BRAIN Initiative: New Technologies and Novel Approaches for Recording and Modulation in the Nervous System (R01 Clinical Trial Not Allowed)

RFA-NS-25-018

NOFO Overview and Requirements

This NOFO is related to the recommendations in section III of the BRAIN 2025 Report, with the goal to ‘produce a dynamic picture of the functioning brain by developing and applying improved methods for large-scale monitoring of neural activity'. Towards this end, the report calls for accelerated development of new and improved technologies for recording and manipulating neural activity at the level of cells and circuits.  These new technologies and approaches will provide unprecedented opportunities for exploring how the nervous system encodes, processes, utilizes, stores, and retrieves vast quantities of information. A better understanding of this dynamic neural activity will enable researchers to seek new ways to diagnose, treat, and prevent brain disorders.

This NOFO is part of a suite of RFAs representing different stages of technology development spanning early proof-of-concept and technology validation through optimization and dissemination, as well as studies aimed at understanding the biological and biophysical mechanisms of neural signals and their modulation (for more information, see https://braininitiative.nih.gov/brain-programs/technology-development). 

This NOFO seeks applications for proof-of-concept testing and development of new technologies and novel approaches for recording and modulation of neural cells and circuits, to address major challenges and to enable transformative understanding of dynamic signaling in the central nervous system. Preliminary feasibility data are not required, and it is expected that the proposed research may be high-risk, but if successful could profoundly change the course of neuroscience research. 

Applications may propose development of instrumentation hardware and/or devices and associated software, and/or molecular constructs for sensing and manipulating neural activity.  Approaches may utilize any modality such as optical, electrical, magnetic, or acoustic recording/manipulation, to target neuronal electrical signals or other forms of neural activity, including intracellular signaling and engagement of non-neuronal cells in circuit function.

A companion NOFO (RFA-NS-25-017) is targeted to projects focused on optimization of instrumentation and devices that are later in the development cycle, where iterative optimization and end-user testing is needed.  The companion FOA does not allow projects primarily focused on development of molecular constructs for recording and manipulating neural activity.  Projects of this nature are supported by RFA-NS-25-018 (i.e., this NOFO) and other BRAIN Initiative announcements, including RFA-MH-22-245 (or its reissue), which is specifically focused on optimization of molecular technologies for functional dissection of neural circuits, as well as more general FOAs including RFA-MH-21-175, and RFA-EY-21-001 (or their reissue). 

For this and the companion NOFO, the aim of the proposed technologies should be to reduce major barriers to conducting neurobiological experiments, including considerations of cost and ease of access, and to enable new discoveries for understanding neural circuit function.  Technologies should address major challenges associated with recording and modulating CNS activity, at cellular or circuit resolution, and should contribute to an overall ecosystem of technologies spanning multiple spatial and temporal scales in any region throughout the CNS.  Precise cellular or circuit targeting may be attained via experimental design features such as genetic manipulation, in combination with the spatial resolution capabilities of the proposed technology. 

Applicants proposing non-invasive neuroimaging technologies (fMRI, PET, etc.) that are not expected to achieve cellular/circuit resolution (see “Applications Not Responsive to this NOFO” below) should consider the following BRAIN Initiative NOFO  (or its reissue):

RFA-EB-22-001, BRAIN Initiative: Transformative Brain Non-invasive Imaging Technology Development (UG3/UH3 Clinical Trial Not Allowed). 

The approaches should be compatible with experiments in behaving animals, with an expectation that they will be validated with in vivo experiments during the course of the project.  Proposed validation experiments must focus on demonstrating the capabilities and potential impact of the technology, rather than advancing the state of biological knowledge as the primary project goal. 

Applicants interested in applying new technologies to understand circuit function, rather than developing technologies, should consult the following website for a listing of relevant BRAIN FOAs: https://braininitiative.nih.gov/brain-programs/understanding-circuits. 

Applications are encouraged to integrate multiple approaches, and where appropriate, to leverage diverse domains of expertise from biological, chemical, and physical sciences, engineering, computational modeling, and statistical analysis.

NOFO Goals

Applications are expected to address any or all the following three general goals for the FOA:

1. Develop New Network Recording Capabilities

Recording dynamic neural activity from complete neural networks, over long periods, in any area of the brain is a challenging but essential goal. Advances in the exploration and development of new technologies for neuronal and non-neuronal cell recording, including methods based on electrodes, microelectronics/microchips, imaging, molecular genetics, and nanoscience are encouraged.

2. Develop Tools for Circuit Manipulation

The ability to activate and inhibit specific populations of neurons is key to understanding functional circuits. It will advance the scope of knowledge from observation of neural phenomena to a mechanistic understanding of neural causation. A new generation of tools for optogenetics, pharmacogenetics, biochemical, electromagnetic and/or acoustic modulation needs to be developed for use in animals, and potentially translated to humans, to enable the immense potential of circuit manipulation.

3. Link Neural Activity to Behavior

The goal of this FOA is to produce technologies with potential to elucidate central nervous system function in the context of complex behaviors. Proposed technologies should be compatible with experiments in behaving animals, with an expectation of in vivo validation during the course of the project. Novel approaches to link neural activity to specific behaviors, including computational and statistical tools, are encouraged. 

Applicants proposing technologies primarily focused on methods to quantify and interpret behavior should consider the following BRAIN Initiative NOFOS (or their reissue):

RFA-MH-22-240 BRAIN Initiative: Brain Behavior Quantification and Synchronization (R61/R33 Clinical Trial Optional)

RFA-DA-23-030 BRAIN Initiative: Brain-Behavior Quantification and Synchronization – Transformative and Integrative Models of Behavior at the Organismal Level (R34 Clinical Trial Not Allowed) 

Example Approaches

The following types of approaches are encouraged. Each bullet includes representative, but not exhaustive, examples.

Probes for Sensing and/or Modulation of Neuronal Activity In Vivo

• Probes for resolving changes in membrane potential, with high spatial and temporal resolution, from large numbers of neurons in behaving animals
• Probes for sampling or manipulating activity over a range of spatial and temporal scales in the same experiment, or for large-scale sampling/manipulation of cellular activity with simultaneous whole-brain activity measurements
• Probes for recording and/or manipulating diverse cell types simultaneously, with distinguishable readouts and interventions (e.g., probes responsive to different ranges of the energy spectrum)
• Probes for neural plasticity events, at the cellular or synaptic level (including genetic and epigenetic events), which underlie network adaptation and learning
• Probes for cellular or network modulatory states (e.g., as assessed by intracellular signaling cascades, or modulatory transmitter levels), which are major determinants of cellular and network responses to incoming information
• Probes for signaling at specific sets of nerve terminals, or by specific neurotransmitters with synaptic resolution, especially techniques/approaches that distinguish transmitters or classes of synapses from one another

Imaging Instrumentation for Recording and/or Modulation of Neural Activity with Cellular or Circuit Resolution In Vivo

• Optical imaging instrumentation with major increases in large-scale sampling capabilities, including frame rates sufficient to capture millisecond-scale signaling events, across full volumes of neural tissue rather than single focal planes
• New imaging modalities for less-invasive or non-invasive cellular-resolution imaging at tissue depths that are currently unavailable, such as structured imaging or adaptive strategies using spatial light modulation and/or wavefront sensing, photoacoustic wavefront shaping, backscattering and deconvolution strategies, or signal relay approaches
• Methods for simultaneous imaging of cellular resolution neuronal activity from multiple brain regions, or for large-scale sampling/manipulation of cellular activity with simultaneous whole-brain activity measurements

 Development of Electrodes for Recording and/or Circuit Modulation In Vivo

• Transformative technologies for simultaneous high-density recording and manipulation of neural activity from multiple brain regions (cortical, sub-cortical, deep-brain) in freely behaving animals
• Adaptable multi-functional platforms to enable new combinations of capabilities sufficient for large-scale recordings in vivo (e.g., combinations of electrical recordings, optical modulation, chemical sensing, and/or fluid delivery)
• Innovative new electrode concepts, delivery methods or biocompatible materials to dramatically reduce the invasiveness of acute or chronic electrode recordings
• Innovative methods to solve the impediments to effective day-to-day stability of single-unit recordings
• New in vivo electrical capabilities, such as chronic multi-unit intracellular recording, or high-density three-dimensional arrays across multiple spatial planes
• Strategies for integrating in vivo electrical recordings with other recording technologies, such as optical imaging and stimulation or high-field MRI

Techniques and Approaches for Recording/Manipulating CNS Activity during Behaviors

• New or improved miniaturized devices for head-mounted recording of neuronal and non-neuronal activity at cellular-resolution in freely behaving animals
• Innovative approaches for head-fixed recording or manipulation of neuronal and non-neuronal activity at cellular resolution, for ethologically robust behavioral analysis
• Innovative methods to transform neural signals into control signals
• In combination with concurrent development of large-scale technology for recording/manipulation, computational and statistical tools to analyze and model neural circuit activity underlying behavior and/or to affect systems of behavior

Application budgets are not limited but need to reflect the actual needs of the proposed project.

60 days prior to the receipt date.

June 02, 2025

Grace M. Hwang, PhD
Edmund (Ned) Talley, PhD
National Institutes of Neurological Disorders and Stroke (NINDS)
Email: BRAIN-FOAs@nih.gov