Causes and consequences of microglial regional specialization within basal ganglia circuits.
Microglia are dynamic, macrophage-like cells within the CNS. In disease and injury contexts, they undergo dramatic changes in cell phenotype that result in powerful neuroprotective and/or neurotoxic effects. In the healthy brain, microglia remove cellular debris and pathogens from surrounding tissue and can modulate both neuronal membrane properties and synapses, positioning these cells as key contributors to both physiological and pathological circuit function.
Microglia are not equivalent throughout the brain and exhibit specialized phenotypes in different nuclei of the basal ganglia (BG), circuits involved in reward and motivation. We know almost nothing about the potential impact of this regional microglial variation on function and resilience of surrounding neurons. Work in the De Biase lab focuses on three overarching questions: 1) How does microglial variation impact synaptic function of BG neurons and associated reinforcement-driven behaviors? 2) How does basal phenotype shape microglial injury responses and influence susceptibility of BG neurons to damage? 3) What regulatory cues instruct basal phenotypes of BG microglia? We pursue these questions using multiple technical approaches including slice electrophysiology, advanced imaging, and molecular biology.
An overarching goal of this research program is to promote innovative approaches to treating CNS circuit dysfunction and disease. Microglia are ubiquitous, capable of self-renewal, highly plastic, and can be influenced from the periphery, making them highly attractive targets for therapeutic interventions in a broad range of pathological contexts. Information obtained from these research efforts will be particularly relevant for pathological alterations that impact BG circuits, such as addiction and other psychiatric illness, neurodegeneration, toxic poisoning, and focal inflammatory conditions.
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