Adolescent Stress and Prefrontal Cortical Circuitry

描述（由申请人提供）：在人类中，抑郁症的发作通常发生在青春期后期，通常伴随着重大的生活压力。此外，青春期的压力或创伤往往与PTSD的后期发展有关。这两种疾病影响女性的人数几乎是男性的两倍，这表明疾病的发展过程是两性二态的。值得注意的是，青少年时期与前额叶皮层连通性的最终发展相吻合，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-情绪回路。在成人中，由于压力或应激激素暴露，前额叶皮层及其靶区会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。本研究采用大鼠模型来验证以下假设：青少年慢性压力会导致前额叶皮层情绪控制回路的短期和长期重组，从而导致皮层对情绪、冲动和应激反应的调节明显受损。Aim 1使用一系列的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、恐惧条件反射的消失、延迟反应学习和糖皮质激素稳态的影响，这些功能由前额皮质控制，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，重点关注前额叶皮层和下游目标突触学的变化，并使用一种新的病毒追踪方法，随着时间的推移，前额叶传出连通性的发展，再次关注男性和女性。目的3测试糖皮质激素受体信号在青春期应激对男性和女性的直接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有时间限制的受体合成抑制。总之，这些研究有望清楚地确定青少年压力在大脑前额叶皮层病理中的作用

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.