Effects of repeated stress on amygdala function during adolescence

 描述(申请人提供)：抑郁症现象学在青少年中是不同的，许多抗抑郁药在青少年中不起作用。但造成这种情况的原因尚不清楚。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。杏仁基底外侧核(BLA)通过输出到不同的神经区来引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。这个项目将检验这样一个假设，即在青少年中，主要的血乳酸输出途径之间的平衡是不同的，这会导致向食欲行为的转变。反复的压力会模仿抑郁症的几种症状，包括快感缺失和焦虑。这个项目还将测试一种假设，即重复的压力会使主要的血乳酸输出的平衡向那些与焦虑有关的人转移，而不是那些引导享乐行为的人，但在成年人和青少年中通过不同的机制。本项目的目的是确定青少年体内两条主要的BLA输出路径之间的平衡，确定重复应激是否对两条主要的BLA输出路径产生相反的作用，以及确定靶向BLA路径是否选择性地逆转应激的行为效应。这项研究将比较重复应激影响的年龄相关机制。这个项目意义重大，因为它可以证明一种新的神经生物学机制，可以解释不同年龄段焦虑和享乐行为的平衡差异，以及压力对青少年精神症状出现的影响的新的有针对性的机制。这些实验具有创新性，因为它们将测试杏仁核在行为重要回路中的作用。这种方法将产生关于BLA电路子集的令人兴奋的新信息。这个项目将导致对BLA中的赤字如何 该药物可导致包括精神综合症在内的异常，并有望在开发治疗青少年抑郁症的替代药理学方法方面开辟一条新的途径。

 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.