Project 4: Convergent behavioral and neurobiological adaptations promoted by rodent models of vulnerability to alcohol use disorder and post-traumatic stress disorder

项目4：啮齿动物模型促进融合的行为和神经生物学适应 易患酒精使用障碍和创伤后应激障碍 杰夫·韦纳、莎拉·琼斯、罗伯特·古尔德、伊娃·巴赫和林赛·柯伊珀 被诊断为创伤后应激障碍的人患酒精使用障碍(AUD)的可能性高出四倍 大多数证据表明，创伤后应激障碍通常先于AUD的发展。焦虑、抑郁和睡眠 中断是AUD的重要危险因素，也是这两种疾病的主要症状。尽管 这一问题的临床重要性，导致这些疾病频繁并存的神经机制 人们对疾病的认识还不够充分。这个项目的首要目标是雇佣一只早期社会啮齿动物 AUD脆弱性的隔离(ESI)模型和PTSD模型，以检验假设 这两种应激源都促进了相似的行为表型，这些表型是由汇聚的神经适应所调节的。 这些研究还将确定ESI SP的“双重打击”是否会加剧这些不适应的变化和 测试一种治疗干预措施以减轻这些影响。行为研究将重点放在焦虑的衡量标准上- 比如行为和消极情绪，恐惧消退方面的缺陷，以及酒精自我管理。神经生物学 研究将检验这一创新假设，即这些模型加强了来自 腹侧小丘(VSub)至伏隔核壳(Nac)。大量证据表明，压力 增强vSub-NAC活性且该通路的刺激调节许多AUD/PTSD相关 行为(如动机、消极情绪)并间接增加伏隔区多巴胺(DA)的释放。 尽管这一环路被认为在许多神经精神障碍中起着不可或缺的作用，但它在很大程度上 在AUD字段中忽略。为了解决这一知识差距，体内和体外的多学科方法将 被用来检验ESI SPS增强vSub-NAC壳突触兴奋和改变的假说 NAC壳DA的释放动力学部分是通过kappa阿片受体功能的增加来实现的。这些研究将 还要确定双重打击是否增加了乙醇刺激的NAC DA释放，并在体内使用闭合循环 光遗传学和药理学方法来确定这些突触适应是否在 这些模型所促进的酒精饮酒表型。最终目标将使用纵向无线EEG来 确定ESI SP和酒精饮酒是否会扰乱睡眠结构和睡眠持续时间，以及这些是否 这种变化可以通过kappa阿片受体拮抗剂来缓解。总而言之，这些研究将提供 首次详细描述了ESI和SPS对与以下相关的关键行为表型的影响 澳大利亚的漏洞和创伤后应激障碍。互补的神经生物学研究可能会识别出一种相对没有特征性的 导致这些适应不良行为的海马顶-纹状体回路。

PROJECT 4: Convergent behavioral and neurobiological adaptations promoted by rodent models of vulnerability to alcohol use disorder and post-traumatic stress disorder Jeff Weiner, Sara Jones, Robert Gould, Eva Bach, and Lindsey Kuiper Individuals diagnosed with PTSD are up to four times more likely to develop alcohol use disorder (AUD) and most evidence suggests that PTSD usually precedes the development of AUD. Anxiety, depression, and sleep disruptions are significant risk factors for AUD as well as major symptoms of both disorders. Despite the clinical importance of this problem, the neural mechanisms responsible for the frequent co-occurance of these disorders are not fully understood. The overarching goal of this project is to employ a rodent early life social isolation (eSI) model of AUD vulnerability and a PTSD model, single prolonged stress, to test the hypothesis that both stressors promote similar behavioral phenotypes that are mediated by convergent neural adaptations. These studies will also determine if the “double hit” of eSI + SPS exacerbates these maladaptive changes and test a therapeutic intervention to mitigate these effects. Behavioral studies will focus on measures of anxiety- like behavior and negative affect, deficits in fear extinction, and ethanol self-administration. Neurobiological studies will test the innovative hypothesis that these models strengthen a glutamatergic projection from the ventral subiculum (vSub) to the nucleus accumbens shell (NAc). Extensive evidence suggests that stress enhances vSub-NAc activity and that stimulation of this pathway modulates many AUD/PTSD-related behaviors (e.g. motivation, negative affect) and indirectly increases accumbal dopamine (DA) release. Although this circuit is thought to play an integral role in many neuropsychiatric disorders, it has been largely ignored in the AUD field. To address this knowledge gap, multidisciplinary in vivo and ex vivo approaches will be employed to test the hypotheses that eSI + SPS strengthens vSub-NAc shell synaptic excitation and alters NAc shell DA release dynamics, in part via an increase in kappa opioid receptor function. These studies will also determine if the double hit increases ethanol-stimulated NAc DA release and use closed loop in vivo optogenetics and pharmacological approaches to determine if these synaptic adaptations play a causal role in the ethanol drinking phenotypes promoted by these models. A final aim will use longitudinal wireless EEG to determine if eSI + SPS and ethanol drinking disrupt sleep architecture and duration and whether these changes can be mitigated by a kappa opioid receptor antagonist. Collectively, these studies will provide the first detailed characterization of the effects of eSI and SPS on critical behavioral phenotypes associated with AUD vulnerability and PTSD. Complementary neurobiological studies may identify a relatively uncharacterized hippocamapal-striatal circuitry that contributes to these maladaptive behaviors.