Corticolimbic circuitry in adaptive stress coping behavior and subsequent alcohol drinking

适应性压力应对行为和随后饮酒的皮质边缘回路

• 批准号: 10672448
• 负责人: Laura C. Ornelas
• 金额: $ 10.31万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10672448
• 关键词: 2-arachidonylglycerol; 2-arachidonylglycerol signaling; Alcohol abuse; Alcohol consumption; Alcohols; Amygdaloid structure; Animal Model; Automobile Driving; Brain; CNR1 gene; Cells; Clinical; Coping Behavior; Coping Skills; Data; Development; Electrophysiology (science); Endocannabinoids; Exposure to; Failure; Female; Foundations; Future; Genetic; Goals; Immobilization; Immunohistochemistry; Individual; Individual Differences; Label; Learning; MAGL inhibitor; Measures; Medial; Mediating; Methods; Modeling; Molecular; Neurons; Neurosciences; Odors; Pathway interactions; Phase; Population; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Prevention strategy; Rattus; Research; Risk; Role; Self Administration; Sex Differences; Signal Transduction; Site; Stress; Stress and Coping; Stressful Event; Subgroup; Techniques; Testing; Training; Trauma; Woman; Work; alcohol comorbidity; alcohol use disorder; behavioral outcome; behavioral pharmacology; behavioral response; career; comorbidity; coping; endocannabinoid signaling; endogenous cannabinoid system; experience; genetic approach; in vivo; job market; liquid chromatography mass spectrometry; maladaptive behavior; male; men; neural circuit; neuroadaptation; neurobiological mechanism; neuromechanism; neuronal excitability; optogenetics; prevent; reduce symptoms; resilience; response; sex; skills; stressor; theories; traumatic stress; treatment strategy

Project Summary Individuals with post-traumatic stress disorder (PTSD) consume alcohol as an attempt to alleviate symptoms, which can increase the risk of developing a drinking problem. However, well-adapted coping responses to stress may protect against development of PTSD and mitigate subsequent alcohol use. Further, not only are women twice as likely as men to suffer from PTSD, but certain individuals may be more susceptible or resilient in adapting to stressful events. This suggests specific brain mechanisms that mediate sex differences in response to stress and also individual differences in coping responses may mitigate against lasting consequences of stress such as alcohol consumption. In this proposal, I will investigate how failure to engage in adaptive coping strategies to stress may be driven by hypofunctioning between corticolimbic regions specifically the prelimbic (PrL) cortex and the basolateral amygdala (BLA), and whether increases in endocannabinoid signaling can restore this maladaptive behavior. I utilize an animal model of stress exposure to the predator odor TMT, which produces distinct coping behaviors between male and female rats, as well as individual differences in subsequent increases in alcohol self-administration. Using this model, I will utilize a variety of chemogenetic, electrophysiological and optogenetic techniques to directly manipulate the PrLBLA circuit and examine its functional role in driving adaptive responses to stress and alcohol self-administration in male and female rats. Further, I will investigate the direct role of endocannabinoid signaling in modulating maladaptive versus adaptive coping responses and whether this signaling can act as a protective mechanism against later escalations in alcohol self-administration. The K99 portion of this proposal involves extensive training using chemogenetic and cell-specific molecular approaches and advanced electrophysiological techniques to probe both functional changes and in vivo neuroadaptive responses. This training will provide me with a stronger neuroscience foundation which will be critical to increase my competitiveness on the job market and will be important in my independent career. Uncovering the neural mechanisms that drive maladaptive coping behavior and subsequent alcohol self-administration within the K99 portion will provide future directions for the R00 phase. Studies within the R00 phase will specifically assess whether endocannabinoids can directly restore PrL hypofunctioning that leads to dysregulated neuroadaptations within the BLA and central amygdala (CeA) circuitry that drives behavioral outcomes to stress. Together, completion of these aims will establish corticolimbic circuitry and endocannabinoid mechanisms that drive coping strategies during predator odor stress and alcohol drinking. Additionally, studies in this application will further my long-term research goal which is to elucidate neurobiological mechanisms that underlie sex differences in comorbid alcohol use and PTSD.

项目摘要 患有创伤后应激障碍（PTSD）的人饮酒是为了缓解症状， 这会增加出现饮酒问题的风险。然而，适应良好的应对压力的反应 可以防止创伤后应激障碍的发展，并减少随后的酒精使用。此外，不仅女性 患有创伤后应激障碍的可能性是男性的两倍，但某些人可能更容易受到影响或更有弹性 适应压力事件。这表明，特定的大脑机制，介导性别差异的反应， 应对压力的个体差异和应对反应的个体差异可能会减轻压力的持久后果 例如酒精消费。在这个建议中，我将研究如何未能从事适应性应对 压力的策略可能是由皮质边缘区，特别是前边缘区， (PrL)皮质和基底外侧杏仁核（BLA），以及内源性大麻素信号的增加是否可以 恢复这种不适应的行为。我利用动物模型的压力暴露于捕食者气味TMT， 在雄性和雌性大鼠之间产生不同的应对行为，以及随后的个体差异。 增加酒精自我管理。使用这个模型，我将利用各种化学遗传学， 电生理学和光遗传学技术直接操纵PrL BLA回路，并检查其 在驱动雄性和雌性大鼠对压力和酒精自我给药的适应性反应中的功能作用。 此外，我将研究内源性大麻素信号在调节适应不良与适应性的直接作用。 应对反应，以及这种信号是否可以作为一种保护机制，防止后来的升级， 酒精自我管理该建议的K99部分涉及使用化学遗传学和 细胞特异性分子方法和先进的电生理学技术来探测功能 变化和体内神经适应性反应。这次训练将为我提供更强的神经科学 这对提高我在就业市场上的竞争力至关重要，对我的职业生涯也很重要。 独立的职业生涯。揭示驱动适应不良应对行为和随后的神经机制 K99部分的酒精自我管理将为R00阶段提供未来的方向。研究范围 R00阶段将特别评估内源性大麻素是否可以直接恢复PrL功能减退， 导致BLA和中央杏仁核（CeA）回路中的神经适应失调， 压力的行为结果。总之，完成这些目标将建立皮质边缘回路， 内源性大麻素机制，驱动在捕食者气味压力和饮酒的应对策略。 此外，在这个应用程序的研究将进一步我的长期研究目标，这是阐明 神经生物学机制是酒精使用和创伤后应激障碍共病的性别差异的基础。