Effects of repeated stress on amygdala function during adolescence

 描述（由申请人提供）：青少年的抑郁现象不同，许多抗抑郁药对青少年无效。但其原因尚不清楚。一种可能的解释是抑郁症的病理生理学差异。我们研究的长期目标是确定杏仁核的异常如何导致情感障碍的症状。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年人情感行为差异的基础。基底外侧杏仁核（BLA）通过输出到不同的神经区域来指导焦虑行为和许多食欲行为。这些BLA输出之间的平衡平衡了焦虑和食欲行为。这个项目将测试的假设，主要BLA输出途径之间的平衡是不同的青少年，这导致了向食欲行为的转变。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。本研究的目的是确定青少年两个主要BLA输出途径之间的平衡，以确定重复的压力是否对两个主要BLA输出途径产生相反的作用，并确定是否有选择性地逆转压力的行为效应。本研究将比较重复应激效应的年龄依赖性机制。这个项目是重要的，因为它可以证明一个新的神经生物学机制的差异，在不同年龄的焦虑和享乐行为的平衡，和新的有针对性的机制，压力的影响，出现在青少年的精神症状。这些实验是创新的，因为它们将测试杏仁核在行为重要回路中的功能。这种方法将产生令人兴奋的BLA电路的子集的新信息。这个项目将导致新的见解如何在BLA赤字可以 导致包括精神病综合征的异常，并有望在开发治疗青少年抑郁症的替代药理学方法方面发现新的途径。

 DESCRIPTION (provided by applicant): Depression phenomenology is different in adolescents, and many antidepressants do not work in adolescents. But the reasons for this are not known. One possible explanation is differences in the pathophysiology of depression. The long-term goal of our research is to determine how abnormalities of the amygdala contribute to symptoms of affective disorders. The short-term goal of these experiments is to test whether differences in specific amygdala output pathways underlie differences between adolescent and adult affective behavior. The basolateral amygdala (BLA) guides anxiety behavior and many appetitive behaviors via outputs to different neural regions. A balance between these BLA outputs balances anxiety and appetitive behavior. This project will test the hypothesis that the balance between major BLA output pathways is different in adolescents, and this leads to a shift towards 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. The Aims of this project are to determine the balance between two major BLA output paths in adolescents, to determine if repeated stress exerts opposite actions on two major BLA output paths, and to determine if targeting BLA paths selectively reverses behavioral effects of stress. This study will compare the age- dependent mechanisms for the effects of repeated stress. 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 novel targetable mechanisms for the impact of stress on emergence of psychiatric symptoms in adolescents. These experiments are innovative because they will test amygdala function in the context of its place in behaviorally important circuits. This approach will yield exciting new information about subsets of BLA circuits. This project will lead to novel insight about how a deficit in the BLA can lead to abnormalities that comprise a psychiatric syndrome, and is expected to uncover a new avenue in the development of an alternative pharmacological approach to treat depression in adolescents.