Key Dates

Related Announcements

• December 20, 2024 - Notice of Special Interest (NOSI): AI/ML in Pre-Clinical Drug Development for Psychiatric Disorders. See Notice NOT-MH-25-050.
• December 18, 2024 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed). See NOFO PA-25-301.
• December 18, 2024 - NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed). See NOFO PA-25-302.
• December 18, 2024 - NIH Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required). See NOFO PA-25-303 
• December 18, 2024 - NIH Research Project Grant (Parent R01 Clinical Trial Required, Mechanistic Studies Only). See NOFO PA-25-305.
• December 18, 2024 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required). See NOFO PA-25-307.
• November 26, 2024 - Academic Research Enhancement Award for Undergraduate-Focused Institutions (R15 Clinical Trial Not Allowed). See NOFO PAR-25-134.
• November 21, 2024 - Novel Assays to Address Translational Gaps in Treatment Development (UG3/UH3 Clinical Trial Optional). See NOFO PAR-25-034.
• November 18, 2024 - Cellular and Molecular Biology of Complex Brain Disorders (R21 Clinical Trial Not Allowed). See NOFO PAR-25-037.
• November 18, 2024 - Cellular and Molecular Biology of Complex Brain Disorders (R01 Clinical Trial Not Allowed). See NOFO PAR-25-038.
• May 26, 2022 - Silvio O. Conte Centers for Basic Neuroscience or Translational Mental Health Research (P50 Clinical Trial Optional). See NOFO PAR-22-155.
• May 10, 2021 - Joint NINDS/NIMH Exploratory Neuroscience Research Grant (R21 Clinical Trial Optional). See NOFO PA-21-219.

Issued by

National Institute of Mental Health (NIMH)

Purpose

Overview:

This Notice of Special Interest (NOSI) encourages computational approaches in fundamental neuroscience research investigating the molecular and cellular mechanisms that drive the structure and function of cells and circuits supporting cognitive, affective, and social domains, in both health and mental illness, during early development and across the lifespan.

Background

The investigation of molecular and cellular mechanisms in complex neural systems had been challenging, partly due to technical limitations in acquiring data with high spatiotemporal resolution.  However, recent technological developments bring the promise of accelerated scientific discovery. New molecular manipulation and imaging technologies have been developed that yield large datasets with high cellular, spatial, and temporal precision. These techniques are being employed to investigate how various molecular and cellular processes within and between neurons and glia contribute to behavior and provide rich and complex datasets. However, the challenge of integrating these datasets into a single coherent picture still impedes progress. Rigorous computational approaches to data synthesis can address this challenge and generate testable predictions to support or refute hypotheses about underlying mechanisms, producing an integrated view. Additionally, they enable testing many conditions while simultaneously controlling other parameters, avoiding the inherent variability in biological experiments.

Utilization of both novel experimental and analytic tools can begin to model the complex spatiotemporal interactions between receptors, ion channels, enzymes, and other signaling intermediates. This integrative approach will enable hypothesis testing and generate new fundamental knowledge about dynamic molecular and cellular processes governing learning, memory, and emotions, and their regulation during neurodevelopment and across the lifespan. It has the potential to significantly advance the understanding of mental illness and may uncover new therapeutic strategies.

Research Objectives

This NOSI invites rigorous, hypothesis-driven studies that integrate the development of biophysically based models of neuronal and glial processes with an experimental component to test model predictions. Use of precise, state-of-the-art experimental techniques that offer high spatial and/or temporal resolution of molecular and cellular processes, as well as advanced methods to manipulate these processes, is encouraged. This NOSI supports studies conducted in vitro, ex vivo, and in vivo toward the goal of uncovering mechanistic links across biological scales.To promote this interdisciplinary research, collaborations between investigators with complementary theoretical/computational and experimental expertise are essential. These partnerships can drive innovative research and address scientific and technical challenges that might be intractable otherwise.

Examples of recent technological developments include, but are not limited to:

• New tools for super-resolution microscopy to observe subcellular structures at near molecular-scale resolution.
• Tools for direct detection of neuromodulators, neuropeptides, and other genetically encoded sensors with high sensitivity, specificity, and spatiotemporal resolution to track these effectors both in vitro and in vivo.
• Pharmacological and genetic (e.g., optogenetics, photopharmacologic) tools to manipulate the expression and function of specific molecules in a manner that targets specific subcellular domains or cell types.

Examples of recent computational tools include, but are not limited to:

• Multi-compartment or micro/nano-domain models of cellular morphology and signal transduction.
• Spatial model of cellular architecture.
• Physiologically-based kinetic modeling of time-dependent cellular states such as postsynaptic currents.
• Stochastic models to simulate molecular processes.
• Machine learning and artificial intelligence algorithms.

Applicants are encouraged to include:

• Integration of computational and experimental approaches, where the development of a computational model is based on either publicly available reference data (e.g., PsychENCODE, BICCN, data archives), previously unpublished data, or data that will be generated as part of the proposed study, and to propose to experimentally test predictions made by the model.
• Interdisciplinary collaboration between scientists with complementary expertise.
• Applications submitted under R15 or R03 mechanisms that are based only on existing experimental data are encouraged to incorporate independent existing experimental datasets for model development, validation, and prediction testing. Additionally, PIs are strongly encouraged to provide a letter of support from an experimental neuroscientist.

Specific Areas of Research Interest under this NOSI

Applications submitted under this NOSI will utilize computational approaches to address a range of scientific research areas, from fundamental research across the spectrum of health and mental illness and throughout development to investigating the mechanism of action of novel therapeutic approaches. Research may include, but is not limited to:

• Investigating the contribution of intrinsically disordered regions (IDRs) of protein structure and their interplay with structured domains to protein functional versatility and neural circuit function.
• Utilizing structural models of proteins to predict sequence-structure-function relationships and interactions with other biomolecules (e.g., receptor-ligand interactions, protein transfer through the cell membrane and across the blood-brain barrier).
• Elucidating the impact of one or more specific biomolecule(s) on downstream pathways and the effects of dysfunction of these molecules on cells and circuit function.
• Mechanistic insights into spatiotemporal dynamics of molecular and cellular processes in microglia and astrocytes, as well as those in neuron-glia signaling, and how such processes affect on the cell’s intrinsic properties, function, and impact on signal transduction
• Elucidating the factors regulating cellular morphology and the impact of morphology on cell function and cell-cell/cell-environment interactions.
• Spatiotemporal dynamics and interaction between biomolecules at the synapse to elucidate mechanisms of synaptic transmission and synaptic plasticity.
• Developmental trajectories and dynamics across molecular and cellular scales, within and across animals. Studies can include the regulation of progenitor numbers in brain size control, combinatorial factors in fate specification, axon projections and connectivity, the relationship between synaptic input and dendritic structure, and changes in circuit function during development.
• The effects of high-confidence risk genes, genetic background, and/or environmental factors that increase disease susceptibility on molecular and cellular processes underlying neuronal and glial function.
• Elucidating the molecular and cellular processes impacted by potential therapeutic candidates and their relation to therapeutic efficacy. For fast-acting therapeutics of interest are processes directly impacted by the compound as well as mechanisms for sustained efficacy after the compound is metabolized. For further information, see NOT-MH-23-125.

Applications focused on utilizing artificial intelligence/machine learning for drug discovery are encouraged to review the research topics represented in NOT-MH-25-050.

Application and Submission Information

This notice applies to due dates on or after February 5, 2025, and subsequent receipt dates through May 10, 2028.

Submit applications for this initiative using one of the following Notices of Funding Opportunity (NOFOs) or any reissues of these announcements through the expiration date of this notice.

• PA-21-219 - Joint NINDS/NIMH Exploratory Neuroscience Research Grant (R21 Clinical Trial Optional)
• PAR-22-155 - Silvio O. Conte Centers for Basic Neuroscience or Translational Mental Health Research (P50 Clinical Trial Optional)
• PA-25-301 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
• PA-25-302 - NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed)
• PAR-25-034 - Novel Assays to Address Translational Gaps in Treatment Development (UG3/UH3 Clinical Trial Optional)
• PAR-25-037 - Cellular and Molecular Biology of Complex Brain Disorders (R21 Clinical Trial Not Allowed)
• PAR-25-038 - Cellular and Molecular Biology of Complex Brain Disorders (R01 Clinical Trial Not Allowed)
• PAR-25-134 - Academic Research Enhancement Award for Undergraduate-Focused Institutions (R15 Clinical Trial Not Allowed)
• PA-25-303 - NIH Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)
• PA-25-305 - NIH Research Project Grant (Parent R01 Clinical Trial Required, Mechanistic Studies Only)
• PA-25-307- NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required)

All instructions in the SF424 (R&R) Application Guide and the notice of funding opportunity used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-MH-25-045” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applicants are strongly encouraged to contact NIMH Program staff when developing their applications to determine the alignment of the proposed work with NIMH programmatic priorities.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:

Scientific/Research Contact(s):

Yael Mandelblat-Cerf, Ph.D
National Institute of Mental Health (NIMH) 
Telephone: 301-793-7563
Email: Yael.Mandelblat-Cerf@nih.gov 
 

Enrique Michelotti, Ph.D
National Institute of Mental Health (NIMH) 
Telephone: 301-443-5415
Email: michelottiel@mail.nih.gov