Microglial Drivers of Circuit Outcomes

Major current microglia research questions:

How do microglia in diverse brain areas differentially modulate connectivity?

What controls the beneficial and harmful effects of microglia in Alzheimer’s and other diseases?

How do microglia contribute to diet induced obesity?

Developmental regulators of microglia phagocytic state. Microglia are the only resident CNS immune cell, and they drive development and neural decline through synapse engulfment. However, the underlying mechanisms that temporally regulate microglia phagocytosis remain poorly understood. Our lab has discovered a surprising neuron cue called signal regulatory protein alpha (SIRPα) that is necessary for microglia phagocytosis. To achieve this, neuronal SIRPα functions as a decoy receptor to prevent microglial SIRPα interaction with the ‘don’t eat me’ cue CD47. These discoveries serve as a foundation for several ongoing projects in the lab.

How is microglia functional and molecular diversity achieved in distinct neural circuits. Despite the overwhelming evidence that microglia demonstrate functional and cellular heterogeneity, there has been little consideration of how this diversity is generated and maintained relative to pro or anti-engulfment cues, circuit location and function, and neuron identity and neurotransmitter use. Nor do we understanding how the plasticity of specific subsets contribute to distinct aspects of development. The central goal of these projects is to bridge this knowledge gap to discover how microglia phagocytic state transitions are instructed by local neuron signals and how microglia subpopulations drive functional outcomes.

Microglia dysregulation in neurological diseases.  In nearly every neurological disease, highly phagocytic and immune activated microglia can modulate disease outcomes. In these projects we ask whether pathogenetic microglia states can be reversed to reduce brain disease progression. As an example of these studies, we are testing whether reducing microglia phagocytic capacity can slow disease progression in mouse models of Alzheimer's disease. We are also testing parallel ideas in mouse models of multiple sclerosis, glaucoma, diabetic retinopathy, and feeding disorders all of which display pathological microglia engulfment states.