Adolescent Stress and Prefrontal Cortical Circuitry

描述(由申请人提供)：在人类中，抑郁疾病的发作通常发生在青春期晚期，通常伴随着巨大的生活压力。此外，青春期的压力或创伤经常与创伤后应激障碍的发展有关。这两种疾病影响的女性人数几乎是男性的两倍，这表明疾病的发展过程存在性别差异。值得注意的是，青春期恰逢前额叶皮质连接性的终末发育，这构成了抑郁症和创伤后应激障碍的关键认知-情绪回路。由于成人的压力或应激激素暴露，前额叶皮质及其靶区经历了异常的结构重排。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，这预示着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。这项建议使用一只大鼠模型来检验这一假说，即青春期慢性应激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、冲动和应激反应的皮质调节明显受损。目的1利用一系列行为和生理测试来确定青春期慢性应激和性别对抑郁样行为、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质控制，已知在抑郁症和创伤后应激障碍中受到干扰。目的2使用解剖学方法测试前额叶投射通路的完整性，重点是前额叶皮质和下游靶点突触的变化，并使用一种新的病毒示踪方法，研究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。目的研究糖皮质激素受体信号在青春期应激的即刻和持久的行为和内分泌效应中的作用，方法是在应激过程中限时抑制受体合成。总之，这些研究有望明确确定青春期应激在青少年前额叶皮质病变中的作用。 包括男性和女性，并提供可能的干预措施，以最大限度地减少与压力有关的疾病在男女之间的发展。

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.