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，被列为成年人疾病负担的主要贡献者 青少年。理解抑郁症发展的一个有希望的病因机制很低。 对奖励的责任感。青春期奖赏反应减弱可预测抑郁症 发病并与症状严重程度的增加有关。鉴于责任弱化的突出作用 在抑郁症的出现和病程中进行奖励，奖励反应可能是治疗的关键目标， 尤其是在青春期，当抑郁症的发病率激增时，当奖励 受影响的年轻人的责任感明显减弱，当奖励制度可能特别 塑料，因此，理论上更容易受到干预。然而，在可以实现干预之前，一个 需要更彻底地理解发展奖励响应性。虽然众所周知，奖赏 责任感在青少年正常发育过程中经历了戏剧性的变化，人们对此知之甚少 这些变化背后的行为或神经机制，无论是在健康发育中还是在青少年中 伴随着患抑郁症风险的增加。拟议的研究将使用现有的项目数据，同时扩展 亲本R01的初步目标，通过进一步探索(1)中与奖励相关的发育表型 奖励响应性的行为维度，以及(2)层级成熟的奖励回路。跨越两个目标， 将使用症状级别的方法来研究形成奖励响应性的潜在机制， 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)。具体地说，AIM 1将使用计算建模来检查 跨规范发展的奖励响应性的不同维度以及与 抑郁症状。由于计算建模允许更多地理解行为反应 从机制上讲，这项研究的发现将为理解调控失调是如何 奖励响应性的特定方面会导致抑郁的发生。目标2将研究微观结构如何 最新发现的奖赏相关白质--内侧前脑束上外侧支的发育 物质通道，在健康的青少年发展和那些有抑郁风险的人中的变化。虽然很宽泛 白质干扰通常与抑郁症有关，拟议的项目将试图证明 白质中奖赏反应与微结构之间的特殊功能-结构关系 具有很高理论相关性的区域。此外，正如强有力的证据表明，神经回路是分层次成熟的。 (从皮质下到皮质)，拟议的项目将研究奖励响应性如何变化与 在连续成熟的管束节段中发育微结构。在这两个目标中，建议的 这项研究很有希望阐明抑郁症病因学的新机制，为 针对高度可塑性青春期奖励反应减弱的治疗学基础。

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.