This K99/R00 proposal will test a critical hypothesis on the mechanisms by which maturation of brain circuits is impacted by early-life adversity, while providing the PI with additional scientific technologies and professional skills, leading to her successful independent career. 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. This proposal will (1) 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. This proposal will significantly enhance the PI?s career development, and advance her towards her career goal of becoming an independent investigator at a research-focused institution. The proposed project provides 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 provides an ideal environment for training, with world-renowned experts in developmental neurobiology, microglia/neuroimmunology and molecular biology. In addition, UCI provides an intellectual environment that encourages collaboration and cooperation, enabling the candidate?s growth as a member of the scientific community. Indeed, the PI will engage in activities designed to prepare her for independence, including training in lab management, networking, grantsmanship, and preparation for the academic job market. In summary, the systematic plan proposed here will enable the PI?s scientific and career-wise growth and independence, thus well-positioning her to attain future R01 funding.
Mental illnesses such as depression are on the rise, now affecting as much as 20% of the US population. Mounting evidence suggests that early-life experiences can have a profound and life-long impact on emotional vulnerabilities and cognitive function, potentially via ?rewiring? the stress-responsive circuits of the brain. This proposal will explore the cellular and molecular mechanisms by which early-life adversity provokes aberrant maturation of brain circuits, with promise for the development of better therapies and preventive interventions for at-risk children.
