Novel circuit mechanism of alcohol dependence vulnerability following early-life adversity

总结 童年的逆境增加了在以后的生活中发展酒精使用障碍的脆弱性， 参与促肾上腺皮质激素释放因子（CRF）信号传导的基因调节这种风险。然而，CRF依赖者 早期生活压力促进酒精滥用的中介机制尚不清楚。我们最近发现 位于丘脑底旁核（PSTN）的CRF神经元可能在这一机制中起关键作用 因为（1）他们控制着自愿的酒精饮用，（2）他们被早年的压力所改变。 值得注意的是，这些神经元向杏仁核中央核（CeA）发送兴奋性投射，其中CRF 已知信号传导促进依赖性动物的乙醇摄入量增加。因此，本项目 将测试从PSTN到CeA的失调CRF传输可能促进 在早期生活压力下转变为酒精依赖。这个项目将利用一种新的小鼠模型 早期生活压力和过量乙醇摄入之间的相互作用，通过限制床上用品和筑巢（LBN） 材料在出生后早期发育，模拟贫困的自然主义模型，并暴露成年小鼠 自愿饮酒与慢性间歇性乙醇蒸汽吸入（CIE）交替进行。我们 建立了LBN饲养加速暴露于CIE和Ellavin的雄性小鼠乙醇摄入量的增加， 负面影响在撤退。在目标1中，我们将确定性别对这些表型的影响， 在易感小鼠中，LBN和CIE对PSTN→CeA CRF活性具有协同作用的假设 神经元在目标2中，我们将试图扭转LBN对CIE诱导的动机的持久后果。 通过化学遗传学方法抑制PSTN→CeA CRF神经元，从而改变情感表型。我们的方法 利用两个经验丰富的合作研究人员的互补专业知识，并利用国家， 用于在体内操纵神经元活性的最先进的方法。我们的发现将为 确定生命早期应激的终身病理后果的分子机制， 这可能最终使个体的个性化治疗策略的发展， 经历了童年的逆境，患有酒精使用障碍。

SUMMARY Childhood adversity increases the vulnerability to develop an alcohol use disorder later in life, and variations in genes involved in corticotropin-releasing factor (CRF) signaling modulate this risk. However, the CRF-dependent mechanism(s) mediating the facilitation of alcohol abuse by early life stress is unknown. We recently discovered that CRF neurons located in the parasubthalamic nucleus (PSTN) may play a critical role in this mechanism because (1) they control voluntary ethanol drinking, and (2) they are enduringly altered by early life stress. Notably, these neurons send excitatory projections to the central nucleus of the amygdala (CeA), where CRF signaling is known to promote ethanol intake escalation in dependent animals. Accordingly, the present project will test the hypothesis that dysregulated CRF transmission from the PSTN to the CeA may facilitate the transition to alcohol dependence following early life stress. This project will leverage a novel mouse model of the interaction between early life stress and excessive ethanol intake by limiting bedding and nesting (LBN) materials during early postnatal development, a naturalistic model of simulated poverty, and exposing adult mice to voluntary ethanol drinking sessions alternated with chronic intermittent ethanol vapor inhalation (CIE). We established that LBN rearing accelerates ethanol intake escalation in male mice exposed to CIE and elicits negative affect during withdrawal. In Aim 1, we will determine the influence of sex on these phenotypes and test the hypothesis that, in vulnerable mice, LBN and CIE exert synergistic effects on the activity of PSTN→CeA CRF neurons. In Aim 2, we will attempt to reverse the enduring consequences of LBN on CIE-induced motivational and affective phenotypes by inhibiting PSTN→CeA CRF neurons using chemogenetics. Our approach capitalizes on the complementary expertise of two experienced collaborating researchers and leverages state- of-the-art methodology for the manipulation of neuronal activity in vivo. Our discoveries will pave the way for the identification of molecular mechanisms underlying the life-long pathological consequences of early life stress, which may ultimately enable the development of personalized therapeutic strategies for individuals who experienced childhood adversity and suffer from an alcohol use disorder.