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.

项目概要 患有创伤后应激障碍（PTSD）的人通过饮酒来缓解症状， 这会增加出现饮酒问题的风险。然而，对压力的适当应对反应 可以预防创伤后应激障碍（PTSD）的发展并减少随后的饮酒。此外，不仅是女性 患有创伤后应激障碍 (PTSD) 的可能性是男性的两倍，但某些人可能更容易受到创伤后应激障碍 (PTSD) 的影响或更有恢复力 适应压力事件。这表明介导反应中性别差异的特定大脑机制 压力以及应对反应的个体差异可能会减轻压力的持久后果 例如饮酒。在本提案中，我将研究未能采取适应性应对措施的情况 应激策略可能是由皮质边缘区域（特别是前边缘区域）之间的功能减退驱动的 (PrL) 皮质和基底外侧杏仁核 (BLA)，以及内源性大麻素信号传导的增加是否可以 恢复这种适应不良的行为。我利用了应激暴露于捕食者气味 TMT 的动物模型， 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 酒精自我管理的增加。使用这个模型，我将利用各种化学遗传学， 电生理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管理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传导在调节适应不良与适应方面的直接作用 应对反应以及这种信号是否可以作为防止后续升级的保护机制 酒精自我管理。该提案的 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技术来探测功能 变化和体内神经适应性反应。这次培训将为我提供更强的神经科学知识 这对于提高我在就业市场上的竞争力至关重要，并且对于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后续行为的神经机制 K99 部分中的酒精自我管理将为 R00 阶段提供未来方向。研究范围 R00阶段将专门评估内源性大麻素是否可以直接恢复PrL功能低下 导致 BLA 和中央杏仁核 (CeA) 电路内的神经适应失调，从而驱动 压力的行为结果。总之，完成这些目标将建立皮质边缘回路和 内源性大麻素机制在捕食者气味压力和饮酒期间驱动应对策略。 此外，该应用程序的研究将进一步推进我的长期研究目标，即阐明 共病饮酒和创伤后应激障碍的性别差异背后的神经生物学机制。