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：由啮齿动物模型促进的行为和神经生物学适应 易于酒精使用障碍和创伤后应激障碍的脆弱性 杰夫·韦纳，萨拉·琼斯，罗伯特·古尔德，伊娃·巴赫和林赛·库珀 诊断为PTSD的人患有酒精饮用障碍（AUD）和 大多数证据表明，PTSD通常在AUD的发展之前。焦虑，沮丧和睡眠 干扰是AUD和两种疾病的主要症状的重要危险因素。尽管有 该问题的临床重要性，这些问题的神经力学经常同时存在 疾病尚未完全理解。该项目的总体目标是雇用啮齿动物的早期生活 AUD脆弱性和PTSD模型的隔离模型（ESI）模型，单个延长应力，以检验假设 两种压力源促进了通过收敛神经适应介导的相似行为表型。 这些研究还将确定ESI + SPS的“双重命中”是否加剧了这些不良适应性的变化和 测试治疗干预以减轻这些影响。行为研究将集中于动画的度量 - 像行为和负面影响一样，在恐惧扩展和乙醇自我管理中定义。神经生物学 研究将检验创新的假设，即这些模型增强了谷氨酸能的投影 腹侧下调（VSUB）到伏隔核的壳（NAC）。大量证据表明压力 增强VSUB-NAC活性并模拟该途径调制许多AUD/PTSD相关 行为（例如动机，负面影响）和间接增加伏托胺（DA）的释放。 尽管该电路被认为在许多神经精神疾病中起着不可或缺的作用，但它在很大程度上是 在AUD字段中被忽略。为了解决这一知识差距，多学科的体内和实体方法将 用于测试ESI + SPS强度的假设VSUB-NAC壳合成兴奋和变化 NAC壳DA释放动力学，部分是通过Kappa阿片受体功能的增加。这些研究会 还确定双重命中是否增加了乙醇刺激的NAC DA释放并在体内使用闭环 光遗传学和药物方法来确定这些合成适应是否在 这些模型促进的乙醇饮用表型。最终目标将使用纵向无线脑电图 确定ESI + SPS和乙醇饮酒是否破坏睡眠结构和持续时间以及这些是否是否 Kappa阿片类药物接收器拮抗剂可以减轻变化。总的来说，这些研究将提供 ESI和SPS对与关键行为表型相关的关键行为表型的影响的首次详细表征 AUD漏洞和PTSD。互补的神经生物学研究可能发现相对未表征 造成这些不良适应行为的河马 - 纹状体电路。