Neural Substrates of Comorbid Alcohol Use Disorder and Post-Traumatic Stress Disorder

共病酒精使用障碍和创伤后应激障碍的神经基质

• 批准号: 9486289
• 负责人: JEFFREY L WEINER
• 金额: $ 38.75万
• 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: 2017-09-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9486289
• 关键词: Address; Adolescence; Adolescent; Alcohol consumption; Amygdaloid structure; Animal Model; Attenuated; Behavior; Behavioral; Behavioral Symptoms; Brain region; Chronic; Comorbidity; Data; Development; Disease; Disease model; Electrophysiology (science); Ethanol; Exhibits; Experimental Designs; Exposure to; Extinction (Psychology); Face; Female; Fright; Hippocampus (Brain); Individual; Knowledge; Lead; Life Stress; Light; Link; Measures; Mediating; Modeling; Neurobiology; Neurons; Phenotype; Play; Population; Post-Traumatic Stress Disorders; Potassium; Procedures; Publishing; Rattus; Recovery; Refractory; Risk; Rodent Model; Role; Self Administration; Series; Signal Transduction; Social isolation; Symptoms; Synapses; Testing; Work; alcohol comorbidity; alcohol risk; alcohol use disorder; anxiety-like behavior; base; behavioral study; conditioned fear; drinking behavior; dual diagnosis; effective therapy; emotional behavior; epidemiology study; experience; innovation; male; multidisciplinary; negative affect; neuroadaptation; novel; novel therapeutics; optogenetics; outcome forecast; relating to nervous system; resilience; stress disorder; stressor

Summary Although alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are highly comorbid, little is known about the neural substrates that contribute to this comorbidity. Moreover, despite the frequent co- occurrence of AUD and PTSD, there is marked variability in the likelihood of developing these disorders and even less is known about the neural substrates that might confer vulnerability or resilience to AUD and PTSD. The scientific premise of this application is that a better understanding of the circuitry and neurobiology that differentiate these vulnerable and resilient populations may reveal novel targets for the development of more effective treatments for individuals suffering from the comorbid condition. To address this challenge, we have extensively characterized a rodent model of early life stress, adolescent social isolation (aSI), and have generated encouraging support for the face, construct and predictive validity of aSI as a model of vulnerability to AUD and PTSD. For example, relative to rats group-housed throughout adolescence (aGH), aSI rats exhibit many behaviors linked with heightened risk of AUD and PTSD, including deficits in fear extinction and enduring increases in ethanol drinking behaviors. Notably, a relatively mild fear conditioning procedure significantly increased ethanol self-administration in aSI rats for at least 8 weeks while having no effect on ethanol drinking in aGH subjects. Published and ongoing neurobiological studies have identified profound adaptations that may contribute to these behavioral phenotypes, including increased measures of excitability within the basolateral amygdala (BLA) and ventral hippocampus (vHC), two highly interconnected brain regions that play an integral role in many of the emotional behaviors that are disrupted in AUD and PTSD. Based on these findings, the studies outlined in this application will employ a multidisciplinary experimental design to determine if the fear conditioning procedure leads to the expression of core behavioral symptoms of AUD and PTSD in aSI rats and whether aGH subjects will be resilient to this stressor. Neurobiological studies will determine if the fear conditioning procedure exacerbates aSI-associated neurobiological adaptations in the BLA and vHC, and specifically within the BLA-vHC circuit, and whether a strengthening of this circuit plays a causal role in AUD/PTSD-like behavioral phenotypes promoted by this model. Additional studies will test a novel therapeutic strategy to reverse the maladaptive behaviors promoted by aSI + fear conditioning. Based on other emerging findings, these studies will also test the innovative hypothesis that aSI + fear conditioning promotes similar neural adaptations in male and female rats but that the behavioral phenotypes engendered by these stressors may be sexually dimorphic. Collectively, these studies will further strengthen the validity of aSI as a model of heightened vulnerability to comorbid AUD and PTSD and potentially lead to the identification of novel neurobiological targets for the development of much needed treatments for the comorbid condition.

概括 尽管酒精使用障碍 (AUD) 和创伤后应激障碍 (PTSD) 高度共存，但很少有 了解导致这种合并症的神经基质。此外，尽管经常共同 AUD 和 PTSD 的发生，发生这些疾病的可能性存在显着差异，并且 对于可能赋予 AUD 和 PTSD 脆弱性或恢复力的神经基质我们知之甚少。 该应用的科学前提是更好地理解电路和神经生物学 区分这些弱势群体和复原力群体可能会揭示更多发展的新目标 对患有共病的个体进行有效的治疗。为了应对这一挑战，我们有 广泛描述了早期生活压力、青少年社会孤立（aSI）的啮齿动物模型，并已 对 ASI 作为脆弱性模型的面貌、构造和预测有效性产生了令人鼓舞的支持 澳元和创伤后应激障碍。例如，相对于整个青春期群养的大鼠 (aGH)，aSI 大鼠表现出 许多行为与 AUD 和 PTSD 风险增加有关，包括恐惧消退和持久能力的缺陷 乙醇饮用行为增加。值得注意的是，相对温和的恐惧条件反射过程显着 增加 aSI 大鼠的乙醇自我给药至少 8 周，同时对乙醇饮用没有影响 在 aGH 受试者中。已发表和正在进行的神经生物学研究已经确定了可能的深刻适应 有助于这些行为表型，包括增加基底外侧兴奋性的测量 杏仁核 (BLA) 和腹侧海马 (vHC)，两个高度互连的大脑区域，发挥着不可或缺的作用 AUD 和 PTSD 中许多情绪行为受到干扰。根据这些发现， 本申请中概述的研究将采用多学科实验设计来确定恐惧是否 条件反射过程导致 ASI 大鼠表现出 AUD 和 PTSD 的核心行为症状 aGH 受试者是否能够适应这种压力源。神经生物学研究将确定恐惧是否 调节程序加剧了 BLA 和 vHC 中与 ASI 相关的神经生物学适应，并且 特别是在 BLA-vHC 回路中，以及该回路的强化是否在 该模型促进了类似 AUD/PTSD 的行为表型。其他研究将测试一种新的治疗方法 扭转由 ASI + 恐惧条件促进的适应不良行为的策略。基于其他新兴的 发现，这些研究还将检验创新假设，即 aSI + 恐惧调节会促进类似的 雄性和雌性大鼠的神经适应，但这些压力源引起的行为表型 可能是两性异形。总的来说，这些研究将进一步加强 aSI 作为模型的有效性 更容易患 AUD 和 PTSD 共病，并可能导致新发现 开发急需的共病治疗方法的神经生物学目标。