A novel role for developmental microglial-parvalbumin interneuron interactions in adult alcohol drinking behavior.

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ABSTRACT Alcohol use disorder (AUD) is a damaging and pervasive mental disorder that presents a large health and socioeconomic burden globally. Strong risk factors for AUD include early life challenges that cause inflammation, such as early life stress and early exposure to alcohol. Microglia, the brain’s resident immune cells, both respond to inflammatory challenges and organize developing circuits, lending strong support to the theory that immune signaling changes during development alter circuit maturation to increase later life drinking. Therefore, in my proposal, I will determine if there is a developmental sensitive window for increased drinking vulnerability controlled by microglia. My preliminary data suggests that microglia are responsible for increased adult alcohol consumption through a developmental mechanism: loss of pro-inflammatory signaling specifically in microglia through the ablation of MyD88, a critical toll-like receptor signaling molecule, increases voluntary adult drinking in both acute and chronic drinking paradigms. Parvalbumin interneurons (PVIs), late-maturing critical regulators of coordinated cell activity across the brain, are also altered in frontal cortex of MyD88-deficient mice, an effect that is exacerbated by early-life inflammation. This PVI change points to a potential mechanism through which microglia are impacting circuit maturation and behavior. Based on this, my central hypothesis is that MyD88- deficient microglia improperly regulate the size of the developing PVI population through reduced phagocytosis, leading to increased inhibitory frontal cortex activity in adulthood that drives excessive drinking. I propose to test this hypothesis in two aims. In Aim 1, I will determine if MyD88-deficient microglia exhibit reduced phagocytosis of PVI cells or synapses during development through immunohistochemical techniques. Then I will test the hypothesis that loss of this function in the frontal cortex during a specific developmental window is sufficient to induce the altered drinking behavior in adulthood. I will do this by administering a temporary microglial phagocytosis blocking compound to the frontal cortex during development and then measure adult drinking. In Aim 2, I will determine whether changes to frontal cortex PVI activity can drive increased adult drinking. Using a Cre-dependent chemogenetic approach, I will deliver excitatory or inhibitory designer receptors exclusively activated by designer drugs (DREADDs) to PVIs in the frontal cortex of adult mice, then deliver a designer drug across the course of an acute drinking paradigm. This will uncover whether increasing or decreasing PVI activity in the frontal cortex is driving the excessive drinking seen in MyD88-deficient animals. The proposed work will have an important positive impact not only on our understanding of AUD and its risk factors, but also will answer basic neurodevelopmental questions about the role of microglia in shaping inhibitory circuits and future behavior. The outcome of this project will be specific targets, such as microglial inflammatory signaling and PVI function in the frontal cortex, to manipulate in future studies to progress the prevention and treatment of AUD.