Funded Awards

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Title Investigator Institute Fiscal Year FOA Number Status Project Number Priority Area Summary
3D neonatal Photoacoustic Tomography (3D-nPAT) to detect Hypoxic-Ischemic brain injury in preterm neonates Nasiriavanaki, Mohammadreza Wayne State University 2019 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

Hypoxic-ischemic brain injury (HII) is a severe condition caused by a lack of oxygen to the brain at or near the time of birth in preterm and low birth weight newborns. Unfortunately, there is a lack of high quality, non-invasive imaging technologies that allow for bed-side imaging of brain hypoxia and monitoring of early brain development in newborn children. Dr. Nasiriavanaki and colleagues will develop a novel, portable, point-of-care 3D neonatal photoacoustic tomography (3D-nPAT) system to detect hypoxic ischemic brain regions in preterm neonates. Unlike current imaging options, this technology will not require sedation, radiation, or radionuclides. 3D-nPAT aims to provide an accurate 3D map of brain tissue oxygen levels within the neonatal cranium, which will improve the diagnostic information of HII.

3D Printed Multifunctional Brain Windows for Simultaneous Optical Imaging and Electrophysiology Kodandaramaiah, Suhasa B (contact) Mcalpine, Michael Applied Universal Dynamics Corporation 2019 Active
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

A mechanistic understanding of the neuronal underpinnings of sensory perception, action, emotion, and cognition requires measuring activities of these neuronal circuits at single cell resolution across several millimeters, and at multiple temporal scales. However, methods providing high spatial resolution often lack concurrent high temporal resolution and vice versa, creating technical challenges. Working with Applied Universal Dynamics Corporation, Dr. Kodandaramaiah and team plan to engineer and commercially disseminate digitally generated, functionalized cranial prostheses (“brain windows”) that combine wide‐field optical imaging with concurrent electrical recordings of neuronal activities for widefield activity mapping of the whole cortex during behavior. These developments will inform fundamentally new experimental paradigms in mice and enable new insights into the neuronal computations that underlie sensory perception, action and cognitive processes.

4D Transcranial Acoustoelectric Imaging for High Resolution Functional Mapping of Neuronal Currents Witte, Russell S (contact) University Of Arizona 2019 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

Achieving high spatiotemporal resolution with non-invasive electrophysiology measurements continues to be a challenge for human neuroscience. One promising method is transcranial acoustoelectric brain imaging (tABI), which uses an ultrasound beam to safely and briefly alter brain tissue conductivity. The rapid detection of these modulations overcomes limitations in conventional electroencephalography that can result in signal blurring. Here, Dr. Witte and a multidisciplinary team of investigators aim to develop, validate and implement tABI for noninvasive functional mapping of neural currents deep in the human brain through the skull. The success of this approach would demonstrate a safe and revolutionary modality for mapping brain electrical activities, enabling future work to transform our understanding of brain function.

A Fully Ultrasonic Approach for Combined Functional Imaging and Neuromodulation in Behaving Animals Caskey, Charles F Oralkan, Omer Pinton, Gianmarco (contact) Univ Of North Carolina Chapel Hill 2019 Active
  • Interventional Tools

Although functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have unique capabilities for imaging the brain, these techniques lack the ability for brain stimulation, lack the temporal resolution compared to ultrasound, and present cost and accessibility challenges. Dr. Pinton and colleagues will create a revolutionary technology that combines ultrafast functional blood flow imaging (i.e., super resolution functional ultrasound imaging) and focused ultrasound neuromodulation in a single integrated platform. Though MR-compatible, this ultrasound system will provide direct real-time blood flow information transcranially in non-human primates, while also having the ability to simultaneously apply neuromodulatory acoustic pulses, without the need for MRI or PET.

A Functional and Selective Toolkit for Choroid Plexus Networks Lehtinen, Maria (contact) Moore, Christopher I Boston Children's Hospital 2019 Active
  • Cell Type
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

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 Massive Library of AAVs to Target Transcriptionally-Defined Primate Cell Types Stauffer, William Richard University Of Pittsburgh At Pittsburgh 2019 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity

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 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
  • Cell Type
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

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
  • Cell Type
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

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 novel optically pumped magnetometer (OPM) system for high resolution magnetocorticography Nugent, Allison C. (contact); Robinson, Stephen E. U.s. National Institute Of Mental Health 2019 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

Magnetoencephalography (MEG) is a non-invasive imaging technology that measures the magnetic field outside the head produced by electrophysiological activity in the brain. Currently available MEG systems, which are based on superconducting quantum interference devices (SQUIDs), often lack spatial resolution because the sensors cannot be placed directly on the scalp. Drs. Nugent, Robinson, and team will develop a new system based on an optically pumped magnetometer (OPM) for non-invasive human brain imaging.  By minimizing the standoff distance, this new magnetocorticography technology will be capable of providing millimeter resolution mapping of cortical brain function in healthy and diseased brains.

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
  • Cell Type
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

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 SAFE AND COMPACT NEONATE TO ADULT NEUROIMAGING MRI SYSTEM Srinivasan, Ravi Advanced Imaging Research, Inc. 2019 Active
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

Magnetic resonance imaging (MRI) is an established diagnostic tool. However, while mapping dynamic anatomical and functional connectivity in the human brain is essential, adult MRI systems are not well-suited for clinical use in infants and children. Working with Advanced Imaging Research Inc., Dr. Ravi Srinivasan and team propose to create a compact MRI system that provides MRI systems to infants, children, and adults in any hospital department. The group will develop, test, and refine a compact MRI system with strong connectome gradients, thus alleviating cost and safety burdens that can be posed by large adult whole-body MRIs. The success of the project could stimulate development of mobile mental health and stroke assessment systems, thereby improving accessibility to MRI systems.

A system for whole-brain recording and control of activated neurons with near-infrared light Shcherbakova, Daria Albert Einstein College Of Medicine, Inc 2019 Active
  • Interventional Tools
  • Monitor Neural Activity

Observing activity across the entire brain should help increase understanding of how it responds to stimuli and leads to behavior. Available technology limits what can be seen by restricting observations to small areas, slowly recording activity, and damaging the brain. Dr. Shcherbakova’s team will develop novel technology that will allow for recording of neuronal activity in the entire mouse brain using noninvasive near-infrared light (NIR). The researchers will develop a NIR optogenetic system of light-inducible protein-protein interaction (PPI), combining a calcium-induced PPI and a NIR-induced PPI to drive gene expression of fluorescent proteins or other optogenetic tools in activated neurons. The system will be optimized in cultured cells and primary neurons, then validated in vivo, targeting the primary motor cortex of mice. This tool will allow researchers to study circuit activity during behavior in freely moving animals, advancing our understanding of how the brain processes information in health and disease.

A unified framework to study history dependence in the nervous system Santamaria, Fidel University Of Texas San Antonio 2019 Active
  • Integrated Approaches
  • Theory & Data Analysis Tools

A central property of the nervous system is history dependence: its ability to change reaction rates based on previous activity. Though the phenomenon is prevalent across scales of neuronal organization, sensory modalities, and species, there is no unified theory for history dependence. For this project, Dr. Fidel Santamaria and team will apply mathematical approaches to history dependence, validate the significance of that approach, and establish collaborations to test the hypothesis across species and scales. Overall, this project aims to provide a unified theoretical framework and in doing so, pave the way toward applications to study, analyze, and design experiments of history-dependent neuronal activity across multiple scales, from synaptic plasticity to complex spiking patterns in neural networks.

A wearable functional-brain-imaging system with full-head coverage and enhanced spatiotemporal-resolution to study complex neural circuits in human subjects Schwindt, Peter D. D. Sandia Corp-sandia National Laboratories 2019 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

Comprehensively studying the brain requires non-invasive neuroimaging methods at high spatiotemporal resolution that can capture the functions in naturalistic behaviors. Magnetoencephalography (MEG) is a promising approach, but its operation uses rigid helmet hardware that compromises signal and spatial resolution. Dr. Schwindt and a team of investigators plan to address these challenges by improving MEG sensors to develop a wearable, conformable, full-head coverage MEG system. After developing the sensor array, the group aims to enhance spatial resolution of the MEG system while accounting for heterogeneity in head shape, and finally validate the performance of the new system against traditional approaches. By providing a whole-head MEG system for people of all head sizes, this advance will enable the study of brain dynamics in increasingly naturalistic environments with cortical spatial resolution rivaling functional MRI.

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
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity

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 optogenetic brain implant with EEG monitoring and response for mice Hashemi, Kevan Open Source Instruments, Inc. 2019 Active
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

Epileptic seizures can be halted or reduced by optogenetic activation of selected inhibitory neurons. By monitoring electroencephalography (EEG) data in real time, seizures can be identified at their onset and correcting pulses of optogenetic stimulation may be applied. Working with Open Source Instruments Inc., Dr. Kevan Hashemi and team propose the development of a fully implantable, wireless EEG monitor that can detect EEG events in real-time and apply correcting pulses of closed-loop optogenetic stimulation. The group will develop the necessary hardware, adapt an algorithm to classify EEG events, and test the device's ability to detect seizures in mice. The success of the project could inform creation of a medical instrument that aborts focal seizures in humans who suffer from epilepsy.

Automating whole brain connectomics: development, validation, and application of an open toolkit Bock, Davi University Of Vermont & St Agric College 2019 Active
  • Cell Type

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
  • Cell Type

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.

Breaking the Barriers to Microscale fMRI Vu, An Northern California Institute 2019 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

The need for improved non-invasive imaging is paramount in order to reveal the underpinnings of both the diseased and healthy human brain. Dr. Vu and colleagues will develop a Stimulus-Locked K-Space (SLIK) approach to achieve meso-resolution imaging for whole human brain fMRI. They will incorporate and evaluate commercially available motion mitigation and navigator-based dynamic B0 correction techniques. This novel technology will build upon existing commercialized 7 Tesla scanners, and therefore, following its development, could be readily disseminated to the neuroscience community.

Cell-Specific Visualization of Endogenous Proteins Mao, Tianyi Zhong, Haining (contact) Oregon Health & Science University 2019 Active
  • Cell Type
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

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.

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
  • Cell Type
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

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.

Close-loop, spatially addressable multiphoton functional imaging Xu, Chris Cornell University 2019 Active
  • Interventional Tools
  • Monitor Neural Activity

The Xu lab aims to help researchers use multiphoton microscopy for watching electrical neural circuit activity in real time. In this project, they plan to develop an adaptive excitation source that will make multiphoton microscopy much faster at imaging activity. They will work with researchers at Cornell and Stanford Universities and at the HHMI Janelia Research Campus to test out and fine tune this new system. The system may help researchers explore how circuits control the brain under healthy and disease conditions.

Customizable, Ultra-high Density Optic Fiber-paired Multielectrode Array by 3D Nanoparticle Printing Panat, Rahul Carnegie-mellon University 2019 Active
  • Interventional Tools

Recording individual neuronal activity across multiple scales at high resolution and low cost is a challenge for neuroscientists. Dr. Panat and colleagues will develop highly-customizable 3D Printed MicroElectrode Arrays (3DP-MEA) for affordable, on-demand, and study-specific fabrication of neural probes. This new method of nanoparticle printing technology for 3D multi-channel, multi-functional electrode arrays should allow neuroscientists to design precise array parameters to manipulate and record the dynamics of large, multi-area neurological circuits at high resolution in in vivo experiments.

Designing and deploying an expanded color palette of voltage indicators engineered for multiphoton microscopy St-pierre, Francois (contact) Tolias, Andreas Baylor College Of Medicine 2019 Active
  • Interventional Tools
  • Monitor Neural Activity

Genetically encoded voltage indicators (GEVIs) are fluorescent proteins designed to help researchers watch electrical activity in neurons. Changes in voltage change the brightness that GEVIs shine. The St. Pierre and Tolias labs plan to develop an array of GEVIs that can measure different types of electrical activity using multi-photon microscopy. To do this, they will make a microscope designed to rapidly search for new GEVIs; create GEVI’s that can detect electrical spikes or synaptic communication between neurons; and tailor the fluorescent colors of GEVI for multi-photon microscopy. Results from this project may help researchers watch brain circuits spark and fire in real time.

Develop a multi-modal cross-scale fMRI platform with laminar-specific cellular recordings through multi-channel tapered photonic crystal fiber array Yu, Xin Massachusetts General Hospital 2019 Active
  • Interventional Tools

Large-scale, whole-brain functional magnetic resonance imaging (fMRI) signal fluctuation, including low-frequency signal fluctuation (LFF), has been linked to specific brain states, such as sleep and arousal. However, linking signals across scales (from cellular and molecular to circuit and systems levels) to behavioral outputs is a challenge. Dr. Yu and colleagues will develop an advanced multi-modal fMRI platform to study cortical, laminar-specific LFF in awake rodent models. The team will combine advanced fMRI methods for intracellular calcium and extracellular glutamate recordings, with an ultimate goal to acquire multi-site, cross-scale brain dynamic signals in both normal and diseased conditions of awake animals.

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
  • Cell Type
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

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
  • Cell Type

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.

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
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity

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 new photo-releasable neuropeptide nano-vesicles for studying modulation in the brain Qin, Zhenpeng (contact) Slesinger, Paul A University Of Texas Dallas 2019 Active
  • Interventional Tools

Neuropeptides are widely-expressed, important neuromodulators in the brain; however, due to current limitations in neurotechnology, little is known about their actions on neural circuits. Drs. Qin, Slesinger, and colleagues will develop a novel, potentially transformative technology using nanotechnology-based photo-release of neuropeptides combined with cell-based neurotransmitter fluorescent engineered reporters to release neuropeptides at localized targets in real-time in awake animals. This project could allow, for the first time, all-optical, spatiotemporal mapping and modulation of neural circuits modulated by neuropeptides.

Dissecting distributed representations by advanced population activity analysis methods and modeling Druckmann, Shaul Stanford University 2019 Active
  • Integrated Approaches
  • Theory & Data Analysis Tools

Sensory information passes through multiple brain areas to ultimately lead to behavior, but there is no clear understanding of how these multiple brain areas interact. Dr. Shaul Druckmann and team will develop analytical techniques that will facilitate interpreting the interactions among brain areas by recording brain activity and studying strategic perturbations of the data patterns. Working with experimental collaborators, they will use three high-quality datasets to design analytical approaches to interpret this data. They will first develop statistical metrics, then validate dimensionality reduction approaches that capture complex data in more interpretable forms. Finally, they will adapt modeling approaches to create mechanistic models of how circuit structure supports the activity dynamics of sensory information. These approaches and tools will have the potential to reveal how brain areas interface with each other and how these interactions shape behavior.

Efficient resource allocation and information retention in working memory circuits Ching, Shinung (contact) Snyder, Lawrence H Washington University 2019 Active
  • Integrated Approaches
  • Theory & Data Analysis Tools

Working memory - our ability to temporarily hold information in mind - is important for many aspects of normal human cognition, but there are critical gaps in our knowledge of how the brain remembers and stores multiple items. Through a combination of behavioral tests and computational modeling, Dr. ShiNung Ching and his team will test the validity of their theory that the organization of networks optimizes efficient resource allocation. Key to this project is the integration of experimental and computation methods to tightly link observed behavioral phenomena, theory, and underlying neural mechanisms. Because dysfunction of working memory occurs in numerous neuropsychiatric illnesses, the success of this project could inform improvements in diagnosing and treating these disorders.

Expanding field-of-view with reduced tissue displacement in micro-endoscopic computational imaging Blair, Steven M (contact) Menon, Rajesh Shepherd, Jason D University Of Utah 2019 Active
  • Interventional Tools
  • Monitor Neural Activity

To improve understanding of the brain, it will be critical to image far beneath the surface. However, it is difficult to achieve high-resolution and fast imaging of deeper brain structures due to limitations in current technology. Drs. Blair, Menon, and Shepherd intend to develop new technology that uses an array of narrow probes, optrodes, to minimize tissue damage when looking at deeper structures in mouse brain, including a unique plan for computational imaging to recreate a large imaging field. This system, sized for small micro-endoscope arrays, may provide a new and more detailed look at deep brain structures, which are currently not easily accessible.

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
  • Cell Type
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity
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
  • Cell Type
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

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.

Genetically targeted high sensitivity voltage sensitive dyes Loew, Leslie M University Of Connecticut Sch Of Med/dnt 2019 Active
  • Interventional Tools
  • Monitor Neural Activity

Brain cells primarily communicate through electrical signals and the ability to measure these ‘conversations’ in real time could help advance our understanding of how the brain works. However, currently available tools for looking at electrical activity are not sensitive or sufficiently specific. Dr. Loew’s group will develop a novel type of hybrid voltage sensor that binds a fluorescent protein to the cell’s surface and is connected to a quenching molecule that moves across the membrane, producing a large florescence signal during electrical activity. The new sensors should be bright, sensitive, and allow researchers to look at specific brain areas or circuits.

Head-mounted miniature microscopes for combined calcium imaging and electrophysiological measurement of neural circuit function in deep brain regions of behaving macaques Nassi, Jonathan J Inscopix, Inc. 2019 Active
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

The ability to record the activity patterns of genetically-defined neuronal populations in freely behaving animals is transforming neural circuits research. To advance our understanding of higher-cognitive function, complex behavior and mental health, a critical need remains to translate such capabilities to research using non-human primates. Working with Inscopix Inc., Dr. Jonathan Nassi and team will build on the success of nVista for rodents, Inscopix's flagship product, to develop and commercialize a next-generation platform for integrated calcium imaging and electrophysiology in behaving macaques. The group will prototype and validate a system that enables cellular-resolution, large-scale recordings deep and distributed throughout the macaque brain. Success of the project could produce a commercial-ready, next-generation platform for neural circuit research in behaving macaques.

High-throughput Physiological Micro-connectivity Mapping in Vivo Adesnik, Hillel University Of California Berkeley 2019 Active
  • Cell Type

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 control of neurons with photoswitchable bioluminescent optogenetics. Shaner, Nathan Christopher University Of California, San Diego 2019 Active
  • Interventional Tools
  • Monitor Neural Activity

Optogenetics allows researchers to turn brain cells on and off to study how they work and identify neurons that may play a role in specific behaviors. Dr. Shaner’s group will develop bioluminescent molecules to improve existing optogenetics technology to create more targeted activation and allow maintained stimulation in the absence of an external light source. The researchers will fuse luciferases to reversible photoswitchable or photoactivatable fluorescent proteins, using directed evolution to optimize the constructs for enhanced on-off contrast, switching efficiency, and kinetics. The optimized constructs will then be combined with optogenetic elements to generate probes for targeted chemogenetic control of selected neurons. The tools will be tested ex vivo, in vitro, and in vivo in mouse neocortex. The development of these bioluminescent probes will allow high-precision “reprogrammable” activation of neurons, which may further our understanding of brain function and neurodegenerative disease.

Imaging Brain Function with Biomechanics Patz, Samuel (contact) Sinkus, Ralph Brigham And Women's Hospital 2019 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

Functional magnetic resonance imaging (fMRI) measures the blood-oxygenation-level dependent (BOLD) response to neuronal activity. Although it has become a ubiquitous tool for high spatial resolution mapping of whole-brain function, the quest for breaking the barrier on temporal resolution has never stopped. Drs. Patz, Sinkus, and team will develop a novel technique, functional magnetic resonance elastography (fMRE), that measures brain tissue stiffness change in response to neural activity. This state-of-the-art, ground-breaking non-invasive imaging technology is poised to provide an order of magnitude improvement of temporal resolution over fMRI, which could potentially provide a new window for assessing brain circuits and function.

IMPLANTABLE MICROARRAY PROBE FOR REAL-TIME GLUTAMATE AND GABA DETECTION MOLDOVAN, NICOLAIE ANDREI ALCORIX 2019 Active
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  • Monitor Neural Activity

Neurotransmitter (NT) sensors that are versatile, selective, sensitive and reliable can facilitate investigation of the neurobiological mechanisms of behavior and disease symptoms. However, existing monitoring methods suffer from the inability to measure NT dynamics continuously, in real time. Working with Alcorix, Dr. Moldovan and team will develop a novel implantable probe for real-time detection of excitatory and inhibitory NTs. The group plans to create the next generation of their biosensor microelectrode array probe, capable of higher sensitivity, selectivity, and reliability, with no need for external reagents. The multiplexing and in vivo capabilities of the probe will facilitate a fundamental understanding of NT homeostasis that can inform more effective animal models and therapeutics for brain diseases and disorders.

Implantable Recording and Integrated Stimulation (IRIS) device for cortical experiments Wilder, Andrew Ripple, Llc 2019 Active
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  • Monitor Neural Activity

Understanding the dynamics of neural activity requires new tools to record and manipulate neural signals in real-time. However, current cortical electrophysiological recording and stimulation implant systems puncture the skin, present a constant danger of infection and irritation, and require extensive attention from investigators to clean and maintain. Working with Ripple LLC, Dr. Andrew Wilder and a team of investigators will develop the Grapevine IRIS (Implantable Recording with Integrated Stimulation) system. IRIS will be a fully implantable system capable of both recording and stimulation on a large number of channels, enabling closed-loop experiments while mitigating the need for skin puncture. The success of IRIS will provide a research platform to enable longer, safer, and better chronic animal studies.

In vivo Imaging of Neuroactivity in the Deep Forward Scattering Regime Using Speckle Identification and Demixing (SPID) Microscopy Gigan, Sylvain Vaziri, Alipasha (contact) Rockefeller University 2019 Active
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A key challenge of optical recording of neuronal activity is the heterogeneous nature and scattering properties of brain tissue. After only a few hundred microns of depth within the brain, there are nearly no ballistic photons left, Thus far, all microscopy techniques rely on exploiting the ballistic component of light and extracting it from the scattered component (at the excitation level in two-photon microscopy; or at the collection level in light-field or light sheet microscopy). Drs. Vaziri, Gigan, and colleagues intend to develop a new imaging platform for in vivo deep tissue calcium imaging in the millimeter depth range in the rodent brain. This technology will include hardware and algorithmic computational tools to separate components of the signal to localize neurons and extract their activity.

Lensless, high-speed and multi-region volumetric Ca2+ imaging of up to 1cm2 brain surface across model animals Robinson, Jacob T. Vaziri, Alipasha (contact) Rockefeller University 2019 Active
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Studying the neural circuits of the brain requires imaging tools that are often costly and limited in scope. Drs. Vaziri, Robinson, and colleagues will develop a new type of wearable and lensless computational imaging system, the 4D-FlatScope, to enable large-scale, fast, and volumetric calcium imaging from freely-moving rodents, birds, and non-human primates. This innovative tool should be relatively low cost, easy to disseminate, and provide a field-of-view covering up to 2.7 million neurons – allowing for the study - across species - of multi-scale neuronal network dynamics and circuit interactions, which underly complex behaviors.

Massively Multiplexed Gold Microprobe Arrays for Whole-Mouse-Brain Recording Fang, Hui (contact) Walker, Ross M Northeastern University 2019 Active
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  • Monitor Neural Activity

Simultaneously recording from tens of thousands of neurons involved in a circuit may help increase understanding of brain function, but current technology is invasive and only allows for surface recording. Drs. Fang and Walker’s teams will develop hair-thin, deep penetrating (up to 1mm), gold microprobes in combination with a thin, CMOS electronic router to record from thousands of neurons in rat cortex. This new, multiplexed technology of 1000 electrodes may eventually be scaled up to include 10,000-100,000 microprobes, enabling recording from multiple brain areas.

Mechanisms of Information Routing in Primate Fronto-striatal Circuits Womelsdorf, Thilo Vanderbilt University 2019 Active
  • Integrated Approaches
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The brain can rapidly reconfigure its activity to switch between goals and tasks, but the neural mechanisms underlying this complex process are not well understood. Based on evidence that changes in routing are driven by quick bursts of neural activity, Dr. Thilo Womelsdorf and his team will develop new analysis tools to investigate the mechanisms of routing information in neural circuits during goal-directed behavior. After first detecting the bursts, the group will characterize how they coordinate within one functional network, then address the impact of that coordination on information flow. The development of these analytical tools to study complex cognition within a rigorous framework has the potential to create a seamless pipeline for translation between experimental findings and analytical solutions.

Multi-region 'Network of Networks' Recurrent Neural Network Models of Adaptive and Maladaptive Learning Rajan, Kanaka Icahn School Of Medicine At Mount Sinai 2019 Active
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Transformative new technologies can now capture neural activity from thousands of single neurons at high resolution. However, they produce large-scale datasets whose analysis and interpretation represent a bottleneck for computational models and theories, which must account for brain areas as interacting, intercommunicating neural circuits. For this project, Dr. Kanaka Rajan and her team will develop powerful, scalable, multi-region, neural network models and analysis tools for addressing this bottleneck.  The group will model the computations occurring across multiple brain regions during complex behavior, first using zebrafish as a test case before scaling up and expanding the range of their models. Success of this project will open up new avenues for probing circuit mechanisms within and between brain regions in both health and disease.

Multielectrode Arrays for Neurotransmitter Detection with Fast Scan Cyclic Voltammetry Zestos, Alexandros George Microprobes For Life Science, Inc. 2019 Active
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To monitor brain states under various conditions, multielectrode arrays can sense neurotransmitters across distributed parts of the brain. However, the brain's complexity and heterogeneity - coupled with technological limitations of these arrays - have created challenges for this approach. Working with Microprobes for Life Science, Dr. Alexander Zestos and a team of investigators will develop and commercialize multielectrode arrays for neurotransmitter detection with fast scan cyclic voltammetry. Multielectrode arrays will be either constructed with carbon fibers or carbon-modified metal microelectrodes and coupled with multichannel hardware to measure neurotransmitter changes in multiple brain regions simultaneously. The success of this project will meet a crucial and currently unmet need in the greater neuroscience community by providing multielectrode arrays with neurotransmitter sensing capabilities.

Multimodal Stainless Steel Neural Interfaces for Large-scale Recording and Modulation in Large Animals Chamanzar, Maysamreza Carnegie-mellon University 2019 Active
  • Interventional Tools

Understanding the neural circuits that underlie healthy and diseased brains is a key goal of the BRAIN Initiative. Dr. Chamanzar and colleagues will design a new, stable, high-density neural implant for large-scale simultaneous recording and optical stimulation in macaques. The device will, for the first time, record and manipulate neural activities across different areas of the brain in non-human primates (NHP) with high spatiotemporal resolution. The findings may lead to a better understanding of the NHP brain, which could be more easily translated to humans.

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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  • Monitor Neural Activity

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.

NeuropixelsUltra: Dense arrays for stable, unbiased, and cell type-specific electrical imaging Harris, Timothy D Olsen, Shawn R. Steinmetz, Nicholas (contact) University Of Washington 2019 Active
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  • Monitor Neural Activity

Despite recent advances, electrophysiological techniques to measure the activity of dispersed neuron populations remain unable to detect certain cell types or record stably in the presence of brain motion. Drs. Harris, Olsen, Steinmetz and colleagues aim to develop a high-density electrode array that will increase the number of recording sites by 10-fold, using probes that provide imaging of ‘electro-morphological’ shapes. Based on the Neuropixel infrastructure, they will test the systems’ ability to record electrical currents from a variety of mouse neuron cell types and during motion. The new system will be disseminated for beta testing and may help researchers perform high-resolution studies on the activity of brain circuits in freely-moving animals.

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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  • Monitor Neural Activity

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 methods and theories to interrogate organizational principles from single cell to neuronal networks Dierssen, Mara Ye, Bing (contact) University Of Michigan At Ann Arbor 2019 Active
  • Integrated Approaches
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Understanding how individual neurons contribute to network functions is fundamental to neuroscience, but the link between neuronal structure and network connectivity is unclear. Dr. Bing Ye and his team will develop and validate a user-friendly toolset for discovering the rules that link neuronal morphology to network connectivity, allowing them to make predictions about neural network properties based on the structure of single neurons. This open-source computational tool will incorporate visualization and analysis of neuronal populations derived from imaging data, as well as models for interrogating the organizational principles underlying brain network architecture. The successful development of these novel computational tools will enable researchers to investigate how the shapes of individual cells contribute to the connectivity of the nervous system in both health and disease.

Next generation all-optical toolkits for functional analysis of neuropeptide dynamics in neural circuits Banghart, Matthew Ryan (contact) Sabatini, Bernardo L Tian, Lin University Of California, San Diego 2019 Active
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  • Monitor Neural Activity

Neuropeptides are effective modulators of brain circuit activity, but measuring the timing and impact of these effects is difficult. Researchers in the Banghart, Sabatini, and Tian labs aim to develop a toolkit that will help neuroscientists study neuropeptides in real time. This kit will include photoactivatable agents to deliver neuropeptides to particular mammalian brain circuits and genetically-encoded sensors that will indicate the best timing for detecting neuropeptides. With these tools, neuroscientists may be able to manipulate neuropeptide effects and gain fundamental insights into how they modulate healthy and diseased brain circuits.

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-generation high-resolution diffusion MRI resolving cortical columns and layers in vivo Song, Allen W (contact) Truong, Trong-kha Duke University 2019 Active
  • Human Neuroscience
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  • Monitor Neural Activity

Development of next generation non-invasive imaging techniques could help clinicians identify neuronal markers of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. Drs. Song, Truong, and colleagues will develop ultrahigh resolution (sub-millimeter) diffusion MRI acquisition methodologies to map white and gray matter neuronal cortical tracts, columns, and layers in the human brain. They will create a new 48-channel iPRES (integrated parallel reception, excitation, and shimming) AIRcoil array (a new generation of radiofrequency coils based on GE Healthcare’s AIR TechnologyTM), integrated with 3 Tesla magnetic field strength, to allow for deep brain penetration with high spatial fidelity. This novel technology will be able to detect subtle, microstructural changes in very early stage neurodegenerative diseases, when interventions can be most effective.

Novel fluorescent sensors for imaging neuromodulation Dan, Yang (contact) Ding, Jun Li, Yulong Lin, Dayu University Of California Berkeley 2019 Active
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  • Monitor Neural Activity

Neurolipids, like endocannabinoids, and neuropeptides, such as oxytocin, can alter brain circuit activity and behavior. To study these molecules, researchers in the Dan, Ding, Li, and Lin labs will optimize the ability of fluorescent sensors for detecting neuropeptide and neurolipid activity. The sensors are based on G protein-coupled receptors for a variety of neuropeptides and neurolipids, including endocannabinoids, vasopressin, and oxytocin. The effectiveness of these sensors will be tested on neural circuit activity recorded in both mouse brain slices and   in vivo in the mouse brain. The tools may help neuroscientists explore the roles neuropeptides and neurolipids play in modulating activity in healthy and diseased brain circuits.

Novel tools for spatiotemporal modulation of astrocytes in neuronal circuits Sur, Mriganka Massachusetts Institute Of Technology 2019 Active
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  • Monitor Neural Activity

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.

Optimization and Delivery of Bioactive Coating for High Yield and Stable Neural Recording Cui, Xinyan Tracy University Of Pittsburgh At Pittsburgh 2019 Active
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  • Monitor Neural Activity

The Cui lab has developed a biomimetic coating for multi-electrode arrays. The coating has been shown to reduce chemical degradation caused by the body’s natural defenses in response to implantation, a response that causes problems with long-term electrode implantation in the brain. Working with researchers across the United States, this group will perform preclinical studies in rodents aimed at optimizing protocols for the sterilization, packaging, and delivery of coated electrodes. The results may help further understanding of the brain’s immune response to the coating, and may one day have clinical relevance to the types of electrodes used in the human brain.

Optimization and dissemination of non-linear Acousto-Optic Lens two-photon microscopy for high speed multiscale 3D imaging Cardin, Jessica A Diamond, Jeffrey S Peterka, Darcy S Silver, Robin Angus (contact) University College London 2019 Active
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  • Monitor Neural Activity

Two-photon microscropy is a technique that scientists use to watch neuronal circuit activity deep within brain tissue. However, it can only detect slower signals. Non-linear acousto-optic lens 3D microscopy is a new high-resolution imaging technique developed by Dr. Silver and colleagues that allows scientists to watch faster signals as brain circuits communicate in real time. In this project, the team aims to improve upon the older technology by enabling ultrafast line-scanning, and disseminating this technology to other researchers. The results may help neuroscientists make fundamental discoveries about brain circuit function.

Opto-Crown: Transparent skulls with embedded optics for cortex-wide cellular resolution imaging in freely moving mice Boyden, Edward S. Kodandaramaiah, Suhasa B (contact) Sherwood, John L University Of Minnesota 2019 Active
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Although existing technology allows for the concurrent recording of hundreds to thousands of neurons, simultaneous mapping of neuronal activities from large brain volumes at cellular resolution is lacking. Dr. Kodandaramaiah and colleagues will develop a novel imaging method called “Opto-Crown,” which will consist of miniaturized optical instrumentation that is customized to fit skull shape and embedded for mapping single cell neuronal activities in the cortex of freely-moving mice at a high temporal resolution. This new chronic imaging technology could have wide application for neuroscientists to investigate the activity of large numbers of neurons across millimeters of cortical surface in mice and, potentially, in other animals.

Quantifying causality for neuroscience Kording, Konrad P. University Of Pennsylvania 2019 Active
  • Integrated Approaches
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Understanding causality is central to neuroscience, both in how the action of one neuron affects another, as well as in medical approaches that aim to produce causal effects. For this project, Dr. Konrad Kording and his team will develop a set of computational techniques that will allow neuroscientists to quantify how neurons causally influence one another. To do so, they will utilize approaches popular in econometrics, wherein the observation of variables that approximate random system perturbations will allow for the discovery of causal relations. The interdisciplinary team will apply these techniques to problems in neuroscience through a combination of machine learning and engineering, paving the way for important advances toward understanding and quantifying causality in both basic and clinical applications.

Re-engineering Rabies Virus Wickersham, Ian R Massachusetts Institute Of Technology 2019 Active
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  • Monitor Neural Activity

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.

Self-Image-Guided Flexible Ultrasonic Interrogation Platform for Neural Dust Kiani, Mehdi Pennsylvania State University-univ Park 2019 Active
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  • Monitor Neural Activity

Monitoring activity in real time across large areas of the brain will be critical in improving understanding of brain functions like sensation or thought, but current methods are limited in the spatiotemporal data they provide or cause tissue scarring. Dr. Kiani’s team plans to expand existing neural dust technology, which involves tiny, implantable sensors, by developing a self-image-guided, ultrasonic, flexible platform that will automatically adjust to changing conditions, allowing for wireless data transmission of large-scale brain activity across brain uneven surfaces and depths. This wireless technology may be applied for large-scale electrophysiological recording and stimulation of neural activity, which should enhance our knowledge of complex brain activity.

Time-Gated Diffuse Correlation Spectroscopy for functional imaging of the human brain Franceschini, Maria Angela Massachusetts General Hospital 2019 Active
  • Human Neuroscience
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  • Monitor Neural Activity

Functional near-infrared spectroscopy (fNIRS) is a non-invasive neuroimaging method that allows scientists to study brain activity through hemodynamic changes but encounters technological limitations. To improve upon the capabilities of fNIRS, Dr. Franceschini and a team of investigators will develop functional diffuse correlation spectroscopy, which measures the fluctuations in light scattering that occur as red blood cells move. The team aims to first characterize this technology in mock tissue, before validating it in healthy volunteers against other non-invasive imaging methods. Successful of this technological approach will enable cerebral blood flow measurements that can occur with greater sensitivity, better spatial resolution, deep inside the brain - allowing for an unprecedented tool to characterize human brain function.

Tools for modeling state-dependent sensory encoding by neural populations across spatial and temporal scales David, Stephen V (contact) Mesgarani, Nima Oregon Health & Science University 2019 Active
  • Integrated Approaches
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Humans and other animals adapt their hearing in noisy environments, but the mechanisms underlying this central auditory process are not well understood. Here, Dr. Stephen David and his team will develop computational tools to understand how the neural populations in the healthy brain represent complex natural sounds. The group will build a software library that can model the functional relationship between auditory stimuli and corresponding neural responses, for which there are few existing models that effectively measure comparisons between the two. The system will also support machine learning methods that will be valuable for large-scale signal processing problems. These experiments will provide novel insight into how the brain solves problems that will allow engineering of new devices and treatments for conditions involving auditory dysfunction.

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.

Transparent neural interface for in vivo interrogation of human organoids Devor, Anna University Of California, San Diego 2019 Active
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  • Monitor Neural Activity

Cultured organoids are 3-D, self-assembled, cellular structures that resemble some brain structures in early developmental stages. Transplanting such organoids into the mouse brain provides a more natural physiological environment for maturing cells. Dr. Devor’s team will expand this work by developing transparent graphene electrode microgrids that can be placed on the mouse cortex, to allow for long-term, 2-photon imaging and recording from skin-derived transplanted organoid cells. This should advance understanding of organoid maturation in vivo and may provide insights into developmental brain disorders.

Ultra-flexible ?LED Optoelectrode Platform for Brain Circuit Mapping: a Longitudinal, Minimally Invasive Tool Buzsaki, Gyorgy Seymour, John P Wise, Kensall David Yoon, Euisik (contact) University Of Michigan At Ann Arbor 2019 Active
  • Interventional Tools

One challenge that neuroscientists face is being able to study long-term changes in neural circuits over time – in both healthy and diseased brain states. Dr. Yoon and colleagues will develop and validate large-scale micro-LEDs and recording electrodes on an ultra-flexible polymer substrate. This new opto-electrode platform will address the challenge of tissue damage (which diminishes the yield in the number of neurons, and creates difficulty in controlling the volume of brain tissue that is illuminated, leading to spurious, off-target effects) in longitudinal optogenetic studies by employing a thin, flexible substrate that allows the array to float within tissue for long-term recording. Such opto-electrodes could potentially be used to study the entire central nervous system, including the brain, spinal cord, ganglia, and nerves directly.

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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  • Monitor Neural Activity

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.

Uncovering Population-Level Cellular Relationships to Behavior via Mesoscale Networks Carlson, David E Duke University 2019 Active
  • Integrated Approaches
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In complex neural circuitry, it is not clearly understood how the activity of individual neurons coordinate with larger networks to ultimately give rise to behavior. Here, Dr. David Carlson and his team will study how neurons’ action potentials, long considered to be a fundamental unit of information, relate to whole-brain spatiotemporal voltage patterns and behavior. To uncover this relationship, they will develop novel computational methods capable of creating generalizable maps that relate voltage signals from multiple brain regions based upon machine learning approaches. These network maps then will be used to classify neurons and employ statistical approaches to uncover meaningful relationships across scales of neural activity and behavior with relevance to health and disease.

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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  • Monitor Neural Activity

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.