Effects of chronic stress on amygdala physiology

 描述（由申请人提供）：迫切需要新的抗抑郁药，在青少年中工作。青少年的抑郁现象有所不同，但其原因尚不清楚。许多抗抑郁药缺乏疗效和不同的现象学的一个可能的解释是，青少年抑郁症的病理生理学存在差异。我们研究的长期目标是确定杏仁核的病理生理学如何导致抑郁症的症状。这些实验的短期目标是测试特定杏仁核输出通路的差异是否是青少年和成人抑郁行为差异的基础。基底外侧杏仁核（BLA）通过输出到不同的神经区域来指导许多焦虑和食欲行为。这些BLA输出之间的相对活动平衡了焦虑和食欲行为。该项目将检验以下假设：青少年的主要BLA输出途径的活性不同，这导致了对食欲行为的偏好。反复的压力模仿抑郁症的几种症状，包括快感缺乏和焦虑。该项目还将测试这一假设，即反复的压力将主要BLA输出的平衡转移到那些与焦虑有关的人身上，远离那些引导享乐行为的人，但在成人和青少年中是通过不同的机制。利用电生理学、行为学和遗传学方法，本项目旨在确定青少年和成人BLA输出的相对活性，以确定重复压力是否对两种主要BLA输出产生年龄依赖性作用，并确定它们对压力行为效应的贡献。此外，这项研究将直接 比较成年人和青少年反复压力的影响机制。该项目具有重要意义，因为它可以证明不同年龄的焦虑和享乐行为平衡差异的新神经生物学机制，并为开发新的青少年抗抑郁药提供新的靶向机制。这些实验是创新的，因为它们将测试特定BLA神经元群体在不同年龄的行为重要回路中的功能。这种方法将产生令人兴奋的新信息的BLA电路的行为的重要性和新的见解形成的精神综合征通过BLA输出活动的不平衡。了解青少年这种不平衡的机制，有望发现治疗青少年抑郁症的替代药理学方法。

 DESCRIPTION (provided by applicant): There is an urgent need for new antidepressants that work in adolescents. Depression phenomenology is different in adolescents, but the reasons for this are not known. One possible explanation for lack of efficacy of many antidepressants and different phenomenology is that there is a difference in the pathophysiology of depression in adolescents. The long-term goal of our research is to determine how pathophysiology of the amygdala contributes to symptoms of depressive disorders. The short-term goal of these experiments is to test whether differences in specific amygdala output pathways underlie differences between adolescent and adult depressive behavior. The basolateral amygdala (BLA) guides many anxiety and appetitive behaviors via outputs to different neural regions. The relative activity between these BLA outputs balances anxiety and appetitive behavior. This project will test the hypothesis that the activity of major BLA output pathways is different in adolescents, and this leads to a favoring of appetitive behaviors. Repeated stress mimics several symptoms of depression, including anhedonia and anxiety. This project will also test the hypothesis that repeated stress shifts the balance of major BLA outputs towards those involved with anxiety and away from those that guide hedonic behaviors, but via different mechanisms in adults and adolescents. Using electrophysiological, behavioral and genetic approaches, this project aims to determine the relative activity of BLA outputs in adolescents and adults, to determine if repeated stress exerts age-dependent actions on two major BLA outputs, and to determine their contribution to behavioral effects of stress. Furthermore, this study will directly compare the mechanisms for the effects of repeated stress in adults and adolescents. This project is significant because it can demonstrate a novel neurobiological mechanism for differences in the balance of anxiety and hedonic behaviors across age, and provide novel targetable mechanisms for the development of new antidepressants for adolescents. These experiments are innovative because they will test the function of specific BLA neuronal populations in the context of their place in behaviorally important circuits across age. This approach will yield exciting new information about the behavioral importance of BLA circuits and novel insight into the formation of a psychiatric syndrome via an imbalance in the activity of BLA outputs. Understanding of the mechanism that underlies this imbalance in adolescents is expected to uncover alternative pharmacological approaches to treat depression in adolescents.