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

基本信息

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
项目类别：
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

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

展开

项目摘要

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）高度合并知道有助于这种合并症的神经底物。而且，尽管经常出现AUD和PTSD，患有这些疾病的可能性有明显的变化关于可能赋予AUD和PTSD脆弱性或韧性的神经底物知之甚少。该应用的科学前提是对电路和神经生物学有更好的了解区分这些脆弱和韧性的人群可能会揭示出更多的发展目标对患有合并症的人的有效治疗。为了应对这一挑战，我们有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，并具有对面部，构建和预测有效性作为脆弱模型产生了鼓励的支持到AUD和PTSD。例如，相对于整个青春期（AGH）的大鼠组，ASI大鼠表现出许多行为与AUD和PTSD风险的增加有关，包括恐惧灭绝和持久的缺陷乙醇饮酒行为的增加。值得注意的是，相对温和的恐惧调节程序明显在ASI大鼠中增加乙醇自我给药至少8周，而对乙醇饮用没有影响在AGH主题中。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度量杏仁核（BLA）和腹海马（VHC），两个高度相互连接的大脑区域，它们的积分不可或缺在AUD和PTSD中破坏的许多情绪行为中的作用。基于这些发现，本应用中概述的研究将采用多学科实验设计来确定恐惧是否存在调节程序导致ASI大鼠中AUD和PTSD的核心行为症状表达 AGH受试者是否对此应激源有弹性。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ASI相关的神经生物学适应，并且特别是在BLA-VHC电路中，以及该电路的加强是否在因果关系中起因果作用该模型促进的AUD/PTSD样行为表型。其他研究将测试一种新型的治疗方法扭转ASI +恐惧条件提倡的不良适应行为的策略。基于其他新兴调查结果，这些研究还将检验以ASI +恐惧条件促进类似的创新假设男性和雌性大鼠的神经适应性，但这些压力源产生的行为表型可能是性二态的。总的来说，这些研究将进一步增强ASI的有效性增强了合并AUD和PTSD的脆弱性，并有可能导致新颖的识别神经生物学目标是为合并症开发急需的治疗方法。