successful OpenfMRI, for an archive of neuroimaging data. The extended archive encompasses a broader range of neuroimaging data including EEG, MEG, diffusion MRI and others. The archive also implements easy-to-use data submission, semi-automated curation and advanced data processing workflows, which run directly on the cloud platform. The archive allows to share the results alongside the data, federate with other relevant repositories, and accessible to all researchers.

Optogenetic signaling inhibitors for studying brain plasticity Gan, Wenbiao Yasuda, Ryohei (contact) Max Planck Florida Corporation 2016 Active
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Although the mechanisms underlying synaptic and behavioral plasticity have been widely studied, understanding spatiotemporal aspects of signaling activity via pharmacological or genetic manipulations remains limited. With their group, Yasuda and Gan will develop a new technique based on genetically encoded, cell-specific, light-inducible kinase inhibitors to improve spatiotemporal resolution of signaling required for synaptic plasticity in vivo. With this technique, they will modulate the activity of various kinases to identify the spatial and temporal window of learning-related dendritic spine turnover, including the consequences on behavioral performance post-learning.
PARALLEL ANALYSIS OF TRANSCRIPTION AND PROTEIN-DNA INTERACTIONS IN SINGLE CNS CELLS Dougherty, Joseph D (contact) Mitra, Robi D Washington University 2018 Active
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The brain consists of hundreds of molecularly, physiologically, and anatomically distinct cell types. Recently-developed methods can measure gene expression in tens of thousands of single cells, to help identify and classify many new types of brain cells. However, existing technologies capture only one aspect of gene regulation – mRNA levels. Dougherty’s team will develop a method to enable the parallel analysis of transcription factor binding and mRNA expression levels in mice to create single-cell Calling Cards, generating novel data and analysis tools. If successful, this project would contribute to neuroscience by providing a broadly useful technology for understanding brain function and development, in health and disease.

Pediatric Deep Brain Stimulation: Neuroethics and Decision Making Blumenthal-barby, Jennifer Lazaro-munoz, Gabriel (contact) Storch, Eric A. Baylor College Of Medicine 2019 Active
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Deep brain stimulation (DBS) is currently used in children with dystonia, epilepsy, and Tourette Syndrome, and this use is expanding to other neuropsychiatric conditions. In doing so, there are several challenging ethical issues, and no consistent guidance on the use of DBS in pediatric populations. To address this challenge, Dr. Gabriel Lazaro-Munoz and team will examine neuroethics issues and decisional and informational needs of families by conducting interviews with pDBS stakeholders (minors, caregivers, and clinicians). These interviews will inform the development of a decision aid for caregivers considering DBS for dystonia, the most common use of pDBS. This project will provide key information about the ethical issues facing families, minors, and clinicians alike when considering pDBS, as well as develop a clinical decision aid for making informed, patient-centered decisions surrounding the clinical use of invasive neuromodulation in minors.

Proprioceptive Coding of Jaw Movement during Orofacial Behavior Olson, William Paul Johns Hopkins University 2019 Active
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Many orofacial behaviors critical for survival, such as chewing, drinking, and breathing, require motor command modulation based on information from proprioceptors. However, since many previous studies of proprioceptors were not performed in awake, behaving animals, our understanding of this system is lacking. Dr. Olson aims to target and record from mouse jaw-innervating proprioceptors in the mensencephalic trigeminal (MeV) nucleus, while the animals perform orofacial behaviors. Using advancements in in vivo physiology, behavioral analysis, and computational techniques, the study will entail recording from these neurons and mapping the functional organization of the area. The findings may improve our understanding of how the brain controls jaw movements in real-time.

RAVE: A New Open Software Tool for Analysis and Visualization of Electrocorticography Data Beauchamp, Michael S Baylor College Of Medicine 2018 Active
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Electrocorticography (ECOG) allows the direct recording of a small population of neurons in human subjects, generating vast amounts of data. Dr. Beauchamp plans to develop the software RAVE (R Analysis and Visualization of Electrocorticography data) to help researchers explore such datasets. Incorporating established and successful informatics approaches that enable standardization, sharing, and re-use of neurophysiology data and analyses, RAVE includes rigorous statistical methodologies and seamless integration with existing analysis platforms. To facilitate user adoption and maximize impact, the developers plan to release RAVE 1.0 to the entire ECOG community within 6 months of the project start.

Re-engineering Rabies Virus Wickersham, Ian R Massachusetts Institute Of Technology 2019 Active
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Rabies viral tools are widely used to identify cells in direct synaptic contact with a targeted group of neurons, but due to their toxicity, they cannot be used in long-term experiments. Here, Dr. Wickersham’s lab aims to develop a new generation of rabies viral vectors and monosynaptic tracing systems that will allow nontoxic fluorescent labeling, optical monitoring, and optogenetic manipulation of connected neuronal networks. The team will characterize and validate the new viral vectors through longitudinal structural and functional two-photon imaging of labeled neurons over month timescales and optimize parameters for in vivo, retrograde monosynaptic tracing in mice. This work could provide new tools to study healthy and disease conditions through longer physiological and behavioral studies in animals.

Realization of Optical Cell-based Reporters for in vivo Detection of Neuropeptides Kleinfeld, David Slesinger, Paul A (contact) Icahn School Of Medicine At Mount Sinai 2016 Active
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Essential neuromodulators in the brain, neuropeptides control cognition and sensorimotor processing, but little is understood about when and where neuropeptides are released. Kleinfeld and colleagues developed new cell-specific fluorescent engineered reporters (CNiFERs) to optically image neurotransmitter release in real-time in vivo. The team will further develop and validate this technique for several neuropeptides, including orexin, somatostatin, and vasoactive intestinal peptide. Altered neuropeptide signals can contribute to brain dysfunction, and the expansion of this new tool will allow researchers to measure this signaling in the brains of awake, behaving animals, facilitating our understanding of complex behaviors and mental illness.
Recombinant Immunolabels for Nanoprecise Brain Mapping Across Scales Trimmer, James UNIVERSITY OF CALIFORNIA AT DAVIS 2018 Active
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Studying how the brain works from the molecular to the circuit level is crucial for improving our understanding of how the brain functions normally, and what goes wrong in various disorders. Antibody probe techniques are effective tools that work at both of those levels. This project will develop a collection of validated, recombinant antibodies that are also highly renewable. In addition, antibodies will be miniaturized to increase binding efficiency and improve labeling precision. These resources will provide a cutting-edge, validated set of research tools to enable neuroscience research across a variety of resolutions from the intracellular to the neuronal network level.

Relating functional MRI to neuronal activity: accounting for effects of microarchitecture Blazejewska, Anna I Massachusetts General Hospital 2019 Active
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fMRI can be a powerful tool to measure activity throughout the entire brain. But, because it is an indirect measure of activity through changes in blood oxygenation, it is subject to error based on local microstructural and microvascular properties of the cortex. Thus, Dr. Blazejewska intends to remove these biases in fMRI results, providing a framework for a more accurate representation of neural activity. Using histology of human brain specimens with advanced ex vivo and in vivo imaging, the team will map between tissue microarchitecture and fMRI results, correcting errors due to microstructure. These results should allow for a more accurate measurement of functional activity across all cortical layers, promoting a better understanding of the brain’s circuitry.

Remote regulation of neural activity Stanley, Sarah Amy Rockefeller University 2014 Complete
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The Stanley team will focus on the development of tools to instantly and precisely target cell activity deep in the brain using radio waves, nanoparticles and genetically modified viruses.
Repetitive transcranial ultrasound stimulation for modulating brain rhythms Dmochowski, Jacek City College Of New York 2018 Active
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Neural oscillations, which are temporal activity patterns in the brain, are recognized as fundamental to the brain’s information processing. Dmochowski and colleagues will evaluate the safety and efficacy of a new form of transcranial ultrasound stimulation (TUS), in which ultrasonic waves will modulate the activity of neural circuits with enhanced precision and specificity (on the order of millimeters). The team will determine whether TUS could be used to modify neural oscillations. This research may contribute foundational knowledge needed for development of new, non-surgical, ultrasonic treatments for disorders associated with abnormal brain rhythms, such as schizophrenia, Parkinson’s, and epilepsy.
Resource for Multiphoton Characterization of Genetically-Encoded Probes Drobizhev, Mikhail MONTANA STATE UNIVERSITY - BOZEMAN 2018 Active
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Two-photon microscopy has emerged as a key technique for studying the activity of living neural networks. However, little optimization has been performed for the associated fluorescent activity probes and sensors. Dr. Drobizhev’s research group will create a resource at Montana State University to characterize the properties of two-photon probes and make that service available to the broader research community. Given increased used of this type of resource by BRAIN Initiative investigators, the research group will also organize meetings to help other labs develop their own characterization processes.

Revealing circuit control of neuronal excitation with next-generation voltage indicators Clandinin, Thomas Robert Lin, Michael Z. (contact) Stanford University 2017 Active
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Recording real-time electrical impulses of individual neurons across multiple cells and with subcellular resolution will enable detailed understanding of neural information processing. When circuity is altered in animal models of neuropsychiatric and substance use disorders, this understanding could help explain pathogenesis and suggest treatments. Lin and colleagues will engineer brighter, more sensitive genetically-encoded voltage indicators (light-emitting proteins that report changes in membrane potential) and develop new two-photon imaging methods to determine how specific inputs affect the electrical activity of specific postsynaptic neurons deep within living fly and mouse brains. This project may open up in vivo two-photon imaging of GEVIs to researchers, potentially transforming how we measure neuronal responses in the brain.
Revealing the connectivity and functionality of brain stem circuits Berg, Darwin K Deschenes, Martin Freund, Yoav Shai Goulding, Martyn D Kleinfeld, David (contact) Knutsen, Per M University Of California San Diego 2014 Complete
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Dr. Kleinfeld and his colleagues will use a variety of tools and techniques to create detailed maps of circuits in the brainstem, the region that regulates many life-sustaining functions such as breathing and swallowing, and match the circuits to actions they control.
Revealing the transcriptional and developmental mechanisms of interneuron identity Crow, Megan Cold Spring Harbor Laboratory 2019 Active
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GABAergic interneurons have a key role in regulating circuits in the brain, and their dysfunction is linked to neurodevelopmental diseases. It is known that diversity exists between classes of interneurons, but the extent and mechanisms of this diversity are unknown. Dr. Crow will explore the transcriptional, epigenetic, and developmental mechanisms that govern interneuron diversity, in a cross-species analysis. The work will leverage computational and phylogenetic models, machine learning, and advances in single cell RNA-sequencing technology to shed light on interneuron identity.

SABER: Scalable Analytics for Brain Exploration Research using X-Ray Microtomography and Electron Microscopy Gray Roncal, William R Johns Hopkins University 2017 Active
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Neuroimaging techniques are advancing at a rapid rate, resulting in high resolution images of brain tissue and large datasets that can be difficult to manage. William Gray Roncal’s team propose an integration framework called SABER: Scalable Analytics for Brain Exploration Research. With a focus on techniques (e.g., electron microscopy) that produce high resolution brain images, SABER will create a unified framework by which these data types are accessible to a broader audience, can be processed in a reproducible, portable way, and can be scaled from small data volumes to large datasets. SABER has the potential to enable discoveries from high-resolution imaging techniques, making the parsing of entire brains a new reality.

Scaling up spatial RNA profiling with compressed sensing Eldar, Yonina Regev, Aviv (contact) Broad Institute, Inc. 2019 Active
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Using currently available imaging technology, capturing a comprehensive 3D molecular snapshot of a single mouse brain takes approximately 3 years. And, to create such a map of one single human brain is estimated to potentially take 6,000 years of imaging time!  Dr. Regev’s team will develop tools based on compressed sensing, a method that uses small amounts of data to model larger images and datasets, to help accelerate the imaging timeline for brain maps. To test the tools, Dr. Regev’s group will use them to create a detailed atlas of specific areas of mouse brain, and will share all protocols and codes to help speed brain mapping across the research community.

Single cell isoform expression across mouse brain regions and development Tilgner, Hagen Weill Medical Coll Of Cornell Univ 2019 Active
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Genetic isoforms are different types of RNA products that come from the same portion of a gene and can affect genetic activity individually or in complex units. It is unknown whether brain-region and development-specific isoforms are generated in specific cell populations. Dr. Tilgner’s group will develop novel genetic tools to closely examine distinct isoforms in 5 regions of the mouse brain at different developmental times, specifically identifying those that occur in broadly from those that appear in specific cell populations. This work could reveal distinct mechanisms for differential RNA-isoform expression, the location and timing of which may be relevant to neurodevelopmental disease.

Single cell transcriptional and epigenomic atlas of the macaque brain across the lifespan Platt, Michael L Shendure, Jay Ashok Snyder-mackler, Noah (contact) University Of Washington 2019 Active
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Molecular profiling, though common in rodent models, has not been extensively applied to the brains of more evolutionarily related model organisms, like Rhesus macaques. To gain insight into what genes are turned on and off in neurons and how that activity changes across the lifespan, Drs. Snyder-Mackler, Platt, Shendure, and colleagues will develop a comprehensive, single-cell molecular atlas of the macaque brain using epigenetic and transcriptomic sequencing of 25 brain regions. This resource of over 16 millions cells will be shared with the research community to allow for more detailed mapping of macaque brains that could eventually help us to better understand human brains.

Single Neuron Analyzer for Multi-modal, Cross-dataset (Epi)genomic Cell Type Datasets Mukamel, Eran A University Of California, San Diego 2019 Active
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The characterization of single neurons is a major theme of research in the BRAIN Initiative Cell Census Network. Dr. Mukamel and team develop Single Neuron Analyzer (SNA), a cloud-based computer tool for interactive data exploration, analysis, and validation for single cell molecular data generated by the BRAIN Initiative. The software specifically implements machine learning and cross-validation techniques to improve the reproducibility of neuronal cell type identification.

Sparse, Strong and Large Area Targeting of Genetically Encoded Indicators Antic, Srdjan D (contact) Knopfel, Thomas University Of Connecticut Sch Of Med/dnt 2015 Complete
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Electrical signals are the primary means of information processing in the brain. Recordings of electrical signals are a key means of discovering neuronal function. Genetically encoded voltage indicators (GEVI) embedded in neurons can convert electrical signals into optical signals that can be captured by powerful cameras, providing a means for observing neural activity from large populations of cells simultaneously. However, the GEVI-produced optical signals from neighboring neurons blend together and are difficult to separate. Antic and Knopfel will utilize a method for targeting GEVIs sparsely, making it possible to resolve the optical signals coming from a smaller population of individual cells.
Spinal Effects of Cortical Stimulation: Mechanisms and Functional Impact Wolpaw, Jonathan Rickel (contact); Carp, Jonathan Saul; Wang, Yu Wadsworth Center 2019 Active
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A research team led by Drs. Carp, Wang, and Wolpaw plans to explore the underlying reasons why electrical stimulation of the cerebral cortex can produce distant changes in the spinal cord. In a rat model system, the researchers will use chemogenetic and neuron tracing techniques to examine how different cortical stimulation parameters may rewire spinal cord circuits. Their results may ultimately help researchers design new treatments for people with movement impairments following neurological injury.

Split RNA polymerases for sensitive, multidimensional analysis of intercellular PPIs at synapses Dickinson, Bryan (contact) Ozkan, Engin University Of Chicago 2017 Active
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Deciphering the complexities of brain structure and function requires full understanding of intercellular protein-protein interactions (PPIs). Connections between neurons and other cells of the brain are orchestrated by thousands of diverse PPIs, but current methods are insufficient for studying multiple PPIs simultaneously. Dickinson and colleagues will develop new split RNA polymerase (RNAP) biosensors, capable of detecting at least four simultaneous PPIs, with novel super-resolution imaging. Because nucleic acid amplification technologies afford signal amplification and the ability to use multiple different RNAPs, RNAP-based detection could promise substantially improved sensitivity. Co-culture experiments employing primary neurons and engineered reporter cells will validate the approach. This work will initiate a new approach to probing intercellular interactions that guide synapse formation and brain signaling.
Sub-micrometer x-ray tomography for neuroanatomy Jacobsen, Chris Johnson (contact) Kording, Konrad P. Northwestern University 2015 Complete
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Understanding how the human brain works and how it can be healed in case of disease is heavily dependent on progress in anatomy. Jacobsen and Kording, working with researchers at Argonne National Lab, will develop a novel and powerful tool using synchrotron-based x-ray tomography to produce ultra-fine scale anatomical maps of whole mouse brains, with the possibility of scaling up the technology to study human brains. This tool will enable better research on brain anatomy and its relationship to diseases of the brain, such as Alzheimer's, schizophrenia and autism.
Subcellular Mapping and Post-Synaptic Impacts of Striatal Dopamine Release During Behavior Vu, Mai-anh Boston University (charles River Campus) 2019 Active
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Dopamine (DA) inputs in the midbrain influence striatal activity in the basal ganglia, and dysfunction in this system is associated with many neurological and psychiatric illnesses. Dr. Vu aims to measure dopamine release onto the dendrites of single striatal neurons in real-time using 2-photon microscopy, and map functionally-relevant dopamine release onto striatal dendrites during different behaviors in mice. This work will inform our understanding of the spatial organization of dopamine inputs onto single neurons in the striatum, as well as how these inputs affect post-synaptic cell firing.

SYNPLA: A scaleable method for monitoring circuit-specific learning-induced changes in synaptic strength Malinow, Roberto Zador, Anthony M (contact) Cold Spring Harbor Laboratory 2015 Complete
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Learning and memory are made possible in part by a phenomenon called long-term potentiation (LTP)—the strengthening of a synapse resulting from increased firing between two neurons. To study LTP, Zador and Malinow are developing a technique they call SYNPLA, a specific, high-throughput method for marking the emergence of LTP with single synapse resolution. By attaching a fluorescent tag to a specific subtype of glutamate receptor (GluA1), which gets inserted into recently activated synapses, SYNPLA gives the researchers a way to visualize the onset of certain forms of LTP at many synapses simultaneously.
Taking DISCO Live: Dual pathway Imaging of Striatal Circuit Output in vivo Calakos, Nicole Duke University 2018 Active
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Physicians currently use therapies that satisfactorily target the basal ganglia to treat movement disorders, but more effective treatments elude clinical implementation due to major gaps in our understanding of functional principles for basal ganglia circuits. Calakos and colleagues will apply in vivo electrophysiological recording, optical activity imaging, and optogenetics to study plasticity of basal ganglia circuitry. The team will develop an approach to image striatal projection neuron activity in the basal ganglia in mice during the formation of a habitual behavior. They will then monitor and manipulate the relative timing-to-fire between two classes of striatal projection neurons and test the behavioral consequences. The knowledge and methodology gained from this project could help reveal new mechanisms for striatal plasticity, which may inform future therapeutic targets for movement and neuropsychiatric disorders.
Technology for functional study of cells and circuits in large postmortem brains ex vivo Sestan, Nenad Yale University 2018 Active
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Studying neural circuitry and function is particularly challenging in the human brain due to ethical considerations and the overall inherent experimental intractability of postmortem tissue. Furthermore, many aspects of human neurobiology are not fully recapitulated in small animal models, and research in large mammals is hindered by cost and experimental difficulties. Sestan’s team will optimize and validate a first-in-class neurotechnology, BrainEx, for the restoration of molecular and cellular functions of the postmortem large mammalian brain to allow connectivity and circuit tracing in myriad regions, as well as functional imaging. They aim to achieve this in the porcine model, in which brain size, complexity, and physiology are highly similar to human brains. These studies could establish the groundwork for the potential translation of this technology for conducting studies in the postmortem human brain.

The Application of Generalized Linear Models to Calcium Imaging Data for Optimal High-Dimensional Receptive Field Estimation and Identification of Latent Network Dynamics Keeley, Stephen L Princeton University 2017 Active
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Dr. Keeley plans to develop and make publically available an efficient and flexible statistical framework to guide analysis of calcium imaging data, extending researchers’ ability to track the activity of hundreds or thousands of neurons at various spatial scales.
The biophysics and potential cell-type selectivity of acoustic neuromodulation Shoham, Shy NEW YORK UNIVERSITY SCHOOL OF MEDICINE 2018 Active
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The NIH BRAIN Initiative aims to facilitate development of new approaches for precisely measuring and modulating brain circuit function. The high tissue penetrability of ultrasound waves presents untapped opportunities for accessing neural circuits throughout the mammalian brain and offers the possibility of transforming our ability to map brain circuit activity, test new models of brain function, and ultimately, to diagnose and treat brain diseases and disorders. This project, led by Drs. Shoham, Froemke, and Kimmel, aims to elucidate the fundamental mechanisms of ultrasound stimulation, via mathematical analyses, computational modeling, and experimental validation in a mouse model. A thorough characterization of how ultrasound affects neural cells and circuits is an essential step forward in basic neuroscience research, and may enable further development of ultrasound as a tool for both neuroscientists and clinicians.

 

The Brainstorm Project: A Collaborative Approach to Facilitating the Neuroethics of Bioengineered Brain Modeling Research Hyun, Insoo Case Western Reserve University 2018 Active
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Organoids, grown in laboratory settings to resemble parts of the developing human brain, hold great potential for shedding light on human brain function and disease. Researchers are working to achieve key bioengineering advancements, including successful vascularization of brain organoids, generating the full complement of cell types present in a human brain, and recording and modulating neural activity in organoids. These anticipated advances in bioengineered human brain modeling research may raise ethical questions about the moral status of large, complex human brain organoids and ethical boundaries on manipulating increasingly realistic engineered brain models. In this project, Dr. Hyun will lead proactive ethical discussions among ethicists and the neuroscientists conducting this cutting-edge work to develop greater awareness and understanding of these ethical implications and to inform future management of ethical issues that may be unique to this novel area of brain research.

The glial mechanism for electrical brain stimulation Wang, Hai-long Worrell, Gregory A (contact) Wu, Long-jun Mayo Clinic Rochester 2019 Active
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Recently, researchers in the Wang, Worrell, and Wu labs showed that electrical stimulation may cause non-neuronal cells, astrocytes, to release or secrete chemical-filled vesicles. In this project, the researchers aim to understand whether this astrocyte signaling may play a role in how the brain reacts to electrical stimulation. They will use cultured astrocytes to examine the molecular mechanism behind astrocytic vesicular release and the effect it has on neighboring brain cells. The results may provide fundamental and novel insights into the role astrocytes play in healthy and diseased brain signaling.

The Neural Mechanism of Interval Timing in Drosophila Smart, Ashley Danielle Stanford University 2019 Active
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Many organisms are capable of interval timing, as it is essential to many tasks important for survival. However, no research has determined a neural mechanism for this process.  Dr. Smart will study the neural mechanisms of interval timing in a coordinated network throughout the brain, and how these estimates of time affect behavior. The work will leverage behavioral assays, whole-brain neural activity imaging, and genetic techniques in the Drosophila brain. These findings will improve our understanding of how the brain keeps time.

The Neuroimaging Data Model: FAIR descriptors of Brain Initiative Imaging Experiments Keator, David Bryant University Of California-irvine 2019 Active
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Inconsistent terminologies of neuroimaging metadata prevent the precise description of the design and intent of an experiment, experimental subject characteristics, and the data acquired. Dr. Keator and colleagues aim to address this problem by developing human neuroimaging domain-specific controlled vocabularies. This will greatly improve our ability to search across datasets; to reuse, compare and integrate data across studies and sites; and to replicate neuroscience findings. They also aim to promote the adoption of the controlled vocabularies through community engagement.

The role of patterned activity in neuronal codes for behavior Maunsell, John Hr University Of Chicago 2014 Complete
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Dr. Maunsell's team will explore how large populations of neurons process visual information, using a newly developed light stimulation technique to induce brain cell activity in the visual cortex of mice.
Tools to broaden access to high-throughput functional connectomics Lee, Wei-chung Allen (contact) Seung, Hyunjune Sebastian Tuthill, John Comber Harvard Medical School 2019 Active
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Mapping the connectivity of sensorimotor neural networks is crucial for understanding how the nervous system controls behavior. However, due to technical barriers it is difficult to overlay high resolution connectivity maps of locomotor circuit with physiological and behavioral data. Here, the labs of Drs. Lee, Seung, and Tuthill plan to develop a pipeline to analyze the neural microcircuits that control walking, using the Drosophila ventral nerve cord (VNC) as a model system. By integrating in vivo two-photon calcium imaging in walking flies, high-throughput transmission electron microscopy, deep-learning connectomic reconstruction, and cell morphology-based analytics, they hope to generate the first dense functional connectomes of the VNC. The publicly available datasets and new tools for high-throughput functional connectomics could have applications to other brain regions and species.

Toward a human adult brain cell atlas with single-cell technologies Chun, Jerold Zhang, Kun (contact) University Of California, San Diego 2018 Active
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Defining a complete cell atlas of the human brain, including a full molecular catalog of all its cell types and their spatial distribution, is a critical step toward understanding the human cognitive machine. Zhang’s team will expand on their previous efforts toward building a complete cell atlas of the whole human adult brain. They will systematically apply novel technologies for scalable, single-nucleus transcriptome sequencing, single-cell DNA accessibility assay, and in situ RNA imaging to MRI-scanned human brains, incorporating innovative computational approaches. If successful, the derived data will facilitate the study of molecular mechanisms underlying brain function and disorders, empowering the scientific community with a massive, readily accessible database of unprecedented scope.

Towards a Complete Description of the Circuitry Underlying Memory replay. Soltesz, Ivan University Of California-irvine 2014 Complete
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Dr. Soltesz's team will combine computer brain modeling and large-scale recordings of hundreds of neurons to understand how the brain generates sharp-wave-ripples, a neuronal activity pattern essential for learning and memory.
Towards integrated 3D reconstruction of whole human brains at subcellular resolution Chung, Kwanghun Massachusetts Institute Of Technology 2018 Active
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Dr. Chung’s team aims to build a three-dimensional proteomic atlas of cells and neural circuits of human brains. To do this, his team plans to develop indestructible and transparent hydrogel-tissue hybrids for multi-rounds of protein labeling and imaging at subcellular resolution. They will stain the tissue via a variety of cellular and molecular labeling techniques and then use automated imaging to visualize different brain cell types, nerve fibers and synapses. The team will also create a supercomputing cloud- based framework and algorithms to analyze petabytes of high-resolution image data. This three- dimensional human brain atlas could give researchers a rapid, low cost way to discover brain cell types and the circuit problems behind neurological and neuropsychiatric disorders.

Towards quantitative cell type-based mapping of the whole mouse brain Osten, Pavel Cold Spring Harbor Laboratory 2014 Complete
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The Osten team will develop an automated system to image different types of brain cells and their connections in mice, to pinpoint differences between males and females, across the lifespan.
Tracing Brain Circuits by Transneuronal Control of Transcription Hong, Elizabeth Jennifer Lois, Carlos (contact) Zinn, Kai G California Institute Of Technology 2015 Complete
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Faulty wiring of brain circuits during development could underlie the progression of many neurological diseases, such as schizophrenia and autism. Lois and colleagues propose the development and validation of a new genetically encoded system to trace brain circuits by trans-synaptic control of gene transcription. In this system, neurons expressing an artificial molecule ("emitter" neurons) activate an engineered receptor on their synaptic partners ("receiver" neurons), triggering the expression of fluorescent proteins in both partners. High-resolution imaging of the fluorescent labels will allow researchers to track the synaptic partners and other neurons in the circuit.
TRACT: A TOOL TO INVESTIGATE BRAIN CONNECTIVITY AND TO GENETICALLY MANIPULATE NEURONS CONNECTED BY SYNAPSES Hong, Elizabeth Jennifer Lois, Carlos (contact) California Institute Of Technology 2018 Active
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For this project, BRAIN Initiative researchers plan to expand and optimize TRansneuronal Activation of Transcription, or TRACT, a technique for mapping synaptic connections in the brain. The technique employs genetically engineered ligands and receptors to help scientists identify and manipulate synaptic connections between neurons. These tools will be used to map circuits implicated in brain diseases such as autism and schizophrenia
Trans-synaptic bidirectional tracing tools for imaging and omics analysis Shah, Nirao Mahesh Ting, Alice Y (contact) Stanford University 2018 Active
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To understand sex differences in brain wiring patterns, this team plans to develop new tools for mapping synaptic connections. Specifically, the project will use yeast-based directed evolution to genetically engineer proteins that will enable scientists to trace specific connections between neurons. These tools may not only help the team understand how brain circuits control differences between the sexes, but also help other researchers explore synaptic differences between healthy and diseased brain.
Ultra-Multiplexed Nanoscale In Situ Proteomics for Understanding Synapse Types Bathe, Mark Boyden, Edward S. (contact) Yin, Peng Massachusetts Institute Of Technology 2014 Complete
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Dr. Boyden's team will simultaneously image both the identities and locations of multiple proteins within individual synapses – made possible by a new technique called DNA-PAINT.
Unbiased Epigenomic and Transcriptomic Profiling of Non-Neuronal Cells in the Mouse Brain Allen, Nicola Jane (contact) Ecker, Joseph R Salk Institute For Biological Studies 2019 Active
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The ability to target specific glial cell populations within particular cortical and sub-cortical circuits during discrete developmental timepoints is stalled by the current lack of cell-type specific genetic markers. Dr. Allen and her team will use single-nucleus methylCytosine and Transcriptome sequencing (snmCT-seq) in the visual system of mice to profile the genetics of myriad glial cells. snmCT-seq should support identification of cell-type, region-type, and developmental stage-specific regulatory elements to improve access to glial cells. Additionally, viral tools will be developed to target and manipulate subsets of glial cells in a circuit-specific manner to further our understanding of the unique identities and roles of glial cells in neuronal circuits.

Understanding Brain Development Through the Lens of Metabolism Bhaduri, Aparna University Of California, San Francisco 2019 Active
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Recent advances in sequencing technology are revealing diverse cell types across the human and mouse brains, with some transient progenitor cell types found to exist only during development. In addition to this diversity of cell types, early evidence points to diversity in lipid expression and function throughout the brain. Dr. Bhaduri aims to characterize the developing human cortex across multiple regions, linking differences in transcriptomic and lipidomic data in order to understand how metabolism and transcriptional regulation interact to determine cell fate decisions in cortical progenitors. The work will offer insight into how the human brain develops.

Understanding how post-translational palmitoylation influences in vivo molecular and circuit dynamics during learning Nelson, Jessica C University Of Pennsylvania 2019 Active
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Habituation is a form of learning by which organisms become less responsive to repetitive stimuli. While often impaired in disorders with complex cognitive symptoms, and thus has relevance to human disease, there are significant gaps in the understanding of habituation learning. To address this challenge, Dr. Nelson will study the critical role of protein modifications in habituation learning, using larval zebrafish as a model system. The project will involve training in protein modification and in vivo electrophysiology, integrating these approaches into a well-rounded system to examine learning across genes, circuits, and behavior. Success of the project may reveal how post-translational protein modifications influence synaptic plasticity within defined neural circuits as we learn.

Unveiling the mechanisms of ultrasound neuromodulation via spatially confined stimulation and temporally resolved recording Cheng, Ji-Xin BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) 2018 Active
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The possibility of harnessing ultrasound to modulate nerve function has interested scientists for many years. Though recent work has demonstrated the feasibility of using ultrasound to stimulate the central and peripheral nervous systems, it remains unclear whether ultrasound directly affects neuronal excitability or acts indirectly on the connections between neurons at the synaptic or circuit level. In this project, Drs. Cheng, Han and colleagues will explore these questions, using cutting-edge approaches to achieve high spatial resolution of stimulation, and high temporal resolution of recording the resultant neuronal effects. This work will inform future design of ultrasound neuro-stimulators for basic neuroscience research and possible novel therapies for neurological disorders.

Validated tools for identifying, characterizing, and targeting all non-neuronal cells in the brain and determining the neuro-glio-vascular connectome Gu, Chenghua Harvard Medical School 2019 Active
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Neuro-glio-vascular interactions are vital to nervous system activity, yet an inventory of vascular cells within defined brain regions and circuits does not exist due to the relatively low numbers of vascular cells compared to neurons and glia. Dr. Gu’s team aims to apply a refined dissociation protocol to isolate vascular cells from small specialized regions of the mouse brain. Using these new tools, they plan to build a comprehensive inventory of vascular and perivascular cells in specific brain regions, identify differences in cellular interactions, and create cell-type and region-specific markers to genetically target these cells for further study. The researchers hope to generate a neuro-glio-vascular connectome database to help researchers better understand the contribution of heterogenous non-neuronal cell types in brain structure and function.

Ventromedial prefrontal cortex regulation of fear memory expression Cummings, Kirstie Alyssa Icahn School Of Medicine At Mount Sinai 2019 Active
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Traumatic events can result in anxiety disorders, including post-traumatic stress disorder (PTSD), a hallmark of which is amplified expression of fear and resistance to behavioral therapies. While the ventromedial prefrontal cortex (vmPFC) is thought to have a fear-inhibiting role, activity in its subregions is also elevated in many PTSD patients. To understand this functional dichotomy, Dr. Cummings will investigate the mechanisms by which vmPFC subregions encode learned fear by using a range of approaches, including calcium imaging, circuit tracing, in vivo optogenetic manipulation, and ex vivo electrophysiology in mice. Success of the project should result in characterization of the role of vmPFC in the regulation of fear memory, which may inform existing models of fear circuitry and help elucidate the mechanisms that are recruited in fear learning.

Vertically integrated approach to visual neuroscience: microcircuits to behavior Euler, Thomas Huberman, Andrew D Meister, Markus Seung, Hyunjune Sebastian (contact) Wong, Rachel O Princeton University 2014 Complete
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Dr. Seung and colleagues Thomas Euler (U Tübingen), Andrew Huberman (UC San Diego), Markus Meister (Caltech), and Rachel Wong (UW Seattle) will use state-of-the-art genetic, electrophysiological, and imaging tools to map the connectivity of the retina, the light-sensing tissue in the eye. The goal is to delineate all the retina's neural circuits and define their specific roles in visual perception and behavior.