Early Life Stress and Depression: Molecular and Functional Imaging Approaches

流行病学研究表明，严重的童年逆境可以解释32-44%的精神疾病，并且与以后生活中抑郁症的4.6倍风险和药物滥用的6.6倍风险相关。新出现的证据表明，20-40%的成年人与儿童性虐待（CSA）的历史报告很少或没有性虐待。尽管有这些流行病学数据，与CSA的适应性（恢复力）和适应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，早期逆境导致中脑边缘和中皮层多巴胺能通路的中断，这些通路与奖赏处理和应激反应密切相关。这些数据与理论观点相一致，即稳定和功能良好的奖励系统以及前额叶皮层功能的增强可能是弹性的标志。所提出的研究的总体目标是调查年龄在5-9岁之间具有CSA病史的年轻成年女性中的中皮质边缘多巴胺能通路，其中CSA/MDD组（CSA/MDD组）和当前诊断为重度抑郁症（MDD）的年轻成年女性（CSA/RES组）。为了理清CSA与MDD相关效应，将这些组不仅与健康对照组进行比较，还与无CSA病史的MDD女性进行比较。此外，为了尽量减少解释问题，将排除既往或当前患有已知影响多巴胺和/或纹状体通路的疾病（注意缺陷多动障碍、物质依赖/滥用、强迫症）或可能代表抑郁通路的疾病（创伤后应激障碍）的受试者。最后，为了增加研究的普遍性和招募的可行性，将允许身体虐待与CSA同时发生，因为之前的研究结果是（1）身体虐待通常与CSA同时发生;（2）CSA和身体虐待同时发生主要会增加发生MDD的风险。我们假设，相对于健康对照组和CSA/RES组，CSA/MDD参与者的特征是：（1）当暴露于急性心理社会应激操纵时，奖励反应性和腹内侧前额叶皮层激活降低，但皮质醇分泌过多，（2）多巴胺能传递减少，（3）多巴胺转运蛋白结合减少。这些假设将使用一种新的整合行为，内分泌和功能/分子成像方法进行测试。提高我们对与不同CSA结果（特别是MDD和恢复力）相关的神经生物学机制的理解至关重要，以便（1）识别具有精神病理学和适应不良行为风险的个体，（2）防止再次受害，（3）开发更有针对性的治疗干预措施。 公共卫生相关性：儿童期性虐待与成年后精神病理学、再次受害和损害健康行为的风险增加有关，但这些结果背后的神经生物学机制在很大程度上仍不清楚。拟议的研究的目标是调查的贡献mesocorticolimbic多巴胺能机制的适应性（弹性）和适应不良（重性抑郁症）后遗症的儿童性虐待使用创新整合的行为，内分泌和功能/分子成像方法。更好地了解与滥用有关的结果的神经生物学基础将有助于制定更有针对性的治疗干预措施，确定年轻时有精神病理学风险的个人，并防止再次受害。

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.