Behavioral and neural mechanisms of reward responsivity across normative and at-risk adolescent development

抑郁症是一个主要的公共卫生问题，是成年人疾病负担的主要贡献者， 青少年。一个有前途的病因学机制，了解抑郁症的发展是低 对奖励的反应。青少年期奖励反应性降低预测抑郁症 发病并与症状严重程度增加相关。考虑到反应性降低的突出作用 在抑郁症的发生和发展过程中，奖赏反应可能是治疗的关键目标， 特别是在青少年时期，当抑郁症发病率飙升时， 受影响的年轻人的反应明显减弱，当奖励系统可能特别 塑料，因此，理论上更容易干预。然而，在采取干预措施之前， 需要更深入地了解奖励反应性的发展。虽然众所周知， 反应性在规范的青少年发展中经历了巨大的变化，对此知之甚少。 这些变化背后的行为或神经机制，无论是在健康发展还是在青少年中 患抑郁症的风险增加拟议的研究将使用现有的项目数据，同时扩展 亲本R 01的初始目标，通过进一步探索发育中的奖励相关表型（1） 奖励反应的行为维度，以及（2）分层成熟的奖励电路。在两个目标中， 发展奖励反应性的机制将使用一个层次的方法进行检查， 纵向设计，比较有和没有抑郁症家族史的青少年（高危和 规范性团体）。具体来说，目标1将使用计算模型来检查发展轨迹， 不同维度的奖励反应性在规范的发展，并在有关的病因 抑郁症症状由于计算建模允许更多地理解行为反应， 机械术语，这项研究的结果将奠定基础，了解如何失调， 奖励反应性的特定方面导致抑郁发作。目标2将研究微观结构如何 内侧前脑束上外侧分支的发育，最近发现的与奖励相关的白色 问题道，在健康的青少年发展和那些有抑郁症风险的变化。虽然广泛 一般来说，白色物质的破坏与抑郁症有关，拟议中的项目将试图证明 白色物质中奖赏反应性和微观结构之间的特定功能-结构关系 具有高度理论相关性。此外，强有力的证据表明，神经回路的成熟是分层次的， (from皮层下到皮层），拟议的项目将研究如何奖励反应性的变化， 在管道的连续成熟段中发展微结构。在这两个目标中， 研究很有希望阐明抑郁症病因的新机制，奠定 针对高度可塑性的青少年时期奖励反应减弱的治疗方法的基础。

Depression is a major public health concern, ranking as a leading contributor of disease burden in adults and adolescents. A promising etiological mechanism for understanding the development of depression is low responsivity to rewards. Diminished reward responsivity during adolescence prospectively predicts depression onset and is associated with increased symptom severity. Given the prominent role of diminished responsivity to reward in the emergence and course of depression, reward response may be a critical target for treatment, particularly during the adolescent period when the prevalence of depression onset spikes, when reward responsivity among affected youth is markedly attenuated, and when the reward system may be particularly plastic, and, thus, theoretically more amenable to intervention. Before interventions can be realized, however, a more thorough understanding of developing reward responsivity is needed. While it is known that reward responsivity undergoes dramatic change across normative adolescent development, very little is known about the behavioral or neural mechanisms underlying these changes, either in healthy development or in adolescents with an increased risk for depression. The proposed research will use existing project data, while extending the initial aims of the parent R01, by further probing the developing reward-related phenotype in terms of (1) behavioral dimensions of reward responsivity, and (2) hierarchically maturing reward circuitry. Across two aims, the mechanisms underlying developing reward responsivity will be examined using a symptom-level approach, longitudinal design, and comparison of adolescents with and without a family history of depression (at-risk and normative groups). Specifically, Aim 1 will use computational modeling to examine developmental trajectories of distinct dimensions of reward responsivity across normative development and in relation to the etiology of depression symptoms. As computational modeling allows behavioral responses to be understood in more mechanistic terms, the findings of this research will lay the foundation for understanding how dysregulation of specific aspects of reward responsivity lead to depression onset. Aim 2 will examine how microstructure development in the superolateral branch of the medial forebrain bundle, a recently identified reward-related white matter tract, changes across healthy adolescent development and in those at-risk for depression. While broad white matter disruptions have been linked to depression generally, the proposed project will seek to demonstrate a specific functional-structural relationship between reward responsivity and microstructure in a white matter tract with high theoretical relevance. Further, as strong evidence suggests neural circuitry matures hierarchically (from subcortical to cortical), the proposed project will examine how reward responsivity changes in relation to developing microstructure in successively maturating segments of the tract. Across both aims, the proposed research has great promise to elucidate novel mechanisms underlying the etiology of depression, laying the foundation for therapeutics that target diminished reward responsivity during the highly plastic adolescent period.