5/8 NADIA U01 Effects of Adolescent Alcohol on adult brain Neurocircuitry

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5/8 NADIA UO1. Effects of Adolescent Alcohol on Adult Brain Neurocircuitry. Abstract Our studies find adolescent intermittent ethanol (AIE) exposure increases adult risky decisions, disinhibition, behavioral inflexibility, and reduces sensitivity to adult ethanol challenge as well as increasing alcohol drinking, all risk factors for human AUD. Acetylcholine is reduced by AIE and plays a critical role in cortical activation and integration as well as maturation of adolescent neurocircuits that could impact ethanol sensitivity. Although AIE does not change adult ethanol elimination, it does reduce adult ethanol motor-sedative, anxiolytic, PFC immediate early gene (IEG) c-fos, and cortical functional connectivity magnetic resonance imaging (fcMRI) responses. We discovered AIE increases adult HMGB1 and its receptors (i.e., Toll-like receptor 4 [TLR4] and receptor for advanced glycation end products [RAGE]) on neurons, and these signals are linked to epigenetic silencing of cholinergic phenotype genes (i.e., ChAT, VAChT, TrkA) and loss of hippocampal neurogenesis, which are examples of AIE-altered neurocircuitry. Low response to ethanol is associated with AUD, and these changes are found in post-mortem human adult AUD brain. Basal forebrain cholinergic neurons integrate neurocircuits, and reductions of these neurons may contribute to AIE pathology. We hypothesize AIE HMGB1→TLR4/RAGE epigenetic silencing of cholinergic neurons alters basal forebrain-cortical- hippocampal neurocircuitry, leading to reduced ethanol sensitivity and increased alcohol drinking in adulthood. Reductions of adult ChAT+ neurons caused by AIE were initially interpreted as neurodegeneration; however, the surprising discovery that AIE reductions of ChAT+ neurons are reversible by exercise and indomethacin supports HMGB1→TLR4/RAGE→NFκB epigenetic silencing of ChAT within neurons persisting into adulthood. Reversal of neuroimmune ChAT silencing suggests AIE pathology is persistent, but not permanent. However, it is not known if AIE-mediated adolescent-like low adult ethanol sensitivity can be prevented or reversed. This proposal therefore has the following Aims. AIM 1. Test the hypothesis that AIE decreases adult ethanol sensitivity to brain fcMRI changes, c-fos expression, ethanol response behaviors (ERBs), and increases adult alcohol drinking. AIM 2 will extend studies testing the hypothesis that HMGB1→TLR4/RAGE→NFκB signaling reduces basal forebrain ChAT+ cholinergic neurons by reversible epigenetic mechanisms. AIM 3 will test the hypothesis that adolescent ChAT silencing mimics adult AIE low- ethanol response and other pathology. AIM 4 will test the hypothesis that anti-inflammatory treatment known to reverse AIE-altered ChAT, neurogenesis, and epigenetic changes, will also recover AIE-altered c-fos, fcMRI, ethanol low behavioral response sensitivity, and adult ethanol drinking. Identifying molecular mechanisms and key neurocircuits regulating low response to alcohol will contribute to our understanding of adolescent brain development and the mechanisms determining low response to ethanol challenge, a known risk factor for AUD, as well as possibly identifying treatment targets.