Funded Awards

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Investigator
Dzirasa, Kafui
Institute
Duke University
Year Funded
2018
FOA Number
Status
Active
Project Number
Priority Area
  • Interventional Tools
  • Monitor Neural Activity
Summary

A barrier to understanding the brain is its geometry. When electrodes are implanted to access deep subcortical structures, brain tissue at the surface is often destroyed in the process. Dzirasa’s team will develop a technology to ‘functionally’ change the geometry of the brain by biologically projecting neural activity onto a flat surface for real-time imaging. In awake-behaving animals, the team will grow (rather than implant) a ‘biological electrode’ into the brain with engineered proteins, then convert the electrical activity into fluorescent light that can be imaged on a flat surface atop the brain. This approach will be scalable to allow recording of 100,000s of neurons simultaneously throughout the entire depth of the brain, revolutionizing neural recordings across model species and humans.

Investigator
Caskey, Charles F Oralkan, Omer Pinton, Gianmarco (contact)
Institute
Univ Of North Carolina Chapel Hill
Year Funded
2019
FOA Number
Status
Active
Project Number
Priority Area
  • Interventional Tools
Summary

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.

Investigator
Lehtinen, Maria (contact) Moore, Christopher I
Institute
Boston Children's Hospital
Year Funded
2019
FOA Number
Status
Active
Project Number
Priority Area
  • Cell Type
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity
Summary

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.

Investigator
Greenberg, Michael E
Institute
Harvard Medical School
Year Funded
2017
FOA Number
Status
Active
Project Number
Priority Area
  • Cell Type
  • Circuit Diagrams
  • Monitor Neural Activity
  • Interventional Tools
Summary
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.
Investigator
Lois, Carlos Prober, David Aaron (contact)
Institute
California Institute Of Technology
Year Funded
2019
FOA Number
Status
Active
Project Number
Priority Area
  • Integrated Approaches
Summary

A goal of the BRAIN Initiative is to help researchers map out complete wiring diagrams of neural circuits. Recently the Prober and Lois group developed an approach called TRACT (Transcellular control of transcription) which allows researchers to map out and genetically manipulate the activity of neural circuits in Drosophila. However, it is difficult to study complex behaviors in these animals. In this project, the Prober and Lois groups plan to tailor the TRACT system for zebrafish, a vertebrates and that is easier for scientists to work with when studying complex behaviors. Their results may help scientists study, in great detail, how neural circuits control behavior under healthy and disease conditions.

Investigator
Contreras-vidal, Jose Luis (contact) Knappe, Svenja
Institute
University Of Houston
Year Funded
2018
FOA Number
Status
Active
Project Number
Priority Area
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
Summary

Non-invasive imaging methods, such as magnetoencephalography (MEG), are powerful in their ability to image brain dynamics without contacting the skull and scalp, but MEG is limited by the requirement of a magnetic shielding environment. In this proof-of-concept project, Drs. Jose Contreras-Vidal, Svenja Knappe, and a team of investigators will develop a wearable, compact, and noninvasive MEG system that can operate without external shielding, while maintaining high performance. The group will then validate the prototype system in a small-scale human study through a closed-loop MEG-based brain-computer interface system. The successful creation of a wearable MEG system will enable behaviorally active human neuroimaging that allows flexible movement in time and space, while providing high-quality sensitivity to neuronal sources.

Investigator
Feller, Marla
Institute
University Of California Berkeley
Year Funded
2016
FOA Number
Status
Complete
Project Number
Priority Area
  • Monitor Neural Activity
  • Interventional Tools
  • Theory & Data Analysis Tools
Summary
Spontaneous neuronal activity plays a role in the wiring of retinal circuits during development. Current imaging techniques are unable to capture such activity accurately. Dr. Feller’s team will assemble a system containing a resonant scanner-based two-photon microscope with the ability to achieve three-dimensional imaging of a single spontaneous firing event in vivo. Her team will utilize this high-speed volumetric two-photon imaging during visual stimulation to study the formation of functional neuronal circuits in the developing mouse retina.
Investigator
Wald, Lawrence L
Institute
Massachusetts General Hospital
Year Funded
2017
FOA Number
Status
Active
Project Number
Priority Area
  • Monitor Neural Activity
  • Interventional Tools
  • Integrated Approaches
  • Human Neuroscience
Summary
A complete understanding of human brain network structure and functional activation requires non-invasive imaging tools that generate high-resolution functional maps with dramatically increased sensitivity. Lawrence Wald and his team believe that achieving the next level of sensitivity of neuroimaging technology will occur through functional magnetic particle imaging (MPI). Unlike functional magnetic resonance imaging (fMRI) which indirectly detects blood oxygenation level, fMPI can directly detect this iron concentration with no intermediate step. Because MPI shares a technological foundation with MRI, the researchers can validate the fMPI method in animals and human simulations before assessing its sensitivity in humans. The development of fMPI could provide brain function information over an order of magnitude more sensitive than fMRI.
Investigator
Stauffer, William Richard
Institute
University Of Pittsburgh At Pittsburgh
Year Funded
2019
FOA Number
Status
Active
Project Number
Priority Area
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity
Summary

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.

Investigator
Arnold, Donald B
Institute
University Of Southern California
Year Funded
2018
FOA Number
Status
Active
Project Number
Priority Area
  • Cell Type
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity
Summary

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.

Investigator
Pesaran, Bijan
Institute
New York University
Year Funded
2017
FOA Number
Status
Active
Project Number
Priority Area
  • Monitor Neural Activity
  • Interventional Tools
Summary
Two-photon optical imaging of large populations of genetically-modified neurons is a powerful tool for studying neuronal circuits. Developed primarily for rodent models, use of this technology in primates is currently very challenging, in part due to the restricted imaging fields of traditional microscopes. Bijan Pesaran and a team of neuroscientists and engineers will develop an automated platform to enable imaging across multiple imaging fields situated over broad areas of the primate neocortex with micrometer precision. The group will leverage a recently developed two-photon random-access mesoscope with a very large field of view for optimal neural recordings. Their goal is to provide a unique perspective into the neural dynamics of the primate brain.
Investigator
Feng, Guoping
Institute
Massachusetts Institute Of Technology
Year Funded
2017
FOA Number
Status
Active
Project Number
Priority Area
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
Summary
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.
Investigator
Lein, Ed
Institute
Allen Institute
Year Funded
2017
FOA Number
Status
Active
Project Number
Priority Area
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
Summary
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.
Investigator
Cai, Dawen (contact) Cui, Meng
Institute
University Of Michigan At Ann Arbor
Year Funded
2019
FOA Number
Status
Active
Project Number
Priority Area
  • Cell Type
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity
Summary

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.

Investigator
Taube, Jeffrey Steven (contact) Van Der Meer, Matthijs
Institute
Dartmouth College
Year Funded
2019
FOA Number
Status
Active
Project Number
Priority Area
  • Integrated Approaches
Summary

How do you find your way around? Navigation relies on a variety of information points such as self-motion and visual landmarks, which help with our sense of direction. Using large-scale recordings, live calcium imaging, and modeling data, Dr. Taube’s group will examine where direction-related information comes from and how the brain puts it all together to determine where an animal is and where it needs to go. This project will improve understanding of how the brain collects information from the eyes, head, and body and combines it with visual landmarks to determine head direction.

Investigator
Brivanlou, Ali H
Institute
Rockefeller University
Year Funded
2019
FOA Number
Status
Active
Project Number
Priority Area
  • Cell Type
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity
Summary

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.

Investigator
Clandinin, Thomas Robert (contact) Shah, Nirao Mahesh
Institute
Stanford University
Year Funded
2015
FOA Number
Status
Complete
Project Number
Priority Area
  • Cell Type
  • Circuit Diagrams
  • Monitor Neural Activity
  • Interventional Tools
Summary
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.
Investigator
Sestan, Nenad
Institute
Yale University
Year Funded
2014
FOA Number
Status
Complete
Project Number
Priority Area
  • Cell Type
Summary
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.
Investigator
Mao, Tianyi Zhong, Haining (contact)
Institute
Oregon Health & Science University
Year Funded
2015
FOA Number
Status
Complete
Project Number
Priority Area
  • Monitor Neural Activity
  • Interventional Tools
Summary
Neuromodulation events, which regulate neuronal excitability and plasticity, have been extensively studied from the standpoint of individual neurons, but their actions and effects in behaving animals are poorly understood because of the absence of a toolset for recording these events in vivo. Zhong and Maowill develop in vivo sensors of cyclic AMP/protein kinase A (cAMP/PKA) signaling, which is an important intracellular target of neuromodulators such as norepinephrine and dopamine. The investigators will optimize cAMP/PKA sensors for 2-photon fluorescent lifetime imaging, which is predicted to be more robust to tissue scattering and differences in probe concentration than traditional methods.
Investigator
Nugent, Allison C. (contact); Robinson, Stephen E.
Institute
U.s. National Institute Of Mental Health
Year Funded
2019
FOA Number
Status
Active
1R01EB028645-01
Priority Area
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
Summary

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.