Early Life Stress and Depression: Molecular and Functional Imaging Approaches

描述（由申请人提供）：流行病学研究表明，严重的童年逆境解释了32-44%的精神疾病，并与4.6倍的抑郁症风险和6.6倍的药物滥用风险相关。新出现的证据表明，20-40%有儿童期性虐待史（CSA）的成年人报告很少或没有症状。尽管有这些流行病学数据，但与CSA的适应性（恢复力）和适应性不良后遗症相关的神经生物学基础在很大程度上仍然未知。临床前研究强烈表明，早期逆境会导致中脑边缘和中脑皮层多巴胺能通路的破坏，这些通路与奖励加工和应激反应密切相关。这些数据与理论观点一致，即一个稳定、运转良好的奖励系统和前额皮质功能的增强可能是适应力的标志。本研究的总体目标是调查5-9岁之间有CSA病史的年轻成年女性（“CSA/MDD组”）和没有（“CSA/RES组”）当前诊断为重度抑郁症（MDD）的中皮质边缘多巴胺能通路。为了弄清CSA与MDD相关的影响，这些组不仅将与健康对照组进行比较，还将与没有CSA病史的MDD女性进行比较。此外，为了尽量减少解释性问题，过去或现在患有已知影响多巴胺和/或纹状体途径的疾病（注意缺陷多动障碍、物质依赖/滥用、强迫症）或可能代表抑郁途径的疾病（创伤后应激障碍）的参与者将被排除在外。最后，为了提高研究的普遍性和招募的可行性，根据先前的研究结果，允许身体虐待与CSA同时发生：(1)身体虐待通常与CSA一起发生；(2) CSA和身体虐待的共同发生主要增加了发生重度抑郁症的风险。我们假设，相对于健康对照组和CSA/RES组，CSA/MDD参与者将表现为：(1)当暴露于急性社会心理应激操作时，奖励反应和腹内侧前额叶皮层激活降低，但皮质醇分泌过高；(2)多巴胺能传递减少；(3)多巴胺转运体结合减少。这些假设将使用行为，内分泌和功能/分子成像方法的新颖整合进行测试。提高我们对与不同CSA结果相关的神经生物学机制的理解（特别是重度抑郁症和恢复力）对于以下方面至关重要：(1)识别有精神病理和适应不良行为风险的个体，(2)防止再次受害，(3)制定更有针对性的治疗干预措施。

DESCRIPTION (provided by applicant): Epidemiological studies show that severe childhood adversity explains 32-44% of psychiatric disorders, and is associated with 4.6-fold risk for depression and 6.6-fold risk for substance abuse later in life. Emerging evidence indicates that 20-40% of adults with a history of childhood sexual abuse (CSA) report little to no symptomatology. In spite of these epidemiological data, the neurobiological underpinnings associated with adaptive (resilience) and maladaptive sequelae of CSA remain largely unknown. Preclinical research strongly suggests that early adversity leads to disruptions within mesolimbic and mesocortical dopaminergic pathways critically implicated in reward processing and stress reactivity. These data are consistent with theoretical arguments that a stable and well-functioning reward system and increased prefrontal cortex function might be markers of resilience. The overarching goal of the proposed research is to investigate mesocorticolimbic dopaminergic pathways within young adult females with a history of CSA between the ages of 5-9 years with ("CSA/MDD group") and without ("CSA/RES group") a current diagnosis of major depressive disorder (MDD). To disentangle CSA- vs. MDD-related effects, these groups will be compared to not only healthy controls but also MDD females without a history of CSA. Moreover, to minimize interpretative issues, participants with a past or current comorbidity of disorders known to affect dopamine and/or striatal pathways (attention deficit hyperactivity disorder, substance dependence/abuse, obsessive compulsive disorder) or disorders that might represent a pathway to depression (post traumatic stress disorder) will be excluded. Finally, to increase study generalizability and recruitment feasibility, co-occurrence of physical abuse with CSA will be allowed in light of prior findings that (1) physical abuse commonly occur with CSA; and (2) co-occurrence of CSA and physical abuse primarily increases the risk of developing MDD. We hypothesize that, relative to healthy control and CSA/RES groups, the CSA/MDD participants will be characterized by (1) reduced reward responsiveness and ventromedial prefrontal cortex activation but cortisol hypersecretion when exposed to an acute psychosocial stress manipulation, (2) reduced dopaminergic transmission, and (3) reduced dopamine transporter binding. These hypotheses will be tested using a novel integration of behavioral, endocrinological, and functional/molecular imaging approaches. Improving our understanding of neurobiological mechanisms associated with different CSA outcomes (specifically MDD and resilience) is of paramount importance in order to (1) identify individuals at risk for psychopathology and maladaptive behavior, (2) prevent revictimization, and (3) develop more targeted therapeutic interventions. PUBLIC HEALTH RELEVANCE: Childhood sexual abuse has been associated with increased risk for psychopathology, revictimization, and health-damaging behavior in adulthood but the neurobiological mechanisms underlying these outcomes remain largely unknown. The goal of the proposed research is to investigate the contributions of mesocorticolimbic dopaminergic mechanisms to adaptive (resilience) and maladaptive (major depression) sequelae of childhood sexual abuse using an innovative integration of behavioral, endocrinological, and functional/molecular imaging approaches. A better understanding of neurobiological underpinnings of abuse-related outcomes will contribute to developing more targeted therapeutic interventions, identifying individuals at risk for psychopathology at a younger age, and preventing revictimization.