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

5/8 Nadia UO1.青春期酒精对成人脑神经回路的影响 摘要 我们的研究发现，青少年间歇性酒精(AIE)暴露会增加成人的危险决定、去抑制、 行为不灵活，降低了对成人酒精挑战的敏感性，以及增加饮酒， 人类澳门氏症的所有危险因素。乙酰胆碱可被AIE还原，并在皮质激活和 青少年神经回路的整合和成熟可能会影响酒精敏感性。尽管AIE 不会改变成人酒精的排出，但会减少成人酒精的运动镇静、抗焦虑、PFC 即刻早期基因(IEG)、c-fos和皮质功能连接磁共振成像(FcMRI) 回应。我们发现AIE增加了成人HMGB1及其受体(即Toll样受体4[TLR4]和 神经元上的晚期糖基化终产物受体(RAGE)，这些信号与表观遗传学有关 胆碱能表型基因(如ChAT、Vacht、TrkA)的沉默和海马神经发生的丧失， 这些都是AIE改变的神经回路的例子。对酒精的低反应与AUD有关，而这些 在死后的成人AUD脑中发现了变化。基底前脑胆碱能神经元整合 神经回路和这些神经元的减少可能参与了AIE的病理过程。我们假设AIE HMGB1、→、TLR4/RAGE对胆碱能神经元的表观遗传沉默改变基底前脑皮质 海马神经回路，导致酒精敏感性降低和饮酒量增加 成人期。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，AIE减少的ChAT+神经元是可逆的运动和 吲哚美辛支持HMGB1、→、TLR4/RAGE、→、NF、κB对神经元内ChAT的表观遗传沉默 进入成年期。神经免疫聊天沉默的逆转表明AIE的病理是持续的，但不是 永久的。然而，尚不清楚AIE介导的青少年样的成人低酒精敏感性是否会 被阻止的或被逆转的因此，这项提议有以下目标。目标1.检验AIE的假设 降低成人对脑fcMRI变化、c-fos表达、酒精反应行为的酒精敏感性 (ERBS)，并增加成人饮酒。目标2将扩展验证假设的研究 HMGB1TLR4/RAGE→→NFκB信号可逆性减少基底前脑ChAT+胆碱能神经元 表观遗传机制。目标3将检验这样一种假设，即青少年聊天沉默模仿成人AIE低- 酒精反应和其他病理学。目标4将检验抗炎治疗已知可以 逆转AIE改变的ChAT、神经发生和表观遗传学改变，也将恢复AIE改变的c-fos、fcMRI、 酒精行为反应敏感度低，成人饮酒。确定分子机制和 调节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 发展和决定对酒精攻击低反应的机制，酒精攻击是AUD的已知风险因素， 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.