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，童年时期的严重逆境可以解释32-44%的精神障碍，并与日后抑郁风险的4.6倍和药物滥用风险的6.6倍有关。新出现的证据表明，有儿童期性虐待(CSA)史的成年人中，有20%-40%的人报告很少或根本没有症状。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不清楚。临床前研究强烈表明，早期的逆境导致中脑边缘和中皮质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一致，即稳定且运转良好的奖励系统和增强的前额叶皮质功能可能是韧性的标志。这项拟议研究的主要目标是调查5-9岁有CSA病史的年轻成年女性(“CSA/MDD组”)和没有目前诊断为严重抑郁障碍(MDD)的(“CSA/RES组”)的中皮质边缘多巴胺能通路。为了弄清CsA与MDD相关的影响，这些组将不仅与健康对照组比较，还与没有CsA病史的MDD女性进行比较。此外，为了尽量减少解释问题，过去或现在有影响多巴胺和/或纹状体通路的障碍(注意力缺陷多动障碍、物质依赖/滥用、强迫症)或可能代表抑郁途径的障碍(创伤后应激障碍)的参与者将被排除在外。最后，为了增加研究的概括性和招募的可行性，将允许身体虐待与CSA一起发生，因为先前的研究结果表明：(1)身体虐待通常与CSA一起发生；以及(2)CSA和身体虐待的同时主要增加发展成MDD的风险。我们假设，与健康对照组和CsA/Res组相比，CsA/MDD参与者的特征是：(1)当暴露于急性心理社会应激操作时，奖赏反应和腹内侧额叶皮质激活降低，但皮质醇分泌增加，(2)多巴胺能传递减少，(3)多巴胺转运体结合减少。这些假说将使用一种新的行为、内分泌和功能/分子成像方法的集成来测试。提高我们对与不同CSA结局(特别是MDD和复原力)相关的神经生物学机制的了解，对于(1)识别有精神病理和适应不良行为风险的个人，(2)防止再次受害，以及(3)开发更有针对性的治疗干预措施，是至关重要的。 公共卫生相关性：儿童期性虐待与成年后精神病理、再次受害和破坏健康的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。这项拟议的研究的目的是利用行为、内分泌和功能/分子成像方法的创新整合，调查中皮质边缘多巴胺能机制对儿童期性虐待的适应性(恢复力)和适应性不良(严重抑郁)后遗症的贡献。更好地了解与虐待相关的后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，在更小的年龄识别有精神病理风险的人，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.