Endocrine regulation of alcohol consumption and fear learning

在美国，酒精使用障碍(AUD)影响着大约15%的成年人。虽然这些数字本身就令人震惊， 被诊断为创伤后应激障碍(PTSD)的患者患AUD的可能性是 对广大民众来说。这种关系在退伍军人群体中更加令人担忧，因为退伍军人病历 提示63%患有AUD的退伍军人被共同诊断为PTSD。共同患病的澳州大学和创伤后应激障碍是一个主要的 鉴于患有创伤后应激障碍的退伍军人长期过量饮酒加剧了医疗保健问题 创伤后应激障碍的症状包括恐惧反应过度泛化和恐惧记忆受损、消退。 临床上，治疗AUD和PTSD共病的能力尚未得到解决，我们对 导致AUD和PTSD共同发病的常见神经通路的不良适应变化是有限的。 因此，为了开发有效的治疗共病的AUD和PTSD的方法，我们必须提高我们的知识 通过使用尖端技术寻求新的假设，为什么这些障碍表现出强烈的相关性。 最近，内分泌激素成纤维细胞生长因子21(FGF21)，以其强大的代谢作用而闻名， 说明了通过一种未描述的需要表达的机制显著减少酒精消耗 FGF21共同受体β-klotho(KLb)在大脑中的专有表达。重要的是，单核苷酸多态在 FGF21和KLB基因座都与人类酒精摄入量的增加高度相关。我们的 该提案中提供的初步数据表明，过度饮酒会促进FGF21 肝脏的分泌物。此外，在肝脏中缺乏FGF21表达的小鼠表现出更多的偏好 酒精提示FGF21信号对酒精消费的反应代表了一种体内平衡反馈 循环，以负向调节酒精消费。此外，我们还发现，FGF21通过KLB传递信号 基底外侧杏仁核(BLA)表达(KLb+)神经元是FGF21抑制酒精所必需的 消费。有趣的是，BLA中的FGF21信号似乎也是增强恐惧记忆所必需的 与长期饮酒有关提示血乳酸中的FGF21信号影响两种酒精 消费和恐惧记忆。在BLA中，我们已经确定了两个不同的KLb+神经元群体 投射到伏隔核(NAC)或中央杏仁核(CEA)。BLA中的神经元投射到 这些区域此前已被说明用于调节酒精消费和恐惧记忆。相关的是， 这些相同的预测群体被描述为编码相关线索的情绪价位 带着奖赏和厌恶。因此，在这个提议中，我们假设FGF21信号通过KLb+神经元在 投射到NAC或CEA的BLA通过以下途径影响饮酒和恐惧记忆 调节这些神经元的价编码特性。这项提议利用了可选技术。 记录、体内钙成像和光遗传学研究投射中的FGF21信号如何定义 脑白质中KLb+神经元的数量影响价编码、饮酒和恐惧 条件反射，以提高我们对共享神经底物如何导致AUD和PTSD的理解。作为一名 博士后研究员，有研究大脑中FGF21信号如何调节的经验 生理动态平衡我将在Dr。 马修·波特霍夫和泰德·亚伯医生。该提案附带的职业发展计划旨在 实现我的长期目标，成为一名独立的退伍军人管理局资助的研究人员。与以下项目相关的近期目标 这项建议，如学习光学电极记录和钙成像，以及获得终身教职 这个职位将有助于我实现长期的职业目标。职业发展计划的主要方面 包括由我的导师和一个科学咨询委员会提供的技术和专业指导 专门为实现这项提案的目标而设计的。关于科学写作和领导力的正式课程 以及研究会议将补充我的科学咨询委员会提供的培训。

In the United States alcohol use disorder (AUD) affects ~15% of adults. While those numbers alone are striking, patients diagnosed with post-traumatic stress disorder (PTSD) are 3 times more likely to develop AUD compared to the population at large. This relationship is even more worrisome in Veteran populations as VA medical records suggest 63% of Veterans with AUD are co-diagnosed with PTSD. Co-morbid AUD and PTSD represents a major healthcare issue given that chronic excessive alcohol consumption in Veteran populations with PTSD intensifies symptoms of PTSD including overgeneralization of the fear response and impaired fear memory extinction. Clinically, the ability to treat co-morbid AUD and PTSD has not been addressed and our understanding of maladaptive changes in common neural pathways which contribute to co-morbidity AUD and PTSD is limited. Therefore, in order to develop effective therapies for co-morbid AUD and PTSD we must improve our knowledge of why these disorders exhibit a strong relationship by pursuing new hypotheses using cutting edge techniques. Recently, the endocrine hormone fibroblast growth factor 21 (FGF21), known for its potent metabolic effects, was illustrated to significantly reduce alcohol consumption via an undescribed mechanism requiring expression of the obligate FGF21 co-receptor β-klotho (KLB) in the brain. Importantly, single nucleotide polymorphisms in both FGF21 and KLB genomic loci are highly associated with increased alcohol consumption in humans. Our preliminary data presented in this proposal illustrates that excessive alcohol consumption promotes FGF21 secretion from the liver. Additionally, mice lacking FGF21 expression in the liver exhibit increased preference for alcohol suggesting FGF21 signaling in response to alcohol consumption represents a homeostatic feedback loop to negatively regulate alcohol consumption. Furthermore, we find that FGF21 signaling through KLB expressing (KLB+) neurons in the basolateral amygdala (BLA) is necessary for FGF21 to suppress alcohol consumption. Interestingly, FGF21 signaling in the BLA also appears to be necessary for enhanced fear memory associated with chronic alcohol consumption suggesting FGF21 signaling in the BLA influences both alcohol consumption and fear memory. In the BLA we have identified two distinct populations of KLB+ neurons which project to the nucleus accumbens (NAc) or the central amygdala (CeA). Neurons in the BLA which project to these regions have previously been illustrated to regulate alcohol consumption and fear memory. Relatedly, these same projection populations have been described to encode the emotional valence of cues associated with reward and aversion. Thus, in this proposal we hypothesize that FGF21 signaling through KLB+ neurons in the BLA which project to the NAc or the CeA influences alcohol consumption and fear memory through modulating the valence encoding properties of these neurons. This proposal takes advantage of optrode recording, in vivo calcium imaging, and optogenetics to investigate how FGF21 signaling in projection defined populations of KLB+ neurons in the BLA influences valence encoding, alcohol consumption, and fear conditioning to improve our understanding of how shared neural substrates contribute to AUD and PTSD. As a postdoctoral research fellow with experience investigating how FGF21 signaling in the brain regulates physiological homeostasis I will perform the experiments described in this proposal under the mentorship of Dr. Matthew Potthoff and Dr. Ted Abel. The career development plan accompanying this proposal is designed to achieve my long-term goal of becoming an independent VA-funded researcher. Immediate goals associated with this proposal, such as learning optrode recording and calcium imaging, as well as obtaining a tenure track faculty position will facilitate accomplishing my long-term career goal. Key aspects of the career development plan include technical and professional mentorship provided by my mentors and a Scientific Advisory Committee designed specifically to accomplish the goals of this proposal. Formal courses on scientific writing and leadership as well as research conferences will supplement the training provided by my Scientific Advisory Committee.