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: 10188342
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188342
• 关键词: Address; Adolescence; Adolescent; Alcohol consumption; Amygdaloid structure; Animal Model; Attenuated; Behavior; Behavioral; Behavioral Symptoms; Brain region; Chronic; Data; Development; Disease; Disease model; Electrophysiology (science); Ethanol; Exhibits; Experimental Designs; Exposure to; Extinction (Psychology); Face; Female; Fright; Hippocampus (Brain); Individual; Knowledge; Lead; Light; Link; Measures; Mediating; Modeling; Neurobiology; Neurons; Play; Population; Post-Traumatic Stress Disorders; Potassium; Procedures; Prognosis; 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 phenotyping; behavioral study; comorbidity; conditioned fear; drinking behavior; dual diagnosis; early life stress; effective therapy; emotional behavior; epidemiology study; experience; innovation; male; multidisciplinary; negative affect; neuroadaptation; novel; novel therapeutic intervention; optogenetics; relating to nervous system; resilience; sexual dimorphism; 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.

总结 虽然酒精使用障碍（AUD）和创伤后应激障碍（PTSD）是高度共病， 我们知道导致这种并发症的神经基质。尽管频繁的合作， 在AUD和PTSD的发生中，发展这些疾病的可能性存在显著的变异性， 关于可能赋予对AUD和PTSD的脆弱性或恢复力的神经基质，我们所知更少。 这项应用的科学前提是，更好地了解电路和神经生物学， 区分这些脆弱和有弹性的人群可能会揭示新的目标， 对患有共病的个体的有效治疗。为了应对这一挑战，我们 广泛表征了早期生活压力、青少年社会隔离（aSI）的啮齿动物模型， 对aSI作为脆弱性模型的面貌、结构和预测有效性产生了令人鼓舞的支持 和创伤后应激障碍例如，相对于整个青春期分组饲养的大鼠（aGH），aSI大鼠表现出 许多与AUD和PTSD风险增加有关的行为，包括恐惧消退和持久性 酒精饮料行为的增加。值得注意的是，一个相对温和的恐惧条件反射程序显着 在aSI大鼠中增加乙醇自我给药至少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深刻的适应性， 有助于这些行为表型，包括增加的措施，兴奋性基底外侧 杏仁核（BLA）和腹侧海马（vHC），两个高度相互关联的大脑区域， 在AUD和PTSD中被破坏的许多情绪行为中起作用。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 条件化程序导致aSI大鼠中AUD和PTSD的核心行为症状的表达， aGH受试者是否会对这种压力源有弹性。神经生物学研究将确定恐惧 条件反射程序加剧了BLA和vHC中aSI相关的神经生物学适应， 特别是在BLA-vHC回路中，以及该回路的加强是否在以下方面起因果作用： 该模型促进的AUD/PTSD样行为表型。进一步的研究将测试一种新的治疗方法， 策略，以扭转aSI +恐惧条件反射促进的适应不良行为。根据其他新兴 这些研究还将测试创新假设，即aSI +恐惧条件反射促进类似的 雄性和雌性大鼠的神经适应，但这些应激源产生的行为表型 可能是两性异形的。总的来说，这些研究将进一步加强aSI作为一种模型的有效性， 对AUD和PTSD共病的易感性增加，并可能导致新的 神经生物学靶点，用于开发急需的共病治疗方法。