Adolescent Stress and Prefrontal Cortical Circuitry

描述（由申请人提供）：在人类中，抑郁症的发作经常发生在青春期后期，通常与重大的生活压力有关。此外，青春期的压力或创伤通常与后期PTSD的发展有关。这两种疾病影响的女性人数几乎是男性的两倍，表明疾病发展的性二态性过程。值得注意的是，青少年时期与前额叶皮层连接的终端发展相吻合，前额叶皮层连接包括抑郁症和创伤后应激障碍中受影响的关键认知情感回路。在成年人中，由于压力或压力激素暴露，前额叶皮层及其靶点发生异常的结构重排。先前的研究表明，糖皮质激素应激激素反应在青春期被夸大，预测这些群体可能选择性地容易受到压力对大脑结构的负面影响。因此，青春期的逆境可能会损害这一关键情绪调节途径的最终发展，导致不适当的情绪调节。该建议使用大鼠模型来检验这一假设，即青少年慢性压力产生短期和长期的前额叶皮质情绪控制回路的重组，导致情绪，冲动和压力反应的皮质调节明显受损。目的1使用一组行为和生理测试来确定青少年慢性压力和性对抑郁样行为、恐惧条件反射消退、延迟反应学习和糖皮质激素稳态的影响，这些功能由前额叶皮层控制，已知在抑郁症和创伤后应激障碍中被破坏。目的2使用解剖学方法来测试前额叶投射通路的完整性，重点是前额叶皮层和下游靶点的突触学变化，并使用一种新的病毒追踪方法，随着时间的推移，前额叶传出连接的发展，再次关注男性和女性。目的3测试糖皮质激素受体信号传导在男性和女性青少年应激的即时和持久的行为和内分泌影响中的作用，在应激暴露期间使用时间限制的受体合成敲低。总之，这些研究有望清楚地确定青少年压力在前额叶皮层病理中的作用， 本报告介绍了对男性和女性进行心理健康教育的情况，并提供了对可能采取的干预措施的深入了解，以尽量减少男性和女性与压力有关的疾病的发展。

DESCRIPTION (provided by applicant): In humans, onset of depressive illness frequently occurs in the late adolescent period, often in conjunction with significant life stress. In additio, adolescent stress or trauma are frequently linked to later development of PTSD. Both disorders affect nearly twice as many women as men, suggesting a sexually dimorphic course of disease development. Notably, the adolescent period coincides with the terminal development of prefrontal cortex connectivity, which comprises the key cognitive-emotional circuit affected in both depressive illness and PTSD. The prefrontal cortex and its targets undergo aberrant structural rearrangement as a consequence of stress or stress hormone exposure in adults. Prior studies indicate that glucocorticoid stress hormone responses are exaggerated in adolescence, predicting that these groups may be selectively vulnerable to negative effects of stress on brain structure. Thus, adversity during adolescence may compromise the final development of this key emotional regulatory pathway, resulting in inappropriate mood regulation. This proposal uses a rat model to test the hypothesis that adolescent chronic stress produces short- and long-term reorganization of prefrontal cortical emotional control circuits, resulting in pronounced impairments in cortical regulation of mood, impulsivity, and stress reactivity. Aim 1 uses a battery of behavioral and physiological tests to establish the impact of adolescent chronic stress and sex on depression-like behavior, extinction of fear conditioning, delayed response learning, and glucocorticoid homeostasis, functions controlled by the prefrontal cortex and known to be disrupted in depression and PTSD. Aim 2 uses anatomical methods to test the integrity of prefrontal projection pathways, focusing on changes in synaptology of the prefrontal cortex and downstream targets and, using a novel viral tracing approach, the development of prefrontal efferent connectivity over time, again focusing on both males and females. Aim 3 tests the role of glucocorticoid receptor signaling in immediate and lasting behavioral and endocrine effects of adolescent stress in males and females, using time-constrained knockdown of receptor synthesis during stress exposure. Together, these studies are expected to clearly identify a role for adolescent stress in prefrontal cortical pathologies in both males and females, and provide insight into possible interventions for minimizing development of stress-related diseases in both sexes.