Harnessing microglia-neuron communication to improve habituation in neurodevelopment disorders

This research proposal explores the role of microglial cells in neurodevelopmental and neuropsychiatric disorders, particularly focusing on habituation deficits induced by maternal immune activation (MIA). Novelty habituation, a fundamental form of behavioral plasticity where the response to a repeated stimulus diminishes over time, is often disrupted in conditions like autism spectrum disorders (ASD). The underlying brain circuits and cellular mechanisms responsible for these deficits remain poorly understood, posing a significant barrier to developing effective therapeutic interventions. Our study hypothesizes that MIA, a model for prenatal infection, shifts microglial cells from a homeostatic to a reactive state, impairing their ability to regulate neuronal activity and thus disrupting habituation processes, via loss of GABA-receptive microglia, which play a critical role in maintaining proper neuronal function. To test this hypothesis, our research will employ cutting-edge techniques such as in vivo fiber photometry to monitor neuronal activity in freely behaving mice and 10x multiome which is a high-throughput single-cell method that aims to capture the transcriptome and chromatin accessibility profiles of individual cells. The proposal is structured around specific aims to define the effect of MIA on habituation via microglial cells and, to profile the molecular alterations in microglia and neurons in the hippocampus induced by MIA. Our study will also explore the effects of deleting and repopulating microglia to determine their role in habituation deficits, specifically focusing on the potential loss of GABA-receptive microglia as a critical mechanism. The expected outcomes include identifying the neuroimmune mechanisms that drive habituation deficits, which could reveal novel therapeutic targets for ASD and other related disorders. By linking MIA-induced changes in microglia, including the loss of GABA-receptive microglia, to specific behavioral outcomes, the research aims to provide a deeper understanding of how immune challenges during development can lead to long-term neuropsychiatric conditions.