NIH – BRAIN Initiative: Development and Validation of Novel Tools to Probe Cell-Specific and Circuit-Specific Processes in the Brain (R01 Clinical Trial Not Allowed)

May 22, 2018 by School of Medicine Webmaster

The NIH BRAIN Initiative® is aimed at revolutionizing our understanding of the human brain. By accelerating the development and application of innovative technologies, researchers will be able to produce a new dynamic picture of the brain that, for the first time, will show how individual cells and complex neural circuits interact in both time and space. It is expected that the application of these new tools and technologies will ultimately lead to new ways to treat and prevent brain disorders.

NIH is one of several federal agencies involved in the BRAIN Initiative. Planning for the NIH component of the BRAIN initiative is guided by the long-term scientific plan, BRAIN 2025: A Scientific Vision, which details seven high-priority research areas and calls for a sustained federal commitment of $4.5 billion over 12 years. This FOA and other FOAs issued as part of the BRAIN initiative are based on careful consideration by the NIH of the recommendations of the BRAIN 2025 Report, and input from the NIH BRAIN Multi-Council Working Group. Videocasts of the NIH BRAIN Multi-council Working Group are available at

To enable rapid progress in development of new technologies as well as in theory and data analysis, the BRAIN Initiative encourages collaborations between neurobiologists and scientists from statistics, physics, mathematics, engineering, and computer and information sciences; NIH welcomes applications from investigators in these disciplines.

NIH encourages BRAIN Initiative applications from investigators that are underrepresented in the biomedical, behavioral, or clinical research workforce (see data at and the most recent report on Women, Minorities, and Persons with Disabilities in Science and Engineering). Such individuals include those from underrepresented racial and ethnic groups, those with disabilities, and those from disadvantaged backgrounds.

In addition to the National BRAIN initiative, the NIH continues to have a substantial annual investment in neuroscience research. The Institutes and Centers contributing to the NIH BRAIN Initiative ( support those research efforts through investigator-initiated applications as well as through specific FOAs. Potential applicants to this FOA are strongly encouraged to contact Scientific/Program staff if they have any questions about the best FOA for their research.

The BRAIN Initiative will require a high level of coordination and sharing between investigators to achieve its goals. While this FOA does not have substantial programmatic involvement and thus does not use a cooperative agreement mechanism, it is expected that BRAIN Initiative awardees will cooperate and coordinate their activities after awards are made by participating in Program Director/Principal Investigator (PD/PI) meetings and in other activities.

This FOA is related to the Recommendations in Section III.1 and 2 of the Final Report ( of the BRAIN working group. Specifically, this FOA solicits applications that will address the recommendations on “Discovering Diversity” and “Maps at Multiple Scales”, (Section III).

Research Objectives

This funding opportunity announcement (FOA) is designed to support development and validation of novel tools to facilitate the detailed analysis of cells and circuits and provide insights into the neural circuitry and structure underlying complex behaviors. The human brain consists of an estimated one hundred billion neurons and more than one trillion supporting glial cells that are uniquely organized to confer the extraordinary computational activities of the brain. Cell types are categorized by their anatomical position, neurotransmitter content, dendritic and axonal connections, receptor profile, gene expression profile and distinct electrical properties. Although the human brain has long been the focus of numerous studies with many major achievements along the way, to date we remain largely ignorant about the specific details such as cell types and connections that are responsible for rapid information processing. Defining cellular and circuit-level function is dependent on detailed knowledge about the components and structure of the circuit. Such knowledge, in turn, is fundamental to understanding how these features underlie cognition and behavior, which should aid in the development of targeted cell-type and circuit-specific therapeutics to treat brain disorders. This initiative is focused on developing tools (or vastly improving existing tools) to enable access to individual cells and defined groups of cells within neuronal circuits. The tools sought through this FOA can include novel genetic or non-genetic methods for targeted delivery of genes, proteins, and chemicals to specific cells or tightly defined cell types and circuits.

Development of novel tools that will delineate anatomical connections between cells and expand our knowledge of circuit architecture and function is an area well poised for additional investment. Several efforts are currently underway to study large-scale, long-range connections, such as the NIH Human Connectome Project, as well as large scale rodent connectional studies. Recent development of new technologies (e.g., CLARITY, expansion microscopy, MerFISH, and several other imaging breakthroughs) allow an unprecedented three-dimensional view into the post-mortem brain. While still at an early stage, these exciting technologies hold promise for mapping short- and long-range connections throughout the brain. Coupled with improved activity monitoring technologies in awake, behaving animals, these new tools promise an understanding of circuitry in action. Further development of these technologies is crucial to push the envelope beyond our current capabilities. To this end, applicants from the biological sciences are encouraged to establish collaborations with nanobiologists, material scientists, engineers and colleagues in other disciplines to develop groundbreaking approaches to study brain activity.

This FOA solicits applications to develop next-generation, innovative technologies to define and target specific cell types in the brain. Of particular interest are first-in-class and/or cross-cutting non-invasive or minimally invasive techniques that permit repeated measurements from cells over time in a non-destructive manner. Tools/technologies relevant for this initiative are expected to be transformative, either through the development of novel tools that may be high-risk or through major advances in current approaches that break through technical barriers and will significantly improve current capabilities. While an emphasis of the BRAIN initiative is the development of novel tools to study the brain, here we highlight the need for innovative approaches to bridge experimental scales. Studies that are able to explore molecular and cellular mechanisms of neural activity permitting improved precision and sensitivity in the analysis of micro-and macro-circuits are strongly encouraged. Progress in understanding how the activity of the brain translates to complex behaviors will be facilitated by non-invasive approaches for both monitoring and manipulating neural activity in awake, behaving organisms.

This FOA seeks applications in areas including, but not limited to:

  • Novel methods (non-genetic and genetic) to deliver active agents to specific neurons in particular neural circuits or brain areas with no or minimal cytotoxic effects.
  • Novel methods for tagging individual neurons such that cellular components of a functional circuit can be explored.
  • Novel trans-synaptic tracers that can be used both at the electron- and light-microscopy level.
  • Innovative approaches to reduce the time and cost of determining high resolution synaptic connectivity by electron microscopy or other approaches.
  • Significantly improved viral-mediated gene delivery that targets specific cells or cell types in the nervous system.
  • Innovative ways to use multiple vectors to deliver ?split? gene products to limit and/or control expression in specific cell types.
  • Novel, transgenic methods in multiple model species to allow more refined cell-specific and circuit-specific manipulation.
  • Chemical or genetic engineering of blood brain barrier-crossing carrier agents (such as tagged antibodies or other tools) to allow delivery of specific cargoes (e.g., neuronal activity, effectors, tracers or sensors) to specific cells or circuits.
  • Novel methods for non-invasive targeted access to, or manipulation of, distinct cell types in defined circuits with spatio-temporal control.
  • Novel trans-synaptic tracers that can work in retrograde and anterograde direction or deliver cargoes to cells in the nervous system.
  • Enhanced temporal and spatial resolution techniques for noninvasive molecular imaging of neuronal cells for in situ brain studies.
  • Unique combinations of tools for multiplex analysis and/or manipulation of single cells in situ to maximize data content over many parameters (e.g., RNAs, proteins, metabolites, organelles, electrochemical dynamics, signal secretion/reception/transduction, cytoarchitecture or migratory changes).
  • Innovative tools that provide significant advances in sensitivity, selectivity or spatiotemporal resolution of molecules/structures/activities within single cells in the brain and between ostensibly similar cells in situ (e.g., high resolution imaging of molecular interactions within single cells).
  • Novel automated and scalable assays for high-throughput analysis of single cells in situ in the brain, including scalability of measured parameters in parallel, cell numbers and/or speed of processing.
  • Unique systems-level single cell computational approaches to help define functional cell types and circuitry.
  • New tools and approaches that minimize tissue and cell perturbations so that cell viability is maintained, allowing for multiple repeated measures in the same cell over time.
  • Development of in situ sequencing using FISH and other sequencing methodologies.
  • Novel methods for visualizing or manipulating epigenomic marks or gene expression in neural cells.
  • Novel computational approaches to analyze and integrate multi-scale datasets to better understand brain function.
  • Innovative approaches to bridge scales of experimental approach. Studies that are able to explore molecular and cellular mechanisms of neural activity in broader contexts are encouraged.
  • Novel techniques for integrating micro-scale connectivity data (e.g., by electron microscopy) with cellular or synaptic phenotypic information.
  • Innovative molecular complementation methods to identify synaptic connections and determine their phenotypes.
  • Novel uses of super-resolution light microscopic approaches for identifying synaptic connections and mapping micro-circuits.
  • Development of cell type-specific molecular sensors and additional tools and approaches to address circuit-specific manipulation and monitoring.

Deadlines:  September 27, 2018; September 6, 2019; September 9,2020 (the FOA lists a single deadline for letters of intent [August 27, 2018], but these are usually due 30 days before a deadline; check with program officials if applying to 2019 or 2020 deadlines)


Filed Under: Funding Opportunities