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Notice of Special Interest: Neuro-Glia Mechanisms Governing Complex Behaviors

National Institutes of Health

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.

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

NOT-MH-22-090