Purpose

Background and Rationale

This Notice of Special Interest (NOSI) encourages projects to experimentally test mechanistic hypotheses on the role of neuro-glia activity coupling in modulating complex behaviors. The human brain regulates complex behavior by processing information across ~170 billion cells, including ~86 billion neurons and ~84 billion glial cells. The influence of glial cell types (i.e., astrocytes, oligodendrocytes, and microglia) on neural activity may explain behavioral processes across broad spatio-temporal scales and hierarchies. For example, astrocytes may regulate cognitive functions by releasing gliotransmitters that activate hundreds of neuronal synapses at once, regulating system-level short-/long-term plasticity. Activity changes in neuro-oligodendrocytes networks may dynamically regulate myelin axon-sheathing, which in turn may affect action potential conduction, neuronal spike timing, and oscillations linked to cognitive/social/affective processes. Finally, microglia activity-dependent synaptic pruning may alter behaviorally activated neural networks over long time scales. Discovering how mechanistic dysfunctions in neuro-glia interactions may alter behavioral phenotypes relevant to mental health is a challenge with potentially high translational impact.

Studying how neuro-glia activity coupling affects complex behavior has been challenging in part due to technical barriers. For example, until recently, the field lacked reliable and selective tools to manipulate glial cells. Biotechnology is now expanding the range of possible investigations into glial function by providing new methods necessary to record and manipulate glial cells with mouse lines and viral methods expressing designer reporters, sensors, and actuators of glial activity. Advances in metabolic imaging and genetically encoded activity measurements allow for simultaneous observation of interactions in neurons and glial activity. Tools are also available for selectively stimulating and silencing glia cells’ calcium signaling in-vivo through designer receptors exclusively activated by designer drugs (DREADDs) and optogenetics.

In parallel, basic behavioral neuroscience has been rapidly advanced by integrating system-level neurotechnology with computational modeling. Computational models (e.g., reinforcement learning, drift-diffusion, Bayesian, biophysically realistic, dynamical systems, and deep neural networks) have directly linked behavioral parameters and the neural substrates that compute them, but the role of non-neuronal cells in these computations have been largely ignored. Thus, the integration of computational modeling approaches to investigate neuro-glia interactions could provide new perspectives on how they enable complex behavior and how they become altered in mental illnesses. Combining newly developed experimental methods for recording and controlling neuro-glia activity with rigorous computational approaches may inform mechanistic models of how neuro-glia interactions may compute or fail to compute cognitive and socio-affective functions relevant to neuropsychiatric disorders.

Responsive Areas of Research

Examples of research areas that may be included in applications submitted under this NOSI include, but are not limited to, the application of existing or novel:

• Experimental methods to measure or control glial activity in behaving animals to elucidate the role of neuro-glia activity in cognitive or socio-affective behaviors.
• Biologically inspired computational approaches to provide a mechanistic explanation of the consequences of neuro-glia interactions during cognitive or socio-affective behaviors.
• Computational models able to map fine-grained cognitive or socio-affective behavioral parameters onto neuro-glia computations.
• Neuro-glia computational principles or mechanistic knowledge derived from animal experiments in Basic Experimental Studies Involving Humans (BESH).

Applications must include both:

• A well-conceived scientific rationale, question, and/or hypothesis grounded in cognitive or socio-affective science, where neuro-glia activity may mechanistically explain a complex behavior.
• Measurement or control neuro-glia activity during complex behavior. Applications proposing to exclusively investigate the effects of glial cells on behavior will be considered responsive to this NOSI, but applications including measurement and/or manipulation of both glia and neurons will be given higher priority.

Applications Not Responsive to this NOSI

• Applications that do not include all the items contained in the “applications must include” section above are not responsive to this NOSI and will not be reviewed.
• Applications exclusively focused on in-vitro preparations - without an in-vivo behavioral component - are not responsive to this NOSI and will not be reviewed.
• Applications proposing to apply animal models of mental disorders or use broad batteries of behavioral tests in animals to address constructs that are accessible only in humans by self-report, such as “depression” or “anxiety,” are non-responsive to this NOSI. For additional information on NIMH’s guidelines and priorities for animal neurobehavioral approaches applicants are strongly encouraged to review NOT-MH-19-053.

Note: NIMH only accepts mechanistic studies that meet NIH's definition of a clinical trial through PA-20-183 and PA-20-184. Applications directed to NIMH for intervention development must be submitted through PAR-21-130. For further information on NIMH clinical trial policies, see NOT-MH-20-105 and NOT-MH-19-006.

Application and Submission Information

This notice applies to due dates on or after June 5, 2022 and subsequent receipt dates through May 8, 2025. 

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

• PA-20-184 - Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)
• PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
• PA-20-196 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required)
• PA-21-219 - Joint NINDS/NIMH Exploratory Neuroscience Research Grant (R21 Clinical Trial Optional)
• PA-21-235 - NIMH Exploratory/Developmental Research Grant (R21 Clinical Trial Not Allowed)
• PAR-21-175 - Understanding and Modifying Temporal Dynamics of Coordinated Neural Activity (R01 Clinical Trial Optional
• PAR-21-176 - Understanding and Modifying Temporal Dynamics of Coordinated Neural Activity (R21 Clinical Trial Optional)

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

• For funding consideration, applicants must include “NOT-MH-22-090” (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.

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 funding opportunity announcements with the following additions/substitutions:

Scientific/Research Contact(s)

Michele Ferrante, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-435-6782
Email: ferrantem@nih.gov

Andrew Breeden, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-1576
Email: andrew.breeden@nih.gov