Adolescent Stress and Prefrontal Cortical Circuitry

青少年压力和前​​额皮质回路

• 批准号: 8702965
• 负责人: James P Herman
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-10 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702965
• 关键词: Adolescence; Adolescent; Adult; Affect; Affective; Amygdaloid structure; Anxiety; Attenuated; Behavior; Behavioral; Behavioral inhibition; Brain; Brain Pathology; Chronic stress; Cognitive; DNA Sequence Rearrangement; Data; Data Aggregation; Development; Disease; Emotional; Emotional Stress; Emotions; Endocrine; Extinction (Psychology); Female; Functional disorder; Glucocorticoid Receptor; Glucocorticoids; Homeostasis; Hormones; Human; Image; Impairment; Impulsivity; Intervention; Learning; Life; Life Stress; Link; Literature; Mediating; Mental Depression; Mental disorders; Methods; Modeling; Monitor; Moods; Nature; Neurons; Output; Pathology; Pathway interactions; Phenotype; Physiological; Pituitary Gland; Population; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Process; Proteins; Rattus; Receptor Signaling; Regulatory Pathway; Resolution; Rodent; Rodent Model; Role; Signal Transduction; Stream; Stress; Structure; Subfamily lentivirinae; Sucrose; Swimming; Synapses; System; Testing; Therapeutic Intervention; Time; Trauma; Viral; Woman; base; biological adaptation to stress; cohort; conditioned fear; depressive symptoms; design; insight; learning extinction; lentiviral-mediated; male; men; mood regulation; nerve supply; neurobehavioral; novel; pediatric trauma; preference; public health relevance; receptor; response; sex; stressor; therapy design; time use

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.

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，通常伴随着巨大的生活压力。此外，青少年压力或创伤常常与创伤后应激障碍 (PTSD) 的后期发展有关。这两种疾病影响的女性人数几乎是男性的两倍，表明疾病发展存在性别二态性。值得注意的是，青春期恰逢前额皮质连接的最终发育，前额皮质连接包括受抑郁症和创伤后应激障碍影响的关键认知情绪回路。由于成年人的压力或应激激素暴露，前额皮质及其目标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，导致情绪调节不当。该提案使用大鼠模型来检验以下假设：青少年慢性压力会导致前额皮质情绪控制回路的短期和长期重组，导致情绪、冲动和压力反应性的皮质调节明显受损。目标 1 使用一系列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、恐惧调节的消除、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 (PTSD) 中会受到干扰。目标 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的突触变化，并使用新型病毒追踪方法，研究前额叶传出连接随时间的发展，再次关注男性和女性。目标 3 通过在压力暴露期间限时抑制受体合成，测试糖皮质激素受体信号传导在男性和女性青少年压力的即时和持久行为和内分泌影响中的作用。总之，这些研究预计将明确确定青少年压力在前额皮质病理中的作用。 男性和女性，并深入了解可能的干预措施，以尽量减少两性压力相关疾病的发展。