Funded Awards

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Title Investigator Institute Fiscal Year FOA Number Status Project Number Priority Area Summary
A BRAIN Initiative Resource: The Neuroscience Multi-omic Data Archive White, Owen R University Of Maryland Baltimore 2017 RFA-MH-17-255 Active
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A thorough understanding of the complexities of the brain’s different cell types requires the sharing and integration of myriad genomic information generated from various data sources. Owen White proposes creating a Neuroscience Multi-Omic (NeMO) Archive, a cloud-based data repository for -omic data. White and his team of researchers will establish an archive for multi-omic data and metadata of the BRAIN Initiative. The group will document and archive data processing workflows to ensure standardization, as well as create resources for user engagement and data visualization. The NeMO Archive will provide an accessible community resource for raw -omics data and for other BRAIN Initiative project data, making them available for computation by the general research community.

A Cellular Resolution Census of the Developing Human Brain Huang, Eric J Kriegstein, Arnold (contact) University Of California, San Francisco 2017 RFA-MH-17-210 Active
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Scientists have yet to achieve high-resolution classification of the billions of neurons and non-neuronal cells in the human brain. To attempt this feat, Arnold Kriegstein and Eric Huang will perform high-throughput, droplet-based single-cell RNA and transposase-accessible chromatin sequencing techniques to collect genetic and epigenetic information from individual cells, which will be sampled from multiple regions of post-mortem human brains that are developmentally between early gestation and adolescence. They will further classify living neurons cultured from select brain regions based on their calcium imaging responses to various chemical stimuli. Finally, they plan to use multiplexed single-molecule fluorescent in situ hybridization (smFISH) to identify the spatial distribution of these various cell types in the brain. After these data are compiled, we will have the most detailed picture to date of genetically and functionally defined cell types in the human brain throughout development.
A Community Resource for Single Cell Data in the Brain Gee, James C Hawrylycz, Michael (contact) Martone, Maryann E Ng, Lydia Lup-ming Philippakis, Anthony Allen Institute 2017 RFA-MH-17-215 Active
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One major technical challenge for the BRAIN Initiative is the storage and dissemination of large amounts of data collected by different project teams. Hawrylycz and colleagues will support the cell census efforts of the BRAIN Initiative by hosting the BRAIN Cell Data Center (BCDC). Through the BCDC, they will store single-cell data on genetics, histology, electrophysiology, morphology, anatomical location, and synaptic connections from multiple species in a standardized manner. They will also develop and provide training for web-based tools to ease data visualization and analysis efforts. This will facilitate the integration of multiple data streams to better identify and characterize the different cell types in the brain.
A Comprehensive Center for Mouse Brain Cell Atlas Huang, Z Josh Cold Spring Harbor Laboratory 2017 RFA-MH-17-225 Complete
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Identifying individual cell types in the brain is a monumental task that is complicated by the limitations of current molecular technologies. To measure genetic diversity in the whole mouse brain, Huang and Arlotta will lead a team using next-generation droplet-based single-cell transcriptome sequencing along with other highly sensitive single-cell techniques that allow for high-throughput data collection. They plan to map these data onto the spatial locations of forebrain neurons with the help of high-resolution microscopy and genetically driven cell markers. These efforts will provide the scientific community with unprecedented detail about neurons’ molecular and spatial characteristics that can be used to develop additional tools for cell-specific manipulations.

A comprehensive whole-brain atlas of cell types in the mouse Zeng, Hongkui Allen Institute 2017 RFA-MH-17-225 Complete
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The large number of cells in the brain and the complexity of their molecular and functional characteristics make it difficult to define individual cell types. Zeng and colleagues plan to complement high throughput droplet-based transcriptome survey with deep sequencing technique and multiplexed error-robust fluorescence in situ hybridization (MERFISH) to comprehensively characterize gene expression information from anatomically mapped cells across the entire mouse brain. Additionally, they will use patch clamp method to measure neuronal function in specific brain regions, and combine electrophysiological with transcriptomic and morphological information to provide integrative profiles of individual cell types. These efforts will refine how we define cell types and will produce a census of individual cells in the mouse brain that can then be targeted for further study.

A Confocal Fluorescence Microscopy Brain Data Archive Bruchez, Marcel P Ropelewski, Alexander J (contact) Watkins, Simon C Carnegie-mellon University 2017 RFA-MH-17-255 Active
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Advances in microscopy and imaging have created new possibilities in many fields of research, but these advances have also generated large amounts of data that can overwhelm traditional data management systems. Along with collaborators at Carnegie Mellon University and the University of Pittsburgh, Alexander Ropelewski plans to establish a BRAIN Imaging Archive that takes advantages of infrastructure and personnel resources at the Pittsburgh Supercomputing Center. The Archive will include a pipeline for data submission, user access and support, and BRAIN Initiative community engagement through an online presence, workshops, and hackathons. This unique resource will provide an accessible and cost-effective way for the research community to analyze, share, and interact with large image datasets of the BRAIN Initiative.

A Facility to Generate Connectomics Information Lichtman, Jeff HARVARD UNIVERSITY 2018 RFA-NS-18-005 Active
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Connectomics describes a field of study that builds maps of the connections within the brain. Dr. Lichtman and colleagues have developed a facility for generating high-resolution, large-volume serial section electron microscopy data that can be used to generate connectomic maps. In this project, access to the facility, techniques, and analytical software will be provided to the broader neuroscience community. This will allow other research groups who may be inexperienced in these techniques to generate data in projects aimed at mapping brain circuitry, a high priority goal in the BRAIN 2025 report. By providing this resource, Dr. Lichtman and colleagues will help researchers classify the cell types within healthy and diseased brains or model systems, which will improve our understanding of brain function and neurological disorders.

A Fast, Accurate and Cloud-based Data Processing Pipeline for High-Density, High-Site-Count Electrophysiology Kimmel, Bruce VIDRIO TECHNOLOGIES, LLC 2018 RFA-MH-17-257 Active
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The community’s need for an integrated open-source analysis platform is rapidly growing due to the increasing capacity of extracellular electrodes and the limited number of new and validated spike- sorting methods. JRCLUST, a free, open-source, standalone spike sorting software, offers a scalable, automated and well-validated spike sorting workflow for analysis of data generated by large multielectrode arrays. The software can tolerate experimental recording conditions from behaving animals, and it can handle a wide range of datasets using a set of pre-optimized parameters making it practical for wide use in the community. JRCLUST has been adopted in 20+ labs worldwide since its inception less than a year ago. Drs. Kimmel and Nathan seek to expand and maintain JRCLUST, thus empowering researchers to elucidate how functionally defined subpopulations of neurons mediate specific information-processing functions at key moments during behavior.

A General Approach for the Development of New Cell-Type-Specific Viral Vectors Greenberg, Michael E Harvard Medical School 2017 RFA-MH-17-220 Active
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The limited ability to genetically access specific neural cell types, based on distinctive gene expression patterns, impedes brain function probing and therapy development. Greenberg and colleagues will generate recombinant viral reagents that target specific cortical cell types, using recent advances in genetics and a novel application of single-cell transcriptome analysis. They propose to identify genetic drivers specific for excitatory and inhibitory mouse cortical neuronal subtypes. If successful, this may establish a general method for identifying cell-type-specific genetic elements that can be used in viral vectors to drive gene expression, could be applied to other brain regions and mammalian species, and may assist cell-type-specific applications like neuronal activity monitoring, optogenetic and chemogenetic manipulation, axonal tracing, gene delivery, and genome editing.
A method for anterograde trans-synaptic tracing Arnold, Donald B University Of Southern California 2018 RFA-MH-17-220 Active
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To understand how the activation of individual neurons in the brain leads to particular behaviors, it is necessary to identify synaptic connections to downstream neurons. Although considerable information about neuronal circuits has been generated using rabies virus to trace trans-synaptic connections in the retrograde direction, there is no comparable technique for trans-synaptic tracing in the anterograde direction. In rodent brains, Arnold and colleagues will optimize a non-toxic method for anterograde monosynaptic tracing from single neurons to virtually any postsynaptic receptor. Their method labels only active synapses, ensuring the technique’s physiological relevance.

A Molecular and Cellular Atlas of the Marmoset Brain Feng, Guoping Massachusetts Institute Of Technology 2017 RFA-MH-17-210 Active
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Although rodents are a highly accessible model and relatively simple to use for genetic studies, it is unclear whether the cell types found in rodent brains match those of primates. To help fill the evolutionary gap in knowledge between rodents and humans, Feng will lead a team to classify cells across the marmoset brain. They will use high-throughput single-cell RNA sequencing to identify cell types in the prefrontal cortex, striatum, and thalamus and will then spatially map the cell types they find in the brain using multiplexed error-robust in situ hybridization (MERFISH). By combining MERFISH with viral expression of marker proteins in subsets of neurons, the team will also correlate cell morphology with genetic information. Altogether these efforts will produce a census of cell types in the marmoset brain, which will be valuable information for future work into the genetics and circuits of the primate brain.
A multimodal atlas of human brain cell types Lein, Ed Allen Institute 2017 RFA-MH-17-210 Active
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Because of technical limitations, most studies identifying individual cell types in the brain have focused on animal models rather than on human tissue, despite a lack of knowledge about how cell types differ between species. Ed Lein and colleagues will perform broad, high-throughput single-cell RNA sequencing techniques across the whole human brain and spinal cord, along with deep sequencing of single cells in select regions of adult post-mortem brain. They will then determine the spatial distribution of various cell types identified through these sequencing experiments by using multiplexed single-molecule fluorescent in situ hybridization (smFISH). To integrate information about neuronal function into their classifications, the team will make combined electrophysiology, morphology, and transcriptome measurements from single cells in adult human cortex obtained via live surgical resection. These efforts will lead to a much deeper understanding about the differences between cell types in the adult human brain and will facilitate future collaborations between researchers to compare cell types across species.
A new strategy for cell-type specific gene disruption in flies and mice Clandinin, Thomas Robert (contact) Shah, Nirao Mahesh Stanford University 2015 RFA-MH-15-225 Complete
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The ability to inactivate targeted genes only in relevant cell types is critical for understanding how specific genes contribute to circuit function and dysfunction. Clandinin's team will generate novel tools to inactivate genes in specific cell-types, and will validate these tools with imaging experiments and behavioral tests in live fruit flies. They will then adapt the tools for use in mice to directly manipulate genes controlling neuronal excitation and inhibition.
A platform for high-throughput production of targeting systems for cell-type-specific transgene expression in wild-type animals Wickersham, Ian R Massachusetts Institute Of Technology 2016 RFA-MH-16-775 Active
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In vivo genetic modification within a specific cell type generally requires production of transgenic or knockout animal models, a time- and resource-consuming process. Wickersham and colleagues will use high-throughput techniques to develop a novel set of viral vectors to allow selective transgene expression in targeted neuronal subpopulations in wild-type mammals. These tools will expand the possibility of optogenetic control, recording, and genomic modification of neural circuits to uncover their organization in healthy and dysfunctional brains, with potential therapeutic use in humans for mental and neurological disorders.
Achieving ethical integration in the development of novel neurotechnologies Chiong, Winston University Of California, San Francisco 2017 RFA-MH-17-260 Active
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Novel neurotechnologies hold promise for treating neuropsychiatric disorders, but also raise profound neuroethics issues including self-ownership of our thoughts, emotions, and actions. Engaging patients and researchers in the early stages of neurotechnology research and clinical translation can help ensure ethical development of the field. This research study will be embedded in one of two projects funded by the DARPA BRAIN Initiative to develop implantable brain stimulation devices that both monitor and adaptively stimulate brain areas involved in mood and behavior regulation. Dr. Chiong and an interdisciplinary team with expertise in neuroscience, clinical care, law, philosophy, and social science will assess neuroethics issues associated with the DARPA-funded brain stimulation project. The overall goal is to enable acceptability and adoption of new treatments for neuropsychiatric disorders, by recognizing and incorporating the perspectives of patients, researchers, and other stakeholders into the design of these novel neurotechnological therapies.
AN INDUCIBLE MOLECULAR MEMORY SYSTEM TO RECORD TRANSIENT STATES OF CNS CELLS Mitra, Robi D Washington University 2015 RFA-MH-15-225 Complete
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Currently, methods that seek to link transient gene expression events to specific brain functions typically require genomic analysis of a population of cells, resulting in the destruction of those cells. This makes it difficult to directly connect molecular changes in a neuron with knowledge of subsequent biological outcomes, such as memory formation, brain development, or neurodegeneration. Mitra and his colleagues will develop a transformative technology called "Calling Cards" that provides a permanent genetic record of molecular events associated with gene expression, which can be read out by DNA sequencing at a later time after relevant biological outcomes have occurred. The data collected with this technique will deepen the understanding of processes such as brain development, memory formation and the progression of neurodegenerative disease.
An optogenetic toolkit for the interrogation and control of single cells. Hannon, Gregory J Cold Spring Harbor Laboratory 2014 RFA-MH-14-216 Complete
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Dr. Hannon's group will develop optogenetic techniques that use pulses of light to control genes and isolate proteins in specific cell types in the brain for molecular studies.
Anatomical characterization of neuronal cell types of the mouse brain Ascoli, Giorgio A Dong, Hong-wei (contact) Lim, Byungkook University Of Southern California 2017 RFA-MH-17-230 Active
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Better anatomical characterization of neurons is needed if we want to identify and distinguish the different cell types in the brain. Dong and colleagues plan to classify neurons based on their spatial anatomy, connections with other neurons, and morphology using multiple neuronal retro- and anterograde tracing methods that will identify connected neurons. This team will first focus on 300 well-defined regions within the limbic system of the adult mouse, a circuit that is important for homeostasis and behavioral motivation, taking high-resolution images and creating high-throughput, three-dimensional reconstructions of these neurons. These data will provide a more complete anatomical picture of the limbic system, and this method can be applied in the future to study additional circuits throughout the brain.
Anion channelrhodopsin-based viral tools to manipulate brain networks in behaving animals Dragoi, Valentin (contact) Janz, Roger Spudich, John Lee University Of Texas Hlth Sci Ctr Houston 2015 RFA-MH-15-225 Complete
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Examining neural circuits requires the ability to activate and silence individual neurons and subsequently assess the impact on circuit function and the circuit's overall influence on behavior. While genetically encoded molecular tools for selectively controlling the activity of neurons with light have been successfully implemented in mice, these tools have had limited success in non-human primates (NHPs). The researchers plan to modify a new class of recently discovered, light-activated molecular tools with superior light sensitivity to work well in NHPs. In addition, they will test a new, possibly more efficient, method of delivering these molecular tools via viral vectors into the neurons of awake, behaving NHPs.
Anterograde monosynaptic tracing Wickersham, Ian R Massachusetts Institute Of Technology 2015 RFA-MH-15-225 Complete
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Using a modified rabies virus, neuroscientists can identify and manipulate neurons directly upstream from any targeted group of neurons in the brain. However, while this retrograde monosynaptic tracing system is now well established, an anterograde counterpart—one that would allow identification and manipulation of neurons directly downstream from a target cell group—has never been constructed. Wickersham and his team propose three different methods for creating an anterograde tracing system. Any one of the methods would greatly expand the types of anatomical and functional studies that can be performed in a large variety of animals, including primates.
Assessing the Effects of Deep Brain Stimulation on Agency Roskies, Adina L Dartmouth College 2018 RFA-MH-18-500 Active
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Deep brain stimulation (DBS), a method of modulating brain circuit function, is FDA-approved for certain brain disorders such as Parkinson’s Disease. The NIH BRAIN Initiative aims to launch neurotechnological developments that include new ways of directly affecting brain circuit function. Use of these novel interventions warrants careful consideration about ways in which brain stimulation may affect personal identity, autonomy, authenticity and, more generally, agency. In this project, Dr. Roskies and her team will develop an assessment tool to measure changes in agency due to direct brain interventions, and establish a database to catalogue these changes in agency in various patient populations receiving DBS. These efforts have the potential to facilitate improvements in therapeutic approaches and informed consent and will be used to develop a framework for further neuroethical thought about brain interventions, allowing us to better identify, articulate, and measure effects on agency.

Autonomously-activating bioluminescent reporters to enable continuous, real-time, non-invasive brain cell imaging Sayler, Gary S 490 Biotech, Inc. 2018 PAR-15-091 Active
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To understand brain function, we need to be able to able to monitor cellular activity in the brain noninvasively over time.  To overcome these limitations Dr. Sayler's group will develop a set of self-exciting, continuously bioluminescent, optical imaging reporters that, unlike existing systems, are pre-engineered to support genetically encoded, autonomous, metabolically-neutral, neuron- or astrocyte-specific fluorescence that can be monitored with common laboratory equipment.

Behavioral readout of spatiotemporal codes dissected by holographic optogenetics Rinberg, Dmitry (contact) Shoham, Shy New York University School Of Medicine 2014 RFA-NS-14-009 Complete
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Dr. Rinberg's team aims to understand how the brain turns odors into nerve signals by activating and recording neurons in the olfactory bulbs of mice as they detect a variety of odors.
BIDS-Derivatives: A data standard for derived data and models in the BRAIN Initiative Poldrack, Russell A Stanford University 2017 RFA-MH-17-256 Active
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The proliferation and heterogeneity of magnetic resonance imaging (MRI) experiments, data analysis pipelines, and statistical modeling procedures presents a challenge for effective data sharing and collaboration. Russell Poldrack and colleagues propose expansion of the Brain Imaging Data Structure (BIDS), which standardizes the description and collection of imaging data/metadata for MRI, with development plans for other neuroimaging types as well. Under BIDS, the group will develop standards for pre-processing data pipelines, computational modeling results, and statistical modeling, using quick validation of any implemented standard so that researchers can assess whether their data fit within BIDS guidelines. These standardization goals will facilitate sharing of data, modeling, and results, ensuring their usability and engaging the greater research community in developing highly useable data standards.

Boss: A cloud-based data archive for electron microscopy and x-ray microtomography Wester, Brock A. Johns Hopkins University 2018 RFA-MH-17-255 Active
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Technological advancements in high-resolution imaging of brain volumes permits the accumulation of huge quantities of data that requires solution for storage and archiving. Dr. Brock’s project develops an open, accessible, and cloud-based data archive for electron microscopy and X-ray microtomography data by leveraging the proven architecture of the existing BossDB database. Allowing for petabyte scale data storage, curation, sharing, visualization and analysis, the archive is scalable and allows for a fast in- memory spatial data store, seamless migration of data between low cost and durable object storage (i.e. S3), and rapid access to the enormous datasets. The system enables computing data quality metrics on large datasets and metadata stores through a standardized interface. The archive is developed through an agile process that actively folds in community stakeholders for regular reviews and continuous opportunities for design input.

Brain circuit mapping using light inducible recombinase systems Cetin, Ali Haydar Allen Institute 2017 RFA-MH-17-220 Active
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Studying vast numbers of functioning neurons in the brain requires precise spatio-temporal tools. Toward this end, researchers are interested in genetically modifying specifically selected cells in vivo, for neuronal subtype-specific, single-cell-level analysis. Cetin and colleagues will modify current genomic manipulation enzymes, making them light inducible, to achieve high-throughput single-cell genomic modification in response to brief pulses of light in the brain. They will generate transgenic mouse lines with these recombinases, use light to trigger site-specific DNA modification, and study the connections, morphology, function, and genetic identity of individual neurons within the brain. This approach may break technical barriers and has a range of potential applications, enabling enhanced precision in analyzing mammalian brain circuitry.
BRAIN Initiative: Integrated Multimodal Analysis of Cell and Circuit-Specific Processes in Hippocampal Function Sweedler, Jonathan V. University Of Illinois At Urbana-champaign 2015 RFA-MH-15-225 Complete
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Individual cell types contain specific combinations of chemical constituents that directly affect cell behavior. However, detailed knowledge of these constituents, as well as a precise method for identifying them, is currently lacking. Sweedler and colleagues will combine two methods for probing the chemical makeup of living tissue—mass spectrometry of individual cells, and stimulated Raman scattering microscopy (SRSM) from unlabeled tissue in brain slices. The combined analyses will be deployed in the dentate gyrus region of the hippocampus to identify the region’s many different cell types and chemical characteristics, and to investigate how this wealth of information relates to functions involved in memory formation.
BRAIN power: expanding reproducibility, quality control, and visualization in AFNI/SUMA COX, ROBERT WILLIAM (contact); NIELSON, DYLAN MILES U.S. NATIONAL INSTITUTE OF MENTAL HEALTH 2018 RFA-MH-17-257 Active
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AFNI (Analysis of Functional NeuroImages) is an open-source software package for neuroimaging analysis and visualization of both functional and structural MRI as well as other modalities. Drs. Cox and Nielson propose to extend this widely used software package by offering containerization, cloud accessibility and web-accessible visualization. The software extension could support evolving BRAIN Initiative standards for human neuroimaging data organization and experiment specification. The project makes it possible for public integration testing of the software package, thus enabling end-user feedback and wider adoption and dissemination within the neuroimaging community.

Brain-wide correlation of single-cell firing properties to patterns of gene expression Cohen, Adam Ezra Harvard University 2018 RFA-MH-17-220 Active
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Different neurons show widely varying patterns of gene expression and widely varying patterns of electrical spiking. It is not currently possible to predict the electrical spiking properties of a cell from its pattern of gene expression. Cohen’s team seeks to develop tools to record gene expression and spiking patterns in thousands of neurons by combining two novel technologies: all-optical electrophysiology and BRAIN Initiative-funded fluorescent in situ hybridization, MERFISH. They will create correlated brain-wide maps of gene expression and neuronal firing, first in rodent acute brain slices and then in the zebrafish spinal cord in vivo . These maps may ultimately help elucidate the roles of genes in governing neural function in health and disease.

C-PAC: A configurable, compute-optimized, cloud-enabled neuroimaging analysis software for reproducible translational and comparative Craddock, Richard Cameron Milham, Michael Peter (contact) Child Mind Institute, Inc. 2018 RFA-MH-17-257 Active
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Novel neuromodulation, recording, and imaging techniques applied to human and non- human primate brains generate datasets that require tools for organizing, processing and analyzing data that are widely available and easy to use. Drs. Milham and Craddock plan to extend C-PAC (Configurable Pipeline for the Analysis of Connectomes), building a configurable data analysis pipeline that incorporates various statistical analysis, machine learning, and network analytic techniques. In addition to adapting methods used in human imaging for non-human primate data, the project will implement a toolbox for alignment of electrophysiological data with brain imaging data. The resulting software enables high- throughput, semiautomated and end-to-end processing and analysis of structural and functional MRI data that are accessed locally or via the cloud.

Cell atlas of mouse brain-spinal cord connectome Dong, Hong-wei Tao, Huizhong Whit Zhang, Li I (contact) University Of Southern California 2018 RFA-MH-17-230 Active
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Systematic studies on the brain-spinal cord connectome are lacking despite great efforts to characterize neuronal cell types in the brain. Zhang’s multi- laboratories project aims to systematically characterize neuronal types in the mouse spinal cord based on their anatomy, connectivity, neuronal morphologies, molecular identities, and electrophysiological properties. Via multiple newly-developed techniques, including an anterograde/retrograde trans-synaptic tagging method to label neurons, gene expression bard coding, and a fast 3D light sheet microscopy method, the team will establish a complete cell-type based brain-spinal cord connectome database, which will be made accessible to the neuroscience community.

Cerebellar network mapping with a high-throughput TEM platform Lee, Wei-chung Allen Harvard Medical School 2017 RFA-MH-17-220 Active
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Understanding cell type-specific neuronal connectivity may help indicate how the brain is altered in nervous system disorders. Lee’s team will use a high-throughput technology for electron microscopy volume image acquisition—capable of up to two orders of magnitude faster acquisition compared to current methods—and comprehensively characterize the cell types and connectivity within the cerebellum. They will reconstruct cerebellar network anatomy computationally and explore the organizational principles underlying cerebellar circuits. The tools and datasets will be released publicly, and may help uncover the role of specific circuit elements in nervous system function.
Circuit mechanisms of evidence accumulation during decision-making Luo, Zhihao Princeton University 2017 RFA-MH-17-250 Active
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Dr. Luo will use optogenetic tools to inactivate specific brain structures while simultaneously recording neuronal activity across other brain areas in the rat during evidence accumulation tasks. This research could uncover the neural circuits that support the gradual accumulation of evidence during decision making.
Collaborative Standards for Brain Microscopy Hamilton, Carol M Research Triangle Institute 2018 RFA-MH-17-256 Active
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Recent tissue-clearing techniques and advances in microscopy have made it possible to produce 3D images of intact brains. to help ensure consistency in data collection and analysis, Dr. Hamilton and her team will develop a set of standards for3D imaging of whole brains for the neuroscience research community.. Dr. Hamilton’s group will convene a Working Group of experts who will work through a consensus process to establish standards that will be distributed to the research community. These standards should help improve the efficiency of imaging research and allow comparisons across studies.

Collaboratory for atlasing cell type anatomy in the female and male mouse brain Osten, Pavel Cold Spring Harbor Laboratory 2017 RFA-MH-17-230 Active
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Although neuronal properties have been studied for over a century, we still have an incomplete idea of how different cell types are distributed throughout the brain. Osten and colleagues will use the automated Cell Counting and Distribution Mapping (CCDM) pipeline that they developed to express specific neuronal markers in the brains of adult mice, take high-resolution images of the neurons, and then spatially map their location. They plan to identify the distribution patterns and somato-dendritic morphology of more than 80 molecularly defined cell types. These data will provide detailed anatomical information about cell circuits that can then be integrated with molecular data to better define cell types in the brain.
Computational and circuit mechanisms for information transmission in the brain Eden, Uri Tzvi Frank, Loren M Ganguli, Surya Kepecs, Adam (contact) Kramer, Mark Alan Machens, Christian Tolosa, Vanessa Cold Spring Harbor Laboratory 2015 RFA-NS-15-005 Complete
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Dr. Kepecs and colleagues are investigating how information is integrated into decision making, and then further transformed into behavior. This project focuses on understanding information flow across specific regions of the brain in trained rats. By performing parallel, large-scale, simultaneous electrical recordings of neural activity in these different brain regions while the animals perform two different types of decision-making tasks, these researchers hope to observe how activity in one area influences activity in a downstream area. In addition, there are plans to identify and manipulate the activity of neurons that connect these brain areas to understand the causal relationships governing information flow among these regions. Gaining such mechanistic insights into how the brain processes information will provide insights into how both the normal and disordered brain operates.
Cortical circuits and information flow during memory-guided perceptual decisions Sur, Mriganka Massachusetts Institute Of Technology 2014 RFA-NS-14-009 Complete
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Dr. Sur and his team will combine a number of cutting-edge, large-scale imaging and computational techniques to determine the exact brain circuits involved in generating short term memories that influence decisions.
Crowd coding in the brain:3D imaging and control of collective neuronal dynamics Kanold, Patrick O (contact) Losert, Wolfgang Plenz, Dietmar Univ Of Maryland, College Park 2014 RFA-NS-14-009 Complete
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Dr. Kanold and his team propose cutting edge methods to stimulate neurons at different depths in the auditory cortex, and will use new computational methods to understand complex interactions between neurons in mice while testing their ability to hear different sounds.
DART2.0: comprehensive cell type-specific behavioral neuropharmacology Tadross, Michael R Duke University 2018 RFA-MH-17-220 Active
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Neuropharmaceuticals provide relief to millions suffering from an array of neurological and neuropsychiatric disorders. However, a barrier to identifying novel therapeutic targets can be attributed to a poor understanding of how the behavioral effects of drugs are mediated by specific neural cell types in the brain. Tadross’ team recently developed DART (Drugs Acutely Restricted by Tethering), the first and only method to date that can map the behavioral effects of clinical drugs by cell type. These tools would reveal circuit origins of desired vs harmful drug effects, explain why some drugs have higher efficacy than others, and potentially empower future rational efficacy advances. This project aims to expand the catalog of available DARTs, increase their subcellular specificity, and improve ease of use – particularly in combination with recording devices across larger brain areas. If successful, these tools will maximize utility to the neuroscience community, enabling previously intractable questions to be addressed.

Data Archive for the Brain Initiative (DABI) Duncan, Dominique Pouratian, Nader Toga, Arthur W (contact) University Of Southern California 2018 RFA-MH-17-255 Active
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This project develops DABI (Data Archive for the Brain Initiative) to aid the dissemination of human neurophysiological data generated through the BRAIN Initiative. Incorporating infrastructure from a pre- existing hub for delivering effective informatics and analytics solutions for major projects in the study of neurological diseases, Drs. Toga, Duncan, and Pouratian will aggregate data related to human electrophysiology, making the data broadly available and accessible to the research community. The group plans to incorporate analysis tools with user interfaces, implement tools for data management and use, and link metadata across different data modalities. The overarching goal of this project is to secure, link, and disseminate BRAIN Initiative data with all pertinent recording and imaging parameters coming from participating sites

Data interface and apps for systems neurophysiology and imaging Van Hooser, Stephen D Brandeis University 2018 RFA-MH-17-256 Active
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Many labs develop unique software to manage and interpret their findings, but those programs are often specific for certain types of datasets, making them difficult to share among researchers. Dr. Van Hooser’s team plans to create an interface standard that establishes a common set of processes for accessing neurophysiological and imaging data. The standard will be tested, and revised accordingly, based on feedback from graduate students and postdoctoral researchers during data access events, or “hack-a-thons.” The interface standard will help increase the speed of research and make data widely available, allowing individuals outside of the neuroscience and research communities to make discoveries.

Dendritome mapping of genetically-defined and sparsely-labeled cortical and striatal projection neurons Dong, Hong-wei Yang, Xiangdong William (contact) University Of California Los Angeles 2018 RFA-MH-17-230 Active
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The precise number of neuronal cell types of about one hundred million highly-interconnected neurons in the mouse brain is unknown. Ultimately, the classification of neuronal cell types in the mammalian brain will require integrating molecular, morphological, and connectomic properties. Yang and colleagues propose to classify neuronal cell types via brain-wide comprehensive profiling of the dendritic morphology of neurons with subsequent digital reconstruction. Their transgenic mouse lines, MORF, enable sparse labeling of genetically-defined neurons in mice, which allow for the resolution and reconstruction of individual cells’ dendritic morphologies within densely populated neuronal networks. This project will help contribute to the BICCN effort to generate a reference mouse brain cell atlas, and data will be shared publicly through the BRAIN Cell Data Center.

Designing low-cost, customizable high-density probes for acute and chronic neural recordings in rodents Van Welie, Ingrid Neural Dynamics Technologies, Llc 2018 PAR-15-091 Active
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To advance our understanding of the function of dynamical neural circuits, there is a need for technologies that can record the activity of hundreds to thousands of neurons simultaneously within and across brain regions in intact brains. Through Neural Dynamics Technologies, LLC, Drs. van Welie, Scholvin, and Boyden propose one way to resolve this issue by developing customizable high-density neural probes for use in acute or chronic recordings of neural population activity with a spatial and temporal resolution that is required for studying neural circuit activity.

Develop and validate novel chemogenetic tools to modulate synaptic transmission Tomita, Susumu Yale University 2017 RFA-MH-17-220 Active
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Neuronal activity modulates the strength of synaptic connections, a phenomenon known as synaptic plasticity, which is critical for forming and maintaining memories, for behavioral adaptations, and is disrupted in a variety of nervous system disorders. Tomita and colleagues will develop tools to chemically modulate excitatory synaptic transmission in vivo, mimicking synaptic plasticity. They will engineer a protein that transiently modulates synaptic activity upon addition of small chemical compounds. They will validate the protein module using a mouse fear conditioning behavioral paradigm and electrophysiology. This approach may help identify precise circuits/mechanisms underlying brain functions like learning and memory.
Developing a noninvasive method to manipulate specific cell types within the mammalian brain Chalasani, Sreekanth H. Salk Institute For Biological Studies 2016 RFA-MH-16-775 Active
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Current optogenetic techniques to manipulate cellular activity rely on an invasive light delivery method which makes control of cells deep in the brain difficult. Chalasani and colleages are developing a non-invasive method of cellular control using mechanosensitive channels that are responsive to low-intensity ultrasound - a novel technique deemed “sonogenetics.” The group can control neuronal activity in vitro by expressing these channels in target cells, and plan to test similar channels to fine-tune responsiveness to ultrasound pulses. Further, the group will develop a head device to deliver ultrasound pulses in mice, test efficacy in vivo via electrophysiological and behavioral analyses. Following development in rodents, this tool could be broadly applicable across multiple species to manipulate specific neuronal and non-neuronal cell types.
Developing drivers for neuron type-specific gene expression Hobert, Oliver Columbia University Health Sciences 2014 RFA-MH-14-216 Complete
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Dr. Hobert and colleagues will create a highly selective technology for experimentally manipulating genes in neurons, by tapping into the regulatory machinery of individual cell types.

Development of a Revolutionary MRI System for Functional Brain Imaging Wagner, Bob S Wang, Sou-tien Bert (contact) Wang Nmr, Inc. 2018 PAR-15-091 Active
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Low-cost, portable Magnetic Resonance Imaging (MRI) systems require use of small-bore magnets that are unable to capture the detail necessary to image the human brain. In this project, Drs. Wang and Wagner propose to further develop an imaging method previously funded by The BRAIN Initiative, by designing, building, and testing a portable 1.5T MRI system to image human brain activity. The novel imaging technology works with a small, lightweight (250 lb.), portable, low-cost, head-only magnet. The compactness and efficiency of this non-invasive imaging system makes the study of the human brain possible in more clinics and in subjects who previously were unable to receive an MRI scan due to constraints of standard systems.

Development of Line-Scan Temporal Focusing for fast structural imaging of synapse assembly/disassembly in vivo Boivin, Josiah R Massachusetts Institute Of Technology 2017 RFA-MH-17-250 Active
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Dr. Boivin will contribute to the development of high-resolution, high-throughput Temporal Focusing (TF) two-photon microscopy to achieve real-time monitoring of synapse assembly/disassembly in developing neural circuits in vivo in the mouse brain.
Development of tools for cell-type specific labeling of human and mouse neocortical neurons Lein, Ed Levi, Boaz Pirie (contact) Ting, Jonathan T Allen Institute 2017 RFA-MH-17-220 Active
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An important strategy for understanding the neural circuits is to identify the component cell types, then determine each cell type’s function. Currently, the characteristics of mammalian neocortical cell types are incompletely characterized, and the necessary investigative tools are lacking. Levi and colleagues will develop cross-species, cell-class-specific viral vector libraries for tagging different cell types in mouse and post-mortem human neocortex, which will be validated using single-cell RNA sequencing and electrophysiology. If successful, this project will achieve novel cell type-specific genetic tools to investigate and compare cross-species neocortical cell types.
DREADD2.0: AN ENHANCED CHEMOGENETIC TOOLKIT Jin, Jian Kash, Thomas L. Roth, Bryan L. (contact) Univ Of North Carolina Chapel Hill 2014 RFA-MH-14-216 Complete
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Dr. Roth and colleagues will build second generation technology that uses artificial neurotransmitters and receptors to manipulate brain activity simultaneously across select cells and pathways to understand their functions and potentially treat brain disorders.
Dual-channel Sub-millisecond Resolution Neural Imaging System Zhao, Youbo Physical Sciences, Inc 2018 PAR-15-091 Active
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Dr. Zhao's project aims to build a highly innovative and low-cost imaging tool that addresses a technological gap in neuroscience research for non-invasive recording of large neuron populations with high spatial and temporal resolution. The team plan to build and validate a fluorescent imaging system that enables parallel recording of multiple neuron populations with sub-cellular and sub-millisecond resolution. The system will include optimization of a benchtop microscope with two detection channels, and subsequent development of a head-mounted device for imaging in rodents. Successful development and commercialization of this technology could significantly advance neuroscience research, and thus improve our understanding of brain function.

Dynamic network computations for foraging in an uncertain environment Angelaki, Dora (contact) Dragoi, Valentin Pitkow, Zachary Samuel Schrater, Paul R Baylor College Of Medicine 2015 RFA-NS-15-005 Complete
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The computational strategies and underlying mechanisms the brain uses to enable animals to interact flexibly with their environment are poorly understood. These researchers will use large-scale, wireless, electrical recordings from six relevant, interconnected brain regions in freely-behaving monkeys to record neuronal activity while the animals engage in foraging behavior-a natural task that involves sensory integration, spatial navigation, memory, and complex decision-making. The research team will use theoretical models of decision-making to interpret the neural activity data gathered as the animals interact with their environment, with the ambitious goal of understanding how brains create and use internal models of the world.
Enabling ethical participation in innovative neuroscience on mental illness and addiction: towards a new screening tool enhancing informed consent for transformative research on the human brain Roberts, Laura W Stanford University 2017 RFA-MH-17-260 Active
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The NIH BRAIN Initiative aims to accelerate the development of innovative neurotechnologies and their application to reduce the burden of brain disorders, including mental illnesses and substance use disorders. However, because the brain is central to our humanity, this kind of research raises profound neuroethics issues, including questions about personal identity, and socially acceptable limits on novel neurotechnologies. Further, research involving participants with brain disorders is complex because these disorders can affect cognition, emotion, behavior, and decision-making capacity. In this project, Dr. Roberts and colleagues will assess the neuroethics issues encountered in neuroscience research related to mental illness and addiction through interviews with neuroscientists, neuroethicists, and institutional review board members. They will also study factors that influence research decision-making by people with mental illness and addiction, as compared with healthy controls and people with diabetes. Finally, they will develop a screening tool to enhance informed consent, as an evidence-informed practice to facilitate ethically sound cutting-edge human neuroscience research.
Engineered viral tropism for cell-type specific manipulation of neuronal circuits Schmidt, Daniel (contact) Thomas, Mark John University Of Minnesota 2015 RFA-MH-15-225 Complete
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Revealing how specific cell types contribute to different neural circuits that underlie cognition, behavior, and disease pathology remains a longstanding goal in neuroscience. Current methods for investigating cell-types are limited, and typically require genetically engineered animal models. Schmidt and his team propose a completely different approach that relies on natural toxins from venomous organisms, which have evolved to bind to specific receptors and ion channels residing on neuronal cell surfaces. The toxin binding domains will be attached to the surface of viruses as a means for them to gain entry into specific cell-types. This method will make it possible to study specific cell types in a wider range of animals than is currently possible.
Engineering optogenetic tools for studying neuropeptide activity French, Alexander Robert Purdue University 2017 RFA-MH-17-250 Active
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Dr. French will develop a high throughput screening platform to identify peptides that activate opioid receptors in response to light, creating high-resolution tools to study the function of specific opioid neural circuits in the brain.
Epigenetic tools and resources for cell-type and spatial analysis of individual mammalian non-neuronal cells Adey, Andrew OREGON HEALTH & SCIENCE UNIVERSITY 2018 RFA-DA-18-018 Active
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Dr. Adey’s team will use advanced single cell analysis techniques to explore the epigenetic properties of non-neuronal brain cells. Techniques will include performing chromatin access assays and genome-wide profiling of DNA methylation, along with studying how a cell’s chromatin folds. Some of their methods will be used to profile and compare glial and vascular cells across brain regions in both rodents and humans. To help further understand the role of non-neuronal cells in the brain, the group plans to make these tools and data available to the research community for additional analyses.

Epigenomic mapping approaches for cell-type classification in the brain Ecker, Joseph R Salk Institute For Biological Studies 2017 RFA-MH-17-225 Complete
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Dr. Ecker's group will use signatures of epigenetics, the switching on-and-off of genes in response to experience, in mouse frontal cortex to help identify different classes of cells and understand their function.

Ethical Safeguards for Exit and Withdrawal from Implanted Neurotechnology Research Sankary, Lauren Cleveland Clinic Lerner Com-cwru 2017 RFA-MH-17-250 Active
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Dr. Sankary will combine an assessment of the experience of research participants exiting from research studies involving implanted neurological devices with a critical evaluation of existing research practices and regulations that protect these subjects. The goal of this research is to determine the responsiveness of these safeguards to patient concerns and lay the groundwork for development of evidence-based guidelines for the ethical conduct of this research.
Ethics of Patients and Care Partners Perspectives on Personality Change in Parkinsons disease and Deep Brain Stimulation Kubu, Cynthia M. S. Cleveland Clinic Lerner Com-cwru 2017 RFA-MH-17-260 Active
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The nature and extent of personality changes following deep brain stimulation (DBS) for the treatment of Parkinson's disease (PD) are unclear. Dr. Kubu and colleagues will analyze patients’ and caregivers’ perspectives on personality characteristics (e.g., extroversion, humility) at different stages of PD and over the course of DBS (patients within one year of diagnosis, within 5 -7 years of diagnosis, and those undergoing DBS). This study will shed light on participant's most valued personality characteristics, and whether those characteristics are captured in the existing informed consent process; the influence of PD and/or DBS on personality; and the extent of agreement between patients’ and caregivers’ perceptions of personality change. These data will facilitate an enhanced, iterative informed consent process that includes systematic assessment of patients’ perceived personality changes, values, and goals; will inform understanding of identity and autonomy in the context of DBS; and may allow clinicians to ease the fears of patients receiving DBS.
Generating Multiple Circuit and Neuron Type Specific AAV Vectors With Cross-Species Applicability He, Zhigang Boston Children's Hospital 2015 RFA-MH-15-225 Complete
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Tools to investigate and manipulate brain functions in a cell-type or circuit-specific manner are critical for understanding how different neurons and circuits underlie cognition and behavior. So far, this capability has primarily been available only for the mouse, and only for a limited number of cell types. Dr. He and his team will screen DNA sequences from ultra-conserved regions of the genome known as "enhancer elements," and test their ability to control region- and cell-type specific gene expression in the brain, as well as for expression that is dependent on neurons' electrical activity. The goal is to produce an expanded, universal tool set consisting of vectors for cell- and circuit-specific gene expression that can be used across a wide variety of species.
Genetic analyses of complete circuit formation in Caenorhabditis elegans Cook, Steven Jay Columbia Univ New York Morningside 2017 RFA-MH-17-250 Active
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Using the model system C. elegans, which has a simple, well characterized nervous system, Dr. Cook will develop new tools to create an exquisitely detailed map of a circuit in live animals and reveal the genetic factors that orchestrate assembly of a complete neural circuit.
Genetic tools and imaging technology for mapping cholinergic engrams of anxiety Role, Lorna W State University New York Stony Brook 2015 RFA-MH-15-225 Complete
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Neuronal circuits are widely modulated by neurotransmitters such as acetylcholine. To explore in detail how acetylcholine impacts neural circuits, Role's team will use gene-activity mapping of neurons involved in a specific cognitive function in mice - recall of anxiety-provoking experiences. During recall, the team's mapping technique will track activity-related gene expression in basal forebrain neurons expressing acetylcholine and the neurons they project to in the hippocampus, amygdala, and cortex. In addition the team will make improvements to an imaging system called 3D SPIM that can be used to track neuronal activity. These improvements have the potential to reduce the time it takes to collect and analyze the imaging data by a factor of 50.
High Throughput Approaches for Cell-Specific Synapse Characterization Barth, Alison L Bruchez, Marcel P (contact) Carnegie-mellon University 2017 RFA-MH-17-220 Active
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Understanding the wiring principles within the cerebral cortex will benefit understanding of cognitive function, and how experiences are encoded into long-term memory. Bruchez and colleagues will develop molecular genetic tools using fluorogen activating proteins (FAPs), a system enabling fluorescence identification of synapses and cell-type specific connectivity, in mice. They will perform pre- and post-synaptic targeting of fluorescent and FAP proteins, respectively, allowing selective detection of connections between genetically selected cell populations. Through cell-type-specific synapse detection via high-throughput 3D imaging and analysis, this project may transform researchers’ ability to study synaptic connectivity.
High throughput mapping of neuronal circuitry using DNA sequencing Zador, Anthony M Cold Spring Harbor Laboratory 2017 RFA-MH-17-220 Active
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Neurons transmit information to distant brain regions via axonal projections. Current neuroanatomical techniques for tracing these projections are expensive and labor intensive. Zador and his team will use high-throughput DNA sequencing to map neuronal circuitry cheaply and efficiently. Their goal is to tag each neuron in the mouse neocortex with many copies of a unique RNA barcode. Because the barcode will be present throughout the neuron, projections can be mapped across brain regions. By converting circuit mapping into a DNA sequencing task, this model will leverage the remarkable advances in high-throughput sequencing. This project could provide a new method for understanding normal neuronal circuitry and a new tool for studying animal models of neural circuit disorders.
Human Agency and Brain-Computer Interfaces: Understanding users? experiences and developing a tool for improved consent Goering, Sara (contact) Klein, Eran University Of Washington 2018 RFA-MH-18-500 Active
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Agency, our ability to act and experience a sense of responsibility for our actions, is central to individual identity and societal conceptions of moral responsibility. Neural devices are currently used to treat some brain disorders, such as Parkinson’s disease, and are being developed to treat others such as depression and obsessive-compulsive disorder, yet their use raises important ethical concerns about potential effects on agency. Dr. Goering, Dr. Klein and their team will investigate agency in individuals receiving brain computer interface devices for sensory, motor, communication, and psychiatric indications. They aim to build a user-centered neural agency framework, and, ultimately, to enhance the informed consent process by developing a communication tool that patient participants might use to better understand and discuss potential changes in agency associated with use of neural devices.

Identification of enhancers whose activity defines cortical interneuron types Rubenstein, John L. R. (contact) Sohal, Vikaas Singh University Of California, San Francisco 2014 RFA-MH-14-216 Complete
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Dr. Rubenstein and colleagues plan to identify enhancer molecules specific to particular types of interneurons – that relay neural signals – and use this information to profile distinct cell types and new ways to manipulate genes.
Illuminating Neurodevelopment through Integrated Analysis and Vizualization of Multi-Omic Data Hertzano, Ronna (contact) White, Owen R University Of Maryland Baltimore 2018 RFA-MH-17-257 Active
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Molecular and cellular neuroscientists often lack the training in computer programming to fully explore “-omics” data common in the BRAIN Initiative. Drs. Hertzano and White will implement analytic software for visualization and interactive genome browsing of gene expression and RNA-seq data, including simple and complex cross-dataset analysis. These tools will be made available in the BRAIN Initiative funded Neuroscience Multi-Omic Data Archive (NeMO) which hosts multi-omic data. The software will provide an easy-to-use web-based work environment for visualization and analysis of multi-modality and multi- omic data, interrogation of relationships between epigenomic signatures and gene expression, and integration of analytical techniques for multivariate analysis, gene co- expression and other analyses.

Imaging and Analysis Techniques to Construct a Cell Census Atlas of the Human Brain Boas, David A Fischl, Bruce (contact) Massachusetts General Hospital 2018 RFA-MH-17-210 Active
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Three-dimensional human brain atlases are increasingly important for integrating complex datasets into useful community resources. Fischl’s team proposes to create a multi-scale atlas—akin to Google Earth™ for the human brain—to map hemisphere-wide networks and also zoom in to see individual, labeled cells at micron resolution. This advance will be made possible through multiple imaging technologies, including light-sheet microscopy, tissue clearing, immunohistochemistry, magnetic resonance imaging, and newly-developed techniques in Optical Coherence Tomography. The ability to probe the cellular properties and multi-scale networks of specific areas in the human brain could evolve to an automated system for visualizing across the entire human brain in health and disease.

In situ transcriptional analysis of brain circuits at single cell resolution Dulac, Catherine G (contact) Regev, Aviv Zhuang, Xiaowei Harvard University 2016 RFA-MH-16-775 Active
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A fundamental challenge to achieving a mechanistic understanding of how the brain works is obtaining a systematic characterization of diverse cell types at single-cell resolution. Dulac, Regev, and Zhuang, will use Multiplexed Error Robust Fluorescent in situ Hybridization (MERFISH) to measure the transcriptome of single cells from intact brain tissue, creating a spatially informed cellular inventory of neural circuits in mouse. By expanding this method into the marmoset and coupling it with behavioral tasks, they will validate a new, unbiased imaging platform and computational toolkit that uses gene expression profiles to classify cells in the functional context of behaviorally relevant circuits.
In Vivo Imaging of Local Synaptic Neuromodulation by Dopamine Evans, Paul Robert Max Planck Florida Corporation 2018 RFA-MH-17-250 Active
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Dopamine is a powerful neurotransmitter that facilitates memory formation and underlies reward-related behaviors, but current techniques to assess dopamine signaling in vivo lack sufficient specificity and spatiotemporal resolution. Evans will develop new fluorescent sensors for dopamine receptors and apply them to investigate the molecular mechanisms that underlie learning in mice in vivo. The biosensors will be used to visualize the dynamic activity of specific dopamine receptors in vitro, before they are virally expressed in the motor cortex in behaving mice. Employed during motor learning, these sensors should generate a sub-micron scale map of how dopamine receptor subtypes modulate long-term structural plasticity of cortical dendritic spines. The results could help shed light on how dopaminergic modulation correlates with structural and functional plasticity.
In-vivo circuit activity measurement at single cell, sub-threshold resolution Forest, Craig (contact) Stanley, Garrett B. Georgia Institute Of Technology 2014 RFA-MH-14-216 Complete
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Dr. Forest's team will use a newly developed robot guided technique to measure precise changes in electrical activity from individual neurons that are connected over long distances across the brain, to understand how these connections change when our brains go into different states, such as sleeping and waking.
Informing Choice for Neurotechnological Innovation in Pediatric Epilepsy Surgery Illes, Judy (contact) Mcdonald, Patrick University Of British Columbia 2018 RFA-MH-18-500 Active
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More than 500,000 children in the US and Canada suffer from epilepsy and 30% of these children continue to experience seizures despite being treated with anti-seizure medication. Unmanaged, epilepsy can result in cognitive decline, social isolation, and poor quality of life, and has substantial economic impact on families and society. Novel approaches for treating epilepsy such as vagal nerve stimulation and responsive neurostimulation are being developed, but this work has been conducted predominately in adults and the outcomes of these trials are often not clearly generalizable to children. In this project, Drs. Illes and McDonald will explore ethical issues confronting families and clinicians when considering new treatment options for drug-resistant epilepsy in children. They aim to develop, evaluate, and deliver patient-directed resources in the form of infographics and informational materials and videos, and clinician resources for family decision-making, clinician counseling, and care.

Integrative approach to classifying neuronal cell types of the mouse hippocampus Dong, Hong-wei (contact) Zhang, Li I University Of Southern California 2017 RFA-MH-17-220 Active
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Identifying the diversity of nervous system cell types may enable their selective manipulation and reveal their functions in health and disease. Dong and his team propose state-of-the-art techniques in viral circuit tracing and molecular and electrophysiological profiling, to classify neuronal cell types of the mouse hippocampus and subiculum. Combined with CLARITY (a tissue-clearing technique), expansion microscopy, and multiphoton imaging, their approach will report the anatomical location, connectivity, morphology, molecular profile, and electrophysiological characteristics of each cell type. Raw and analyzed data will be publicly shared on the Mouse Connectome Project website. If successful, this work can be applied toward characterizing neuronal cell types of the entire brain.
Integrative Functional Mapping of Sensory-Motor Pathways Dickinson, Michael H (contact) Holmes, Philip J Mann, Richard S Wilson, Rachel California Institute Of Technology 2014 RFA-NS-14-009 Complete
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Dr. Dickinson will lead an interdisciplinary team to study how the brain uses sensory information to guide movements, by recording the activity of individual neurons from across the brain in fruit flies, as they walk on a treadmill and see and smell a variety of sights and odors.
Intrabody-dependent activation of cell-specific gene expression in CNS Blackshaw, Seth Johns Hopkins University 2015 RFA-MH-15-225 Complete
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Techniques for inducing specific cell types to express certain proteins typically require using genetically engineered animals, which are limited primarily to rodents and can take years to develop. Blackshaw and colleagues are developing tools that will allow specific cells to be labeled and manipulated without complex genetic approaches. If successful, this technology would enable the labeling and modification of multiple types of specific neurons in nearly any animal, at a fraction of the cost and time of current techniques.
Investigating the hypocretin to VTA circuit in memory consolidation during sleep Borniger, Jeremy Stanford University 2018 RFA-MH-17-250 Active
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Brain-computer interfaces and neuroprosthetics have provided a significant benefit to patients with cervical spinal cord injuries. However, current technology is limited in its abilities to allow the user to control how much force is exerted by the prosthesis and to provide sensory feedback from the prosthetic hand. In a public-private collaboration with Blackrock Microsystems, Dr. Boninger and colleagues are looking to improve the dexterity of neuroprostheses by incorporating microstimulation of the somatosensory cortex. This stimulation could provide tactile feedback to the user and hopefully allow the user to better control the force applied. Ultimately, this approach will improve the dexterity and control of prosthetic limbs used by patients with spinal cord injuries.

Investigating the Role of Neurotensin on Valence Assignment During Associative Learning in the Basolateral Amygdala Olson, Jacob Michael Massachusetts Institute Of Technology 2017 RFA-MH-17-250 Active
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Dr. Olson will systematically identify, manipulate, and characterize the neural projections that release the neuropeptide neurotensin to the basolateral amygdala during behavior conditioning tests in mice to identify a new circuit that regulates associative learning.
Is the Treatment Perceived to be Worse than the Disease?: Ethical Concerns and Attitudes towards Psychiatric Electroceutical Interventions Cabrera Trujillo, Laura Yenisa Michigan State University 2018 RFA-MH-18-500 Active
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The NIH BRAIN Initiative aims to catalyze novel tools and technologies to modulate brain circuit function, paving the way for new treatment options for brain disorders. However, such interventions also have the potential to cause unintended changes in aspects of cognition, behavior, and emotion. These changes, in turn, raise concerns regarding autonomy, personal identity, and capacity for informed consent. In this study, Dr. Cabrera Trujillo and her team will study ethical concerns, beliefs, and attitudes about the use of novel bioelectric approaches among clinicians, patients, and the broader public. The work will provide stakeholder perspectives that will be valuable for informing the responsible development and use of these novel neurotechnologies.

Lagging or Leading? Linking Substantia Nigra Activity to Spontaneous Motor Sequences Adams, Ryan Prescott Datta, Sandeep R Sabatini, Bernardo L (contact) Harvard Medical School 2015 RFA-NS-15-005 Complete
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One of the goals of the BRAIN Initiative is to understand how the brain generates behaviors. These researchers are utilizing a novel 3D machine vision technology to automate classification of spontaneous behavior when freely-moving mice are confronted with stimuli; they are then correlating that information with dense recordings of neural activity in key regions of the brain implicated in movement disorders. Researchers are then manipulating the activity of specific neurons in this brain region with light to test their role in the animal’s behavior. Dr. Sabatini and colleagues offer an innovative ‘grammatical’ structure to understanding how the brain produces complex, systematic behavior.
Large-scale monitoring of sensory transformations in the mammalian olfactory system Burton, Shawn Denver University Of Utah 2017 RFA-MH-17-250 Active
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Dr. Burton will leverage recent enhancements in calcium indicators to image pre- and post-synaptic neural activity simultaneously in the mammalian olfactory system, gaining insight into how sensory information is transformed as it moves through a neural circuit.
LIPS: A novel technology for spatial and temporal control of protein synthesis in dendritic spines Gan, Wenbiao Jaffrey, Samie R (contact) Weill Medical Coll Of Cornell Univ 2015 RFA-MH-15-225 Complete
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Synaptic plasticity involves changes in protein expression that are precisely localized to dendrites and synaptic spines, but current techniques for manipulating gene expression are not able to approach these small scales. Jaffrey and colleagues propose a method called light-induced protein synthesis (LIPS), using RNA transcripts under control of plant-derived phytochrome proteins that can be activated by microscopic laser spots. The ability to directly manipulate the protein content at specific synapses and spines may greatly enhance efforts to decipher the roles of synaptic proteins in learning, memory, behavior, and disease.
Magnetic camera based on optical magnetometer for neuroscience research Alem, Orang FIELDLINE, INC. 2018 PAR-15-090 Active
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A camera that could image neuronal current distributions with a large array of pixels and a spatial resolution better than 1 ms resolution could dramatically enhance our understanding of neuronal circuitry. In this Phase I STTR, Fieldline, Inc. will develop a novel type of magnetographic camera, capable of providing single-shot images of electrical currents in neuronal circuits in vitro and in vivo with a millisecond time resolution. The team will first build a bench-top camera before combining it with electrode arrays, testing the ability to image neuronal connections across the circuit in vitro with turtle cerebellem. This will potentially lead to a completely portable, economical multi-pixel camera that can be produced for neuroscience research. 

Mapping and controlling gene expression in inhibitory interneurons mammals Fishell, Gordon J New York University School Of Medicine 2016 RFA-MH-16-775 Complete
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In order to better understand what influences normal brain development, it is necessary to track changes in gene expression over time and in different contexts, including learning and development. Fishell and colleagues modified DNA Adenine Methyltransferase Identification technology (DamID) to make it inducible in forebrain interneurons at particular developmental time points to measure gene activation. The new DamID will provide a transcriptome timestamp in a diverse cell population without requiring transgenic tools. The group intends to use transcriptome data and computational programming to expand into viral vectors to modulate interneuron subgroups in mice and non-human primates.
Mapping neuronal chloride microdomains Staley, Kevin J. Massachusetts General Hospital 2014 RFA-MH-14-216 Complete
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Using protein engineering technology to monitor the movement of chloride through inhibitory neurotransmitter receptor channels, Dr. Staley's group aims to understand the role of chloride microdomains in memory.
Mechanisms of neural circuit dynamics in working memory Bialek, William Brody, Carlos D (contact) Seung, Hyunjune Sebastian Tank, David W Wang, Samuel Sheng-hung Witten, Ilana Princeton University 2014 RFA-NS-14-009 Complete
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Dr. Brody and his colleagues will study the underlying neuronal circuitry that contributes to short-term "working" memory, using tools to record circuit activity across many brain areas simultaneously while rodents run on a track-ball through virtual mazes projected onto a screen.
Model behavior in zebrafish: characterization of the startle response Meserve, Joy Hart University Of Pennsylvania 2018 RFA-MH-17-250 Active
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The startle response is disrupted (i.e., uncoordinated or weak) in several neurological and psychiatric disorders. Meserve will investigate the startle response using live imaging of neural activity in transparent larval zebrafish. The slc5a7 gene (required for acetylcholine synthesis) modulates the startle response in zebrafish, and human slc5a7 mutations are implicated in attention deficit disorder and major depression. This project will study slc5a7a’s role in neural circuit development and/or startle response. Circuit defects in slc5a7a mutants will be investigated via calcium imaging and whole-brain activity mapping of neurons known to be required for the startle response. Integrated studies on gene function, neural circuitry, and behavior will uncover the developmental stage and anatomical region where slc5a7a is required. These experiments may determine how slc5a7a promotes normal startle response, and contribute knowledge about how acetylcholine regulates behavior.
Multi-channel MR-compatible flexible microelectrode for recording and stimulation Shih, Yen-Yu BLACKROCK MICROSYSTEMS 2018 PAR-15-090 Active
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Given the increasing use of magnetic resonance imaging (MRI) in brain research, understanding of what MRI signals really represent has become a fundamental yet fully elusive research topic. Recent neuroscience/neuroimaging research has also emphasized the importance of using multi-modal approaches, in which the data are acquired by multiple techniques to combine higher temporal resolution with spatial resolution of brain activity.  Drs. Shih and Franklin aim to bridge two of the most powerful and widely used research/clinical tools used in neuroscience – MRI and electrophysiology – by creating a novel MR-compatible 16-channel microelectrode array. This microelectrode array addresses two major applications: high resolution electrophysiology and deep brain stimulation. Both of which, in combination with simultaneous MRI, comprise a highly innovative platform which is intended to improve our understanding of brain function and neural circuit connectivity.

Multi-channel MR-compatible flexible microelectrode for recording and stimulation Franklin, Robert Kyle Shih, Yen-yu Ian (contact) Blackrock Microsystems 2016 PAR-15-090 Active
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Given the increasing use of magnetic resonance imaging (MRI) in brain research, understanding of what MRI signals really represent has become a fundamental yet fully elusive research topic. Recent neuroscience/neuroimaging research has also emphasized the importance of using multi-modal approaches, in which the data are acquired by multiple techniques to combine higher temporal resolution with spatial resolution of brain activity.  Drs. Shih and Franklin aim to bridge two of the most powerful and widely used research/clinical tools used in neuroscience – MRI and electrophysiology – by creating a novel MR-compatible 16-channel microelectrode array. This microelectrode array addresses two major applications: high resolution electrophysiology and deep brain stimulation. Both of which, in combination with simultaneous MRI, comprise a highly innovative platform which is intended to improve our understanding of brain function and neural circuit connectivity.

Multi-context software for robust and reproducible neuroscience image analysis Papademetris, Xenophon (contact) Scheinost, Dustin Yale University 2017 RFA-MH-17-257 Active
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A thorough understanding of brain function requires the integration of neuroscience data across species and scales. While current software can verify data quality within one or a handful of data sources, reproducibility across multiple data sources is limited. Xenophon Papademetris and colleagues are developing software tools with cross-scale, cross-species reproducibility analysis in mind. By leveraging data created by two other BRAIN Initiative projects at Yale University, Papademetris will extend current software algorithms to incorporate data from multiple sources, design the software to be cross-platform compatible, validate the software through rigorous testing, and finally, distribute it to the community. The potential for a set of software tools to reliably and reproducibly analyze multiple heterogeneous neuroscience data types will help to break down data barriers for the greater neuroscience community.

Multiparametric Biosensor Imaging in Brain Slices Blanpied, Thomas A Meredith, Andrea L Rizzo, Mark A (contact) University Of Maryland Baltimore 2016 RFA-MH-16-775 Active
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The coordinated observation of spatial and temporal interactions of multiple signaling pathways within individual cells and across intact circuits is limited by an inability to simultaneously track dynamic molecular activity. Rizzo and colleagues will validate and further develop a new methodology, Fluorescent Anisotropy Reporters (FLAREs), for simultaneous optical imaging of multiple biosensors within single neurons of mouse brain slices during neural coding. The group will improve the optical sectioning microscopy methodology and increase the range of signaling molecules measurable with FLAREs. This technique may enhance subcellular spatial resolution and cellular temporal resolution of signaling pathways, and could scale to visualize coordinated cellular activities and neural coding in intact brain circuits.
Multiplex in vivo imaging of cell-specific and circuit-specific signaling pathways during synaptic plasticity Huganir, Richard L (contact) Zhang, Jin Johns Hopkins University 2016 RFA-MH-16-775 Active
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Kinase signaling pathways that regulate synaptic plasticity help integrate multiple types of synaptic inputs to control neuronal circuit adaptation during behavior. However, monitoring more than one of these pathways simultaneously in awake behaving animals remains a challenge. Huganir and Zhang plan to develop and validate new genetically encoded fluorescent biosensors and use two-photon microscopy to image activity of multiple kinase signaling pathways in awake, behaving mice. This tool will improve rapid (seconds to minutes) detection of dynamic signaling pathways during physiologically relevant sensory experiences and learning tasks, greatly improving our ability to visualize cell-specific and circuit-specific signaling pathways.
MULTISCALE ANALYSIS OF SENSORY-MOTOR CORTICAL GATING IN BEHAVING MICE Jaeger, Dieter (contact) Stanley, Garrett B. Emory University 2015 RFA-NS-15-005 Complete
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The neural circuitry underlying how animals make motor decisions, especially in response to sensory or environmental cues, is not well understood. Many motor disorders, including Parkinson’s and Huntington’s disease, are linked to faulty circuits in a region of the brain called the basal ganglia. Researchers will use a variety of advanced methods to image, record, and manipulate the activity of neurons in this area as well as in the areas of the brain involved in sensory perception and movement. By employing these methods at multiple scales – from the individual neuron to neuronal networks – and then correlating these data with the behavior of awake, behaving mice, researchers hope to reveal how sensory information is integrated with input from the basal ganglia to result in the decision to initiate or suppress movement.
Multiscale Imaging of Spontaneous Activity in Cortex: Mechanisms, Development and Function Constable, R. Todd Crair, Michael (contact) Yale University 2015 RFA-NS-15-005 Complete
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Being able to observe the activity of a single neuron while simultaneously observing the activity of entire brain regions is a critical step in bridging the gap in understanding of how a collection of nerve cells ultimately generates an organized behavior. Dr. Crair and colleagues will develop and use two different imaging techniques to measure the activity of individual neurons, regions of the brain, and the whole brain, during different behavior states, such as REM and non-REM sleep, in developing mice. Bridging their analyses and insights between and within scales will allow these researchers to examine neural circuits and networks in different brain states and determine how they are modulated through development.
Nano-switches for optogenetic control of neuronal proteins with ultra-specificity Wang, Lei University Of California, San Francisco 2017 RFA-MH-17-220 Active
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Optogenetics is a powerful tool for controlling the activity of neurons with light, but it currently cannot be readily applied on any protein of choice, and lacks specificity. Wang and his team propose a nano-switch technology, in which unnatural amino acids (UAA) will be incorporated into neuronal proteins at single sites, achieving reversible optical control of the protein. Compared with existing methods using large, light-sensitive proteins, this method uses only a single UAA for light sensitivity, and can photo-modulate a protein without knowing its function in advance. This project’s success in model organisms will introduce vast opportunities for investigating previously-inaccessible neuronal processes at the molecular level.
Network basis of action selection Komiyama, Takaki Kreitzer, Anatol (contact) Lim, Byungkook J. David Gladstone Institutes 2015 RFA-NS-15-005 Complete
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Three separate research groups are collaborating to understand in detail how three distinct areas of the brain function and work together to enable learning and decision-making behaviors. Drs. Kreitzer, Komiyama, and Lim are leveraging an impressive set of technologies to monitor and perturb different cell types in each brain region while the mice perform learning and decision-making tasks. By applying multiple recording methods across these brain regions at both the level of a single neuron and entire subpopulations of neurons, while the animals perform the same set of tasks, researchers hope to develop a single model of how vertebrate animals make choices about what to do next.

Neural circuits in zebrafish: form, function and plasticity Cepko, Constance L Engert, Florian (contact) Lichtman, Jeff W Sompolinsky, Haim Harvard University 2014 RFA-NS-14-009 Complete
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Dr. Engert's team will combine a wide array of cutting-edge neuroscience techniques to watch the entire brain activity of a see-through fish while it swims, and to make detailed maps of its brain circuitry.
Neural ensembles underlying natural tracking behavior Fiete, Ila R. Huk, Alexander C Priebe, Nicholas J. (contact) University Of Texas, Austin 2015 RFA-NS-15-005 Complete
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Animals move their eyes to track the movement of objects around them. These researchers will measure and manipulate the activity of populations of identified neurons in marmosets during pursuit eye movements. This work will allow a detailed understanding of how the pursuit circuit integrates information from a large number regions is a critical step in bridging the gap in understanding of how a collection of nerve cells ultimately generates an organized behavior. Dr. Crair and colleagues will develop and use two different imaging techniques to measure the activity of individual neurons, regions of the brain, and the whole brain, during different behavior states, such as REM and non-REM sleep, in developing mice. Bridging their analyses and insights between and within scales will allow these researchers to examine neural circuits and networks in different brain states and determine how they are modulated through development.
Neural Implant Insertion System using Ultrasonic Vibration to Reduce Tissue Dimpling and Improve Insertion Precision of Floating Arrays in the Neocortex Mulvihill, Maureen L. Actuated Medical, Inc. 2018 PAR-15-091 Active
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Penetrating electrode arrays have an expanding application in neuroscience research as they can provide direct access to neural signals across the central and peripheral nervous system with high spatial resolution. Chronic electrode implants could revolutionize treatment for a range of medical conditions, including prosthetic motor control and proprioception for amputees, and brain-machine interfacing for paraplegics. Unfortunately, device implantation applies forces to the neural tissue resulting in significant brain compression (dimpling) at the implant site, which increases risk of implantation trauma, bleeding and inflammation. Actuated Medical, Inc. will develop a neural implant inserter, the Ultrasonic Precision Insertion of Neural Devices (UPIND) system, that will reduce the insertion force by applying ultrasonic energy to electrode arrays during insertion. This system aims to enable greater placement control of floating microware arrays, while reducing tissue trauma.

Neuroethics of aDBS Systems Targeting Neuropsychiatric and Movement Disorders Goodman, Wayne K Lazaro-munoz, Gabriel (contact) Mcguire, Amy Lynn Baylor College Of Medicine 2017 RFA-MH-17-260 Active
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A technological advance beyond traditional, open-loop DBS devices, adaptive deep brain stimulation (aDBS) devices monitor local neural activity to adjust stimulation in real time when treating certain movement and neuropsychiatric disorders. However, because aDBS devices autonomously record neural data and provide neuromodulation to affect motor function and mood, these systems raise important neuroethics issues, including changes in perception of autonomy and personal identity; risk-taking propensity; and privacy, use, and ownership of neural data. In this project, Dr. Lazaro-Munoz and colleagues will gather data from participants in existing aDBS clinical trials, their caregivers, people who declined to receive aDBS, and the aDBS researchers, to identify and assess the most pressing neuroethics issues related to aDBS research and translation. The long-term goal of this research program is to develop an empirically-informed and ethically-justified framework for the responsible development and clinical translation of aDBS systems, which will help maximize the social utility of this type of novel neurotechnology.
Neuronal and Dopaminergic Contributions to Dissimilar Evoked Hemodynamic Responses in the Striatum Walton, Lindsay Univ Of North Carolina Chapel Hill 2018 RFA-MH-17-250 Active
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Blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI) is a non-invasive imaging technique that infers increased brain activity from observed increases in cerebral blood flow. A notable exception to this relationship occurs in the striatum. Walton will investigate the activity of dopamine neurons, medium spiny neurons, and dopamine receptors, under conditions that evoke either blood vessel dilatation or constriction in the striatum. She will utilize optogenetic stimulation, synthetically-derived receptors, and receptor antagonist drugs to reveal the mechanisms underlying striatal positive and negative fMRI responses. These studies are important for the accurate interpretation of BOLD fMRI signals from brain regions with atypical hemodynamic responses.
NeuroPET HD: A low-cost high performance neuro-PET imaging system Hunter, William Coulis Jason Pet/x, Llc 2017 PAR-15-090 Active
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Positron Emission Tomography (PET) has the potential to be an important tool in understanding the human brain. However, current PET systems used in oncology are expensive and lack the level of resolution necessary for human neuroimaging studies. Drs. Hunter and Coulis plan to combine a novel detector technology with innovative system architecture for commercial production of a cost-effective PET brain imaging system (Neuro-PET HD). In the Phase I STTR, PET/X LLC will create and validate the performance of a new PET detector ring system before generating a full commercial prototype. The goal is to reduce system cost, while providing a significantly more compact, mobile system that provides rigorously accurate images of brain function.

New Proteomic and Genome Engineering Approaches to Decipher Astrocyte Function at Synapses SODERLING, SCOTT DUKE UNIVERSITY 2018 RFA-DA-18-018 Active
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Star-shaped astrocytes are the most abundant non-neuronal cells of the brain. Their thin processes envelop neuronal synapses and critically shape their formation and function. In this project, BRAIN Initiative-funded researchers, Drs. Eroglu and Soderling, will develop and use a novel chemicogenetic approach called iBioID enabling the capture of astrocyte processes and the identification of the key proteins that form the interface between neurons and astrocytes. The team will use this technique in combination with gene editing to study how these proteins regulate the growth and maintenance of synapses in the healthy brain and explore what role they may play in neurological disorders.

New tools to target, identify and characterize astrocytes in the adult nervous system Gradinaru, Viviana Khakh, Baljit (contact) University Of California Los Angeles 2018 RFA-DA-18-018 Active
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Nearly 40 percent of the central nervous system is made up of astrocytes, star-shaped cells thought to provide synaptic support and facilitate neuronal signaling. For this project Drs. Khakh and Gradinaru plan to accelerate the development of tools for studying astrocytes. These tools include advanced methods for studying RNA and proteins, ATP biosensors for monitoring astrocyte communication, and viruses for delivering genes to astrocytes in different parts of the brain. A complement of such tools could help advance our understanding of the role of astrocytes in the healthy and diseased brain.
Next-gen Opto-GPCRs: spatiotemporal simulation of neuromodulator signaling Bruchas, Michael R (contact) Sunahara, Roger K Washington University 2016 RFA-MH-16-775 Active
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Current tools for controlling neural activity in awake behaving animals, like optogenetics and designer receptors, are still limited in spatial and temporal control of diverse, discrete cell types. Bruchas, Sunahara, and their team will address these limitations by developing and validating a broader array of optically controlled G-protein coupled receptors with enhanced signaling dynamics and greater sensitivity and efficacy across myriad pathways. These Opto-XRs can be used in both neurons and glia, expanding the scope of experimentation in mapping brain circuitry in freely behaving animals, allowing discrete control and optodynamic stimulation of neuromodulatory signaling in brain tissues.
Noninvasive Gene Delivery for Monitoring and Perturbing Cell Types and Circuits in Transgenic and Non-Transgenic Animals Gradinaru, Viviana California Institute Of Technology 2018 RFA-MH-17-220 Active
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When used in conjunction with transgenic animals to restrict expression to cell populations of interest, adeno-associated viruses (AAVs) can provide well-tolerated, targeted transgene expression enabling long-term behavioral, in vivo imaging, and physiological experiments. From previous BRAIN Initiative funding, Gradinaru’s team developed a method that allows systemic delivery of viral vectors capable of crossing the blood brain barrier, circumventing the need for transgenic animals. Here the team proposes to improve on this methodology by enabling select AAV variants to anterogradely cross synapses. This will be achieved through targeted evolution of AAVs. This ability to cross synapses with cell-specificity will also provide neural connectivity information. One could envision eventually being able to deliver therapeutics systemically that target disrupted circuitry with cell-specificity.

Novel Genetic Strategy for Sparse Labeling and Manipulation of Mammalian Neurons Yang, Xiangdong William University Of California Los Angeles 2014 RFA-MH-14-216 Complete
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Dr. Yang's team will develop a new way to genetically target specific neurons, incorporating streamlined imaging and mapping methods that will enable the detection of sparse populations of cells that often elude existing methods.
Novel technologies for nontoxic transsynaptic tracing Wickersham, Ian R Massachusetts Institute Of Technology 2014 RFA-MH-14-216 Complete
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Dr. Wickersham and colleagues will develop nontoxic viral tracers to assist in the study of neural circuitry underlying complex behaviors.
Novel tools for cell-specific imaging of functional connectivity and circuit operations Isacoff, Ehud University Of California Berkeley 2015 RFA-MH-15-225 Complete
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Fundamental to understanding brain function in health and disease is the ability to relate the firing patterns of specific brain neurons to the synaptic connections they share with other neurons, and determine the strength of those connections. Isacoff and colleagues will develop novel, genetically encoded light-activated indicators in zebrafish, fruit fly, and mouse, which can selectively image neural activity in highly detailed structures of single neurons. Additional light-activated indicators will be targeted to synapses to quantify the release of neurotransmitters simultaneously at hundreds to thousands of synapses associated with a single neuron. This information can be used for tracking the strength of synapses over time in order to explore mechanisms of learning and brain adaptation.
NWB:N: A Data Standard and Software Ecosystem for Neurophysiology Ng, Lydia Lup-ming Ruebel, Oliver (contact) University Of Calif-lawrenc Berkeley Lab 2018 RFA-MH-17-256 Active
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Neurophysiology research, which focuses on recording brain cell activity, produces enormous amounts of complex data that are difficult to manage. Drs. Rubel and Ng will build upon the Neurodata Without Borders: Neurophysiology project to create a system that will allow for standardizing, sharing, and reusing neurophysiological data. The team will design an open source software system; develop methods to establish a consistent vocabulary for defining cell types, measurements, and behavioral tasks; and create tools to help the community adopt these new resources and standards. The proposed system will help accelerate neurophysiological discoveries as well as reproducibility studies.

Objective, MRI biomarkers for pre-symptomatic detection of autism spectrum disorder at 6 months old: commercial software development and optimization Bower, Bradley PRIMENEURO, INC. 2018 PAR-18-501 Active
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Magnetic Resonance Imaging (MRI) technology is being used to identify biomarkers in the central nervous system of children 6 months of age with Autism Spectrum Disorder (ASD). A potential promising group of biomarkers include data derived from both structural and functional MRI data acquired on infants. Dr. Bower’s group seeks to translate existing academic clinical research into a commercial product for potential clinical adoption by developing software that is a single, integrated, easy-to-use solution for MRI data collection, processing, and analysis for objectively evaluating a young child’s risk for ASD.

OpenNeuro: An open archive for analysis and sharing of BRAIN Initiative data Poldrack, Russell A Stanford University 2018 RFA-MH-17-255 Active
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To leverage the public investment in the BRAIN Initiative, the sharing of data produced by its myriad projects is paramount. Dr. Podrack’s project extends the recently released OpenNeuro, which was developed based on the well-established and successful OpenfMRI, for an archive of neuroimaging data. The extended archive encompasses a broader range of neuroimaging data including EEG, MEG, diffusion MRI and others. The archive also implements easy-to-use data submission, semi-automated curation and advanced data processing workflows, which run directly on the cloud platform. The archive allows to share the results alongside the data, federate with other relevant repositories, and accessible to all researchers.

Optogenetic signaling inhibitors for studying brain plasticity Gan, Wenbiao Yasuda, Ryohei (contact) Max Planck Florida Corporation 2016 RFA-MH-16-775 Active
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Although the mechanisms underlying synaptic and behavioral plasticity have been widely studied, understanding spatiotemporal aspects of signaling activity via pharmacological or genetic manipulations remains limited. With their group, Yasuda and Gan will develop a new technique based on genetically encoded, cell-specific, light-inducible kinase inhibitors to improve spatiotemporal resolution of signaling required for synaptic plasticity in vivo. With this technique, they will modulate the activity of various kinases to identify the spatial and temporal window of learning-related dendritic spine turnover, including the consequences on behavioral performance post-learning.
PARALLEL ANALYSIS OF TRANSCRIPTION AND PROTEIN-DNA INTERACTIONS IN SINGLE CNS CELLS Dougherty, Joseph D (contact) Mitra, Robi D Washington University 2018 RFA-MH-17-220 Active
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The brain consists of hundreds of molecularly, physiologically, and anatomically distinct cell types. Recently-developed methods can measure gene expression in tens of thousands of single cells, to help identify and classify many new types of brain cells. However, existing technologies capture only one aspect of gene regulation – mRNA levels. Dougherty’s team will develop a method to enable the parallel analysis of transcription factor binding and mRNA expression levels in mice to create single-cell Calling Cards, generating novel data and analysis tools. If successful, this project would contribute to neuroscience by providing a broadly useful technology for understanding brain function and development, in health and disease.

Prosthetic System for Large-Scale Recording and Manipulation of Neural Circuit Activity in Non-Human Primates Goodell, Albert Baldwin Graymatter Research 2017 PAR-15-091 Active
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Though current implantable devices which can record neuronal activity in awake, behaving animals exist, Goodell and colleagues seek to increase the size and number of brain circuits that can be both measured and manipulated long-term. The group plans to engineer and implement a system that can control hundreds of implanted electrodes to record activity from cells at any location in the brain of non-human primates, and will couple this advancement with optogenetic technologies to control neuronal firing as well. These experiments, when applied to behaviors like visual discrimination, would dramatically enhance the ability of researchers to systematically map and characterize cortical function.

RAVE: A New Open Software Tool for Analysis and Visualization of Electrocorticography Data Beauchamp, Michael S Baylor College Of Medicine 2018 RFA-MH-17-257 Active
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Electrocorticography (ECOG) allows the direct recording of a small population of neurons in human subjects, generating vast amounts of data. Dr. Beauchamp plans to develop the software RAVE (R Analysis and Visualization of Electrocorticography data) to help researchers explore such datasets. Incorporating established and successful informatics approaches that enable standardization, sharing, and re-use of neurophysiology data and analyses, RAVE includes rigorous statistical methodologies and seamless integration with existing analysis platforms. To facilitate user adoption and maximize impact, the developers plan to release RAVE 1.0 to the entire ECOG community within 6 months of the project start.

Realization of Optical Cell-based Reporters for in vivo Detection of Neuropeptides Kleinfeld, David Slesinger, Paul A (contact) Icahn School Of Medicine At Mount Sinai 2016 RFA-MH-16-775 Active
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Essential neuromodulators in the brain, neuropeptides control cognition and sensorimotor processing, but little is understood about when and where neuropeptides are released. Kleinfeld and colleagues developed new cell-specific fluorescent engineered reporters (CNiFERs) to optically image neurotransmitter release in real-time in vivo. The team will further develop and validate this technique for several neuropeptides, including orexin, somatostatin, and vasoactive intestinal peptide. Altered neuropeptide signals can contribute to brain dysfunction, and the expansion of this new tool will allow researchers to measure this signaling in the brains of awake, behaving animals, facilitating our understanding of complex behaviors and mental illness.
Recombinant Immunolabels for Nanoprecise Brain Mapping Across Scales Trimmer, James UNIVERSITY OF CALIFORNIA AT DAVIS 2018 RFA-NS-18-005 Active
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Studying how the brain works from the molecular to the circuit level is crucial for improving our understanding of how the brain functions normally, and what goes wrong in various disorders. Antibody probe techniques are effective tools that work at both of those levels. This project will develop a collection of validated, recombinant antibodies that are also highly renewable. In addition, antibodies will be miniaturized to increase binding efficiency and improve labeling precision. These resources will provide a cutting-edge, validated set of research tools to enable neuroscience research across a variety of resolutions from the intracellular to the neuronal network level.

Remote regulation of neural activity Stanley, Sarah Amy Rockefeller University 2014 RFA-MH-14-216 Complete
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The Stanley team will focus on the development of tools to instantly and precisely target cell activity deep in the brain using radio waves, nanoparticles and genetically modified viruses.
Repetitive transcranial ultrasound stimulation for modulating brain rhythms Dmochowski, Jacek City College Of New York 2018 RFA-DA-17-022 Active
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Neural oscillations, which are temporal activity patterns in the brain, are recognized as fundamental to the brain’s information processing. Dmochowski and colleagues will evaluate the safety and efficacy of a new form of transcranial ultrasound stimulation (TUS), in which ultrasonic waves will modulate the activity of neural circuits with enhanced precision and specificity (on the order of millimeters). The team will determine whether TUS could be used to modify neural oscillations. This research may contribute foundational knowledge needed for development of new, non-surgical, ultrasonic treatments for disorders associated with abnormal brain rhythms, such as schizophrenia, Parkinson’s, and epilepsy.
Resource for Multiphoton Characterization of Genetically-Encoded Probes Drobizhev, Mikhail MONTANA STATE UNIVERSITY - BOZEMAN 2018 RFA-NS-18-005 Active
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Two-photon microscopy has emerged as a key technique for studying the activity of living neural networks. However, little optimization has been performed for the associated fluorescent activity probes and sensors. Dr. Drobizhev’s research group will create a resource at Montana State University to characterize the properties of two-photon probes and make that service available to the broader research community. Given increased used of this type of resource by BRAIN Initiative investigators, the research group will also organize meetings to help other labs develop their own characterization processes.

Revealing circuit control of neuronal excitation with next-generation voltage indicators Clandinin, Thomas Robert Lin, Michael Z. (contact) Stanford University 2017 RFA-MH-17-220 Active
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Recording real-time electrical impulses of individual neurons across multiple cells and with subcellular resolution will enable detailed understanding of neural information processing. When circuity is altered in animal models of neuropsychiatric and substance use disorders, this understanding could help explain pathogenesis and suggest treatments. Lin and colleagues will engineer brighter, more sensitive genetically-encoded voltage indicators (light-emitting proteins that report changes in membrane potential) and develop new two-photon imaging methods to determine how specific inputs affect the electrical activity of specific postsynaptic neurons deep within living fly and mouse brains. This project may open up in vivo two-photon imaging of GEVIs to researchers, potentially transforming how we measure neuronal responses in the brain.
Revealing the connectivity and functionality of brain stem circuits Berg, Darwin K Deschenes, Martin Freund, Yoav Shai Goulding, Martyn D Kleinfeld, David (contact) Knutsen, Per M University Of California San Diego 2014 RFA-NS-14-009 Complete
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Dr. Kleinfeld and his colleagues will use a variety of tools and techniques to create detailed maps of circuits in the brainstem, the region that regulates many life-sustaining functions such as breathing and swallowing, and match the circuits to actions they control.
SABER: Scalable Analytics for Brain Exploration Research using X-Ray Microtomography and Electron Microscopy Gray Roncal, William R Johns Hopkins University 2017 RFA-MH-17-257 Active
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Neuroimaging techniques are advancing at a rapid rate, resulting in high resolution images of brain tissue and large datasets that can be difficult to manage. William Gray Roncal’s team propose an integration framework called SABER: Scalable Analytics for Brain Exploration Research. With a focus on techniques (e.g., electron microscopy) that produce high resolution brain images, SABER will create a unified framework by which these data types are accessible to a broader audience, can be processed in a reproducible, portable way, and can be scaled from small data volumes to large datasets. SABER has the potential to enable discoveries from high-resolution imaging techniques, making the parsing of entire brains a new reality.

Sparse, Strong and Large Area Targeting of Genetically Encoded Indicators Antic, Srdjan D (contact) Knopfel, Thomas University Of Connecticut Sch Of Med/dnt 2015 RFA-MH-15-225 Complete
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Electrical signals are the primary means of information processing in the brain. Recordings of electrical signals are a key means of discovering neuronal function. Genetically encoded voltage indicators (GEVI) embedded in neurons can convert electrical signals into optical signals that can be captured by powerful cameras, providing a means for observing neural activity from large populations of cells simultaneously. However, the GEVI-produced optical signals from neighboring neurons blend together and are difficult to separate. Antic and Knopfel will utilize a method for targeting GEVIs sparsely, making it possible to resolve the optical signals coming from a smaller population of individual cells.
Split RNA polymerases for sensitive, multidimensional analysis of intercellular PPIs at synapses Dickinson, Bryan (contact) Ozkan, Engin University Of Chicago 2017 RFA-MH-17-220 Active
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Deciphering the complexities of brain structure and function requires full understanding of intercellular protein-protein interactions (PPIs). Connections between neurons and other cells of the brain are orchestrated by thousands of diverse PPIs, but current methods are insufficient for studying multiple PPIs simultaneously. Dickinson and colleagues will develop new split RNA polymerase (RNAP) biosensors, capable of detecting at least four simultaneous PPIs, with novel super-resolution imaging. Because nucleic acid amplification technologies afford signal amplification and the ability to use multiple different RNAPs, RNAP-based detection could promise substantially improved sensitivity. Co-culture experiments employing primary neurons and engineered reporter cells will validate the approach. This work will initiate a new approach to probing intercellular interactions that guide synapse formation and brain signaling.
Sub-micrometer x-ray tomography for neuroanatomy Jacobsen, Chris Johnson (contact) Kording, Konrad P. Northwestern University 2015 RFA-MH-15-225 Complete
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Understanding how the human brain works and how it can be healed in case of disease is heavily dependent on progress in anatomy. Jacobsen and Kording, working with researchers at Argonne National Lab, will develop a novel and powerful tool using synchrotron-based x-ray tomography to produce ultra-fine scale anatomical maps of whole mouse brains, with the possibility of scaling up the technology to study human brains. This tool will enable better research on brain anatomy and its relationship to diseases of the brain, such as Alzheimer's, schizophrenia and autism.
SYNPLA: A scaleable method for monitoring circuit-specific learning-induced changes in synaptic strength Malinow, Roberto Zador, Anthony M (contact) Cold Spring Harbor Laboratory 2015 RFA-MH-15-225 Complete
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Learning and memory are made possible in part by a phenomenon called long-term potentiation (LTP)—the strengthening of a synapse resulting from increased firing between two neurons. To study LTP, Zador and Malinow are developing a technique they call SYNPLA, a specific, high-throughput method for marking the emergence of LTP with single synapse resolution. By attaching a fluorescent tag to a specific subtype of glutamate receptor (GluA1), which gets inserted into recently activated synapses, SYNPLA gives the researchers a way to visualize the onset of certain forms of LTP at many synapses simultaneously.
Taking DISCO Live: Dual pathway Imaging of Striatal Circuit Output in vivo Calakos, Nicole Duke University 2018 RFA-DA-17-022 Active
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Physicians currently use therapies that satisfactorily target the basal ganglia to treat movement disorders, but more effective treatments elude clinical implementation due to major gaps in our understanding of functional principles for basal ganglia circuits. Calakos and colleagues will apply in vivo electrophysiological recording, optical activity imaging, and optogenetics to study plasticity of basal ganglia circuitry. The team will develop an approach to image striatal projection neuron activity in the basal ganglia in mice during the formation of a habitual behavior. They will then monitor and manipulate the relative timing-to-fire between two classes of striatal projection neurons and test the behavioral consequences. The knowledge and methodology gained from this project could help reveal new mechanisms for striatal plasticity, which may inform future therapeutic targets for movement and neuropsychiatric disorders.
Technology for functional study of cells and circuits in large postmortem brains ex vivo Sestan, Nenad Yale University 2018 RFA-MH-17-220 Active
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Studying neural circuitry and function is particularly challenging in the human brain due to ethical considerations and the overall inherent experimental intractability of postmortem tissue. Furthermore, many aspects of human neurobiology are not fully recapitulated in small animal models, and research in large mammals is hindered by cost and experimental difficulties. Sestan’s team will optimize and validate a first-in-class neurotechnology, BrainEx, for the restoration of molecular and cellular functions of the postmortem large mammalian brain to allow connectivity and circuit tracing in myriad regions, as well as functional imaging. They aim to achieve this in the porcine model, in which brain size, complexity, and physiology are highly similar to human brains. These studies could establish the groundwork for the potential translation of this technology for conducting studies in the postmortem human brain.

The Application of Generalized Linear Models to Calcium Imaging Data for Optimal High-Dimensional Receptive Field Estimation and Identification of Latent Network Dynamics Keeley, Stephen L Princeton University 2017 RFA-MH-17-250 Active
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Dr. Keeley plans to develop and make publically available an efficient and flexible statistical framework to guide analysis of calcium imaging data, extending researchers’ ability to track the activity of hundreds or thousands of neurons at various spatial scales.
The Brainstorm Project: A Collaborative Approach to Facilitating the Neuroethics of Bioengineered Brain Modeling Research Hyun, Insoo Case Western Reserve University 2018 RFA-MH-18-500 Active
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Organoids, grown in laboratory settings to resemble parts of the developing human brain, hold great potential for shedding light on human brain function and disease. Researchers are working to achieve key bioengineering advancements, including successful vascularization of brain organoids, generating the full complement of cell types present in a human brain, and recording and modulating neural activity in organoids. These anticipated advances in bioengineered human brain modeling research may raise ethical questions about the moral status of large, complex human brain organoids and ethical boundaries on manipulating increasingly realistic engineered brain models. In this project, Dr. Hyun will lead proactive ethical discussions among ethicists and the neuroscientists conducting this cutting-edge work to develop greater awareness and understanding of these ethical implications and to inform future management of ethical issues that may be unique to this novel area of brain research.

The role of patterned activity in neuronal codes for behavior Maunsell, John Hr University Of Chicago 2014 RFA-NS-14-009 Complete
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Dr. Maunsell's team will explore how large populations of neurons process visual information, using a newly developed light stimulation technique to induce brain cell activity in the visual cortex of mice.
Toward a human adult brain cell atlas with single-cell technologies Chun, Jerold Zhang, Kun (contact) University Of California, San Diego 2018 RFA-MH-17-210 Active
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Defining a complete cell atlas of the human brain, including a full molecular catalog of all its cell types and their spatial distribution, is a critical step toward understanding the human cognitive machine. Zhang’s team will expand on their previous efforts toward building a complete cell atlas of the whole human adult brain. They will systematically apply novel technologies for scalable, single-nucleus transcriptome sequencing, single-cell DNA accessibility assay, and in situ RNA imaging to MRI-scanned human brains, incorporating innovative computational approaches. If successful, the derived data will facilitate the study of molecular mechanisms underlying brain function and disorders, empowering the scientific community with a massive, readily accessible database of unprecedented scope.

Towards a Complete Description of the Circuitry Underlying Memory replay. Soltesz, Ivan University Of California-irvine 2014 RFA-NS-14-009 Complete
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Dr. Soltesz's team will combine computer brain modeling and large-scale recordings of hundreds of neurons to understand how the brain generates sharp-wave-ripples, a neuronal activity pattern essential for learning and memory.
Towards integrated 3D reconstruction of whole human brains at subcellular resolution Chung, Kwanghun Massachusetts Institute Of Technology 2018 RFA-MH-17-210 Active
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Dr. Chung’s team aims to build a three-dimensional proteomic atlas of cells and neural circuits of human brains. To do this, his team plans to develop indestructible and transparent hydrogel-tissue hybrids for multi-rounds of protein labeling and imaging at subcellular resolution. They will stain the tissue via a variety of cellular and molecular labeling techniques and then use automated imaging to visualize different brain cell types, nerve fibers and synapses. The team will also create a supercomputing cloud- based framework and algorithms to analyze petabytes of high-resolution image data. This three- dimensional human brain atlas could give researchers a rapid, low cost way to discover brain cell types and the circuit problems behind neurological and neuropsychiatric disorders.

Tracing Brain Circuits by Transneuronal Control of Transcription Hong, Elizabeth Jennifer Lois, Carlos (contact) Zinn, Kai G California Institute Of Technology 2015 RFA-MH-15-225 Complete
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Faulty wiring of brain circuits during development could underlie the progression of many neurological diseases, such as schizophrenia and autism. Lois and colleagues propose the development and validation of a new genetically encoded system to trace brain circuits by trans-synaptic control of gene transcription. In this system, neurons expressing an artificial molecule ("emitter" neurons) activate an engineered receptor on their synaptic partners ("receiver" neurons), triggering the expression of fluorescent proteins in both partners. High-resolution imaging of the fluorescent labels will allow researchers to track the synaptic partners and other neurons in the circuit.
Ultra-Multiplexed Nanoscale In Situ Proteomics for Understanding Synapse Types Bathe, Mark Boyden, Edward S. (contact) Yin, Peng Massachusetts Institute Of Technology 2014 RFA-MH-14-216 Complete
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Dr. Boyden's team will simultaneously image both the identities and locations of multiple proteins within individual synapses – made possible by a new technique called DNA-PAINT.
Vertically integrated approach to visual neuroscience: microcircuits to behavior Euler, Thomas Huberman, Andrew D Meister, Markus Seung, Hyunjune Sebastian (contact) Wong, Rachel O Princeton University 2014 RFA-NS-14-009 Complete
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Dr. Seung and colleagues Thomas Euler (U Tübingen), Andrew Huberman (UC San Diego), Markus Meister (Caltech), and Rachel Wong (UW Seattle) will use state-of-the-art genetic, electrophysiological, and imaging tools to map the connectivity of the retina, the light-sensing tissue in the eye. The goal is to delineate all the retina's neural circuits and define their specific roles in visual perception and behavior.