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：通过啮齿类动物模型促进收敛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、萨拉·琼斯、罗伯特·古尔德、伊娃·巴赫和林赛·柯伊伯 被诊断患有创伤后应激障碍的人患酒精使用障碍（AUD）的可能性高达四倍， 大多数证据表明PTSD通常先于AUD的发展。焦虑、抑郁和睡眠 中断是AUD的重要风险因素，也是这两种疾病的主要症状。尽管 这个问题的临床重要性，神经机制负责这些频繁的共同发生， 疾病尚未完全了解。该项目的总体目标是采用啮齿动物早期生活社会 AUD脆弱性的隔离（eSI）模型和PTSD模型，单一的长期压力，以检验假设 这两种应激源都促进了相似的行为表型，这些表型是由收敛性神经适应介导的。 这些研究还将确定eSI + SPS的“双重打击”是否加剧了这些适应不良的变化， 测试治疗干预以减轻这些影响。行为研究将集中在焦虑的测量上- 如行为和负面影响，恐惧消退的缺陷，以及乙醇自我管理。神经生物 研究将测试创新的假设，即这些模型加强了从大脑中投射出的神经元投射。 腹侧下托（vSub）到核壳（NAc）。大量证据表明， 增强vSub-NAc活性，刺激该途径可调节许多AUD/PTSD相关的 行为（例如动机，负面影响）并间接增加多巴胺（DA）的释放。 虽然这个回路被认为在许多神经精神疾病中起着不可或缺的作用，但它在很大程度上被认为是神经精神疾病的一部分。 在AUD字段中忽略。为了解决这一知识差距，多学科的体内和体外方法将 eSI + SPS增强vSub-NAc壳突触兴奋， NAc壳DA释放动力学，部分通过增加κ阿片受体功能。这些研究将 还确定双重打击是否增加乙醇刺激的NAc DA释放，并在体内使用闭环 光遗传学和药理学方法来确定这些突触适应是否在 这些模型促进的乙醇饮用表型。最后一个目标是使用纵向无线脑电图， 确定eSI + SPS和乙醇饮用是否会破坏睡眠结构和持续时间，以及这些是否会影响睡眠结构和持续时间。 可通过κ阿片样物质受体拮抗剂减轻这种变化。总的来说，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： AUD脆弱性和PTSD。补充的神经生物学研究可能会发现一个相对不典型的 导致这些适应不良行为的丘脑-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.