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：易患酒精使用障碍和创伤后应激障碍的啮齿动物模型促进趋同的行为和神经生物学适应

• 批准号: 10526646
• 负责人: JEFFREY L WEINER
• 金额: $ 32.87万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-10 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10526646
• 关键词: Address; Adolescent; Alcohol consumption; Amygdaloid structure; Animal Model; Animals; Anxiety; Architecture; Behavior; Behavioral; Clinical; Corpus striatum structure; Development; Diagnosis; Disease; Dopamine; Electroencephalography; Electrophysiology (science); Epidemiology; Ethanol; Extinction; Female; Fiber; Fright; Glutamates; Goals; Hippocampus; Individual; Knowledge; Life; Link; Measures; Mediating; Mental Depression; Modeling; Motivation; Neurobiology; Nucleus Accumbens; Opioid Antagonist; Pathway interactions; Phenotype; Photometry; Play; Post-Traumatic Stress Disorders; Procedures; Publishing; Rattus; Risk Factors; Rodent; Rodent Model; Role; Self Administration; Sleep; Sleep Architecture; Sleep disturbances; Social isolation; Stress; Symptoms; Synapses; Synaptic Transmission; Testing; Therapeutic Intervention; Vulnerable Populations; alcohol research; alcohol risk; alcohol use disorder; anxiety-like behavior; behavioral phenotyping; behavioral study; drinking; early childhood; efficacy evaluation; forest; human subject; in vivo; innovation; kappa opioid receptors; maladaptive behavior; male; multidisciplinary; negative affect; neural; neuroadaptation; neurochemistry; neuromechanism; neuropsychiatric disorder; optogenetics; pharmacologic; receptor function; resilience; sex; stressor; symptomatology; translational study; wireless

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.

项目 4：啮齿动物模型促进趋同的行为和神经生物学适应 容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 (PTSD) 的人患酒精使用障碍 (AUD) 的可能性高出四倍，并且 大多数证据表明，PTSD 通常先于 AUD 的发展。 尽管干扰是 AUD 的重要危险因素，也是这两种疾病的主要症状。 这个问题的临床重要性，导致这些问题频繁同时发生的神经机制 该项目的总体目标是利用啮齿动物的早期社会性。 AUD 脆弱性的隔离 (eSI) 模型和 PTSD 模型（单一长期压力）来检验假设 两种压力源都会促进由聚合神经适应介导的相似行为表型。 这些研究还将确定 eSI + SPS 的“双重打击”是否会恶化这些适应不良的变化以及 测试治疗干预措施以减轻这些影响。行为研究将侧重于焦虑的测量。 例如行为和负面影响、恐惧消退的缺陷以及乙醇的自我管理。 研究将检验这一创新假设，即这些模型增强了谷氨酸能投射 大量证据表明，腹侧下托（vSub）与伏隔核壳（NAc）之间存在压力。 增强 vSub-NAc 活性，刺激该通路可调节许多 AUD/PTSD 相关的 行为（例如动机、负面情绪）并间接增加累积多巴胺（DA）的释放。 尽管该回路被认为在许多神经精神疾病中发挥着不可或缺的作用，但它在很大程度上已被 为了解决这一知识差距，体内和离体多学科方法将被忽视。 用于测试 eSI + SPS 增强 vSub-NAc 壳突触兴奋并改变的假设 NAc 壳 DA 释放动力学，部分通过 kappa 阿片受体功能的增加这些研究将进行。 还确定命中双倍是否会增加乙醇刺激的 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的最终目标是使用纵向无线脑电图来研究。 确定 eSI + SPS 和乙醇饮用是否会扰乱睡眠结构和持续时间，以及这些是否 总的来说，这些研究将提供 kappa 阿片受体拮抗剂来减轻变化。 首次详细描述了 eSI 和 SPS 对与相关的关键行为表型的影响 AUD 脆弱性和 PTSD 的补充神经生物学研究可能会发现相对不典型的特征。 海马-纹状体回路会导致这些适应不良行为。