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

摘要 尽管酒精使用障碍(AUD)和创伤后应激障碍(PTSD)高度并存，但很少有 已知导致这种共病的神经底物。此外，尽管经常联合- AUD和创伤后应激障碍的发生，在发展这些疾病的可能性和 对于可能导致AUD和PTSD的脆弱性或复原性的神经底物更是知之甚少。 这一应用的科学前提是更好地理解电路和神经生物学 区分这些脆弱和有弹性的人群可能会揭示出开发更多 对患有合并症的个人进行有效的治疗。为了应对这一挑战，我们有 广泛地描述了早期生活压力、青少年社交隔离(ASI)的啮齿动物模型，并有 为ASI作为脆弱性模型的面貌、结构和预测有效性提供了令人鼓舞的支持 澳元和创伤后应激障碍。例如，相对于在整个青春期(AGH)居住的大鼠，ASI大鼠表现出 许多行为都与患澳门氏症和创伤后应激障碍的风险增加有关，包括在消除恐惧和忍耐方面的缺陷 饮酒行为增多。值得注意的是，相对温和的恐惧条件反射程序显著 ASI大鼠酒精自我给药增加至少8周，但对饮酒没有影响 在高龄受试者中。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，可能 有助于这些行为表型，包括基底外侧区内兴奋性的增加 杏仁核(BLA)和腹侧海马区(VHC)是两个高度相互联系的大脑区域，在大脑中起着不可或缺的作用 在AUD和创伤后应激障碍的许多情绪行为中扮演重要角色。基于这些发现， 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 条件反射程序导致ASI大鼠AUD和PTSD核心行为症状的表达 老年受试者是否会对这一应激源具有弹性。神经生物学研究将确定恐惧是否 条件反射过程加剧了BLA和VHC中ASI相关的神经生物学适应，并且 特别是在BLA-VHC回路中，以及该回路的加强是否在 这一模型促进了AUD/PTSD样行为表型。其他研究将测试一种新的治疗方法 逆转ASI+恐惧条件反射促进的不适应行为的策略。基于其他新兴市场 发现，这些研究还将检验ASI+恐惧条件作用促进类似的创新假设 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 可能是两性型的。总的来说，这些研究将进一步加强ASI作为一种模式的有效性 对AUD和PTSD共病的易感性增加，并可能导致识别新的 为开发治疗这种并存疾病急需的治疗手段提供了神经生物学目标。

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.