Ontogenic factors in adolescent-emergent depression and decision-making

描述(由申请人提供)：流行病学证据表明，青春期是抑郁症发展的更容易发生的时期，特别是耐药抑郁症。此外，青少年抑郁症的治疗选择比成年人更有限，青春期出现抑郁症会增加吸烟、肥胖、药物滥用、失业和终生抑郁复发的风险。这些结果可能与逆境的影响有关--例如社交孤立或压力荷尔蒙暴露--对前额叶皮质的影响，只有在青春期结束时才能达到完全的结构成熟。我们和其他人假设，当逆境对前额叶皮质细胞结构的长期影响与青春期显著的神经可塑性重合时，可能会被夸大，因此可能会产生累加的、持久的、甚至是永久的后果。然而，经验证据是有限的，因为在典型的、更不病态的环境下，协调青春期结构成熟的生物事件对行为的影响知之甚少。为了填补当前知识的这一空白，我们将首先分离早期生活逆境对深层前额叶皮质神经元结构的神经生物学影响。我们将利用体外和体内成像，以及分别为男性和女性青少年开发的两种抑郁症小鼠模型。这一点至关重要，因为青春期出现的抑郁症在女性中更常见，但对女性人群的研究仍然严重不足。接下来，为了测试针对前额叶皮质细胞细化分子机制的治疗干预的可能性，我们将筛选两种作用于肌动蛋白细胞骨架调节器的药物化合物，测量它们的抗抑郁药效。我们的目标是阻止早年逆境带来的长期行为后果。最后，由于抑郁会减弱对奖励的敏感性，扰乱完成目标所必需的决策过程，甚至会削弱执行日常任务的动力，因此，作为最后的目标，我们将使用病毒介导的基因沉默和改进的外科手术切断技术来同时分离目标导向的行动选择的分子和神经解剖学机制。我们将集中讨论对出生后结构优化至关重要的分子相互作用：脑源性神经营养因子与高亲和力TrkB受体的结合以及p120RasGAP-p190RhoGAP信号复合体的形成。这一建议特别适合NIMH Brains项目：使用不同的实验方法，并利用由该领域杰出人士组成的咨询委员会，我们将绘制早期生活逆境后细胞和行为结果的轨迹；我们将改进未被研究的人群中抑郁症精神病理学的新治疗方法；我们将分离精神疾病核心组成部分的发育和分子机制。

DESCRIPTION (provided by applicant): Epidemiological evidence indicates that adolescence represents a period of increased vulnerability to the development of depression, specifically depression that is treatment-resistant. Moreover, treatment options for depressed adolescents are more limited than for adults, and depression onset in adolescence increases the risk of smoking, obesity, substance abuse, unemployment, and depression recurrence across the lifespan. These outcomes may relate to the effects of adversity-such as social isolation or stress hormone exposure- on the prefrontal cortex, which reaches full structural maturity only at the end of adolescence. We and others have hypothesized that the long-term effects of adversity on cellular structure within the prefrontal cortex may be exaggerated when it coincides with the marked neural plasticity of adolescence, and may thereby have additive, persistent, and perhaps even permanent consequences. Empirical evidence is limited, however, because little is known about the behavioral impact of biological events that coordinate structural maturation during adolescence under typical, much less pathological, circumstances. To fill this gap in current knowledge, we will first isolate the neurobiological consequences of early-life adversity on the structure of deep-layer prefrontal cortical neurons. We will utilize in vitro and in vivo imaging, as well as two mouse models of depression that have been developed for male and female adolescents, respectively. This is crucial because adolescent-emergent depression is more common among women, yet female populations remain grossly understudied. Next, to test the potential for therapeutic interventions that target the molecular mechanisms of prefrontal cortical cellular refinement, we will screen two pharmacological compounds that act on regulators of the actin cytoskeleton, measuring their antidepressant-like efficacy. We aim to block the long-term behavioral consequences of early-life adversity. Finally, because depression attenuates reward sensitivity, disrupts decision-making processes essential to accomplishing goals, and diminishes motivation to perform even everyday tasks, we will, as a last aim, use viral-mediated gene silencing and modified surgical disconnection techniques to simultaneously isolate the molecular and neuroanatomical mechanisms of goal-directed action selection. We will focus on molecular interactions critical to postnatal structural refinement: Brain-derived Neurotrophic Factor binding to the high- affinity trkB receptor and formation of the p120RasGAP-p190RhoGAP signaling complex. This proposal is uniquely suited to the NIMH BRAINS program: Using diverse experimental approaches, and drawing on an advisory committee comprised of luminaries in the field, we will chart the trajectory of cellular and behavioral outcomes after early-life adversity; we will refine novel treatment approaches to depression psychopathology in understudied populations; and we will isolate developmental and molecular mechanisms of core components of psychiatric disease.