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

5/8纳迪亚UO 1。青少年酒精对成人脑神经回路的影响。 摘要 我们的研究发现，青少年间歇性乙醇（AIE）暴露会增加成年人的风险决策，抑制解除， 行为能力，并降低对成人乙醇挑战的敏感性以及增加饮酒量， 人类AUD的所有风险因素。乙酰胆碱被AIE减少，并在皮层激活和神经再生中起关键作用。 整合以及青少年神经回路的成熟可能会影响乙醇敏感性。虽然AIE 不改变成人乙醇的消除，但确实减少了成人乙醇的运动镇静剂、抗焦虑剂、PFC 即刻早期基因（IEG）c-fos和皮质功能连接磁共振成像（fcMRI） 应答我们发现AIE增加了成人HMGB 1及其受体（即，Toll样受体4 [TLR 4]和 晚期糖基化终末产物受体（Advanced Glycation End Products receptor），这些信号与表观遗传有关。 胆碱能表型基因的沉默（即，ChAT、VAChT、TrkA）和海马神经发生的丧失， 这是AIE改变神经回路的例子。对乙醇的低反应与AUD相关，这些 在死后的成年人AUD脑中发现了变化。基底前脑胆碱能神经元整合 这些神经元的减少可能有助于AIE病理学。我们假设AIE 胆碱能神经元HMGB 1 → TLR 4/HMGB 1表观遗传沉默改变基底前脑-皮质-海马--海马-海马- 海马神经回路，导致乙醇敏感性降低和饮酒增加， 成年AIE引起的成年ChAT+神经元减少最初被解释为神经变性; 然而，令人惊讶的发现是，ChAT+神经元的AIE减少通过运动是可逆的， 吲哚美辛支持神经元内ChAT的HMGB 1 → TLR 4/NFκB表观遗传沉默 长大成人神经免疫ChAT沉默的恢复表明AIE病理学是持久的，但不是永久性的。 永久的然而，目前尚不清楚AIE介导的酒精样低成人酒精敏感性是否可以被 阻止或逆转。因此，这项建议的目的如下。AIM 1.检验AIE的假设 降低成年人酒精敏感性脑fcMRI变化，c-fos表达，乙醇反应行为 （ERB），并增加成人饮酒。AIM 2将扩展测试假设的研究， HMGB 1 → TLR 4/NFκB →NFκB信号通过可逆途径减少基底前脑ChAT+胆碱能神经元 表观遗传机制AIM 3将检验青少年ChAT沉默模仿成人AIE低水平的假设。 乙醇反应和其他病理学。AIM 4将检验已知的抗炎治疗 逆转AIE改变的ChAT，神经发生和表观遗传变化，也将恢复AIE改变的c-fos，fcMRI， 乙醇行为反应敏感性低，成年人饮用乙醇。识别分子机制和 调节对酒精低反应的关键神经回路将有助于我们对青少年大脑的理解 发展和机制确定低反应乙醇挑战，一个已知的风险因素AUD， 以及可能识别治疗目标。

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.