Neuron-Glia Computations Governing Complex Behaviors

Presenter:

Michele Ferrante, Ph.D.
Division of Neuroscience and Basic Behavioral Science and
Division of Translational Research

Goal:

The goal of this concept is to facilitate behavioral systems-level neuroscience research on neuron-glia interactions. There are major gaps in the understanding of how neuron-glia interactions enable complex behavior. Recent developments in biotechnology and computational approaches have primed the nascent systems-level neuroscience field to explore neuron-glia computations governing complex behaviors. This concept encourages collaborative projects testing mechanistic hypotheses on the role of neuron-glia activity coupling modulating cognitive, affective, and social behaviors. While neural dysfunction is known to contribute to psychiatric disorders, glial disruptions have also been implicated. Thus, understanding how systems-level neuron-glia processes contribute to mental health behaviors might have a high translational impact.

Rationale:

The human brain regulates complex behavior by processing information across ~170B cells (~86B neurons and ~84B glial cells). The physiological properties of the three primary glial cell types (astrocytes, oligodendrocytes, and microglia) coupled with those of neurons could explain behavioral processes happening across many spatio-temporal scales. For example, astrocytes may couple neurons into functional assemblies by releasing gliotransmitters that may regulate short-/long-term plasticity, possibly involved in memory encoding. Oligodendrocytes regulate myelin and may affect action potential conduction, neuronal spike timing, and behaviorally relevant oscillations. Finally, microglia prune synapses in an activity-dependent manner that may alter behaviorally activated neural networks over long time scales.

Studying how neuron-glia activity coupling affects complex behavior has been challenging in part because of some technical barriers. For example, until recently, we 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 astrocyte activity. Tools are also available for selectively stimulating and silencing astrocyte Ca2+ signaling in vivo (e.g., designer receptors exclusively activated by designer drugs (DREADDs) and optogenetics). In parallel, basic behavioral neuroscience is rapidly advanced by experimentally grounded, system-level approaches and technologies, including computational modeling. Using these integrative approaches to examine glial functions could provide new perspectives on how the brain governs complex behavior. Combining newly developed experimental methods for neuronal and glial recording/manipulation with rigorous computational approaches may inform mechanistic models of how neuron-glia interactions may enable encoding important mental health functions (e.g., working memory, emotion regulation, social behaviors, higher-level executive functions).