Defining the Role of Microglia in the Synaptic Rewiring of the Hypothalamus by Early life Adversity

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PROJECT SUMMARY: Early-life adversity can profoundly impact an individual’s risk for stress-related emotional disorders including depression, likely by modulating the maturation of the underlying brain circuits. We find that early-life exposure to an impoverished environment provokes core symptoms of depression (anhedonia), accompanied by altered connectivity of stress-sensitive neurons. Specifically, we find an increase in the number of excitatory synapses onto corticotropin-releasing hormone (CRH) expressing neurons in the paraventricular nucleus of the hypothalamus (PVN). Further, these synaptic changes suffice to induce enduring epigenomic changes in the expression of critical neuronal genes including CRH. However, the mechanisms by which early-life adversity modulates synapse development and persistence in stress-related brain circuits remain unknown. Microglia, the brain’s resident immune cells, have emerged as key effectors in the shaping of synaptic connectivity in the developing visual and somatosensory systems. Microglia are thus attractive candidates for playing a similar role in sculpting connectivity of stress-related hypothalamic neurons. Aim 1 will test the hypothesis that microglia regulate excitatory synapse number on CRH-expressing neurons in the PVN, a key stress-responsive brain region. Aim 2 will test the hypothesis that early-life adversity influences the interactions of microglia with PVN-CRH neurons and their excitatory synapses. The final Aim will employ both hypothesis-driven and data-driven approaches to identify molecular mechanisms underlying adversity-provoked microglial dysfunction. Together, the proposed experiments will, for the first time, elucidate the role of microglia in aberrant maturation of brain circuits following early-life adversity. The K99 phase provided training in cutting-edge research skills, including live 2-photon imaging and 4-D analysis, as well as “big-data” analysis of transcriptomics. The University of California-Irvine provided an ideal environment for this training, with world-renowned experts in developmental neurobiology, microglia/neuroimmunology and molecular biology. In addition, UCI provided an intellectual environment that encourages collaboration and cooperation, enabling the candidate’s growth as a member of the scientific community. As a result, the PI was able to attain a tenure-track assistant professor position at Georgia State University, where the Neuroscience Institute boasts faculty members that are experts in neuron-glia interactions, neuropeptide signaling in the PVN, live 2-photon imaging, and behavioral neuroscience. In this excellent environment, the candidate will receive formal mentoring on the tenure-track path, forge close research collaborations, and establish her own independent research program on how microglia-neuron interactions during brain development shape future mental health.