Ontogenic factors in adolescent-emergent depression and decision-making

青少年突发抑郁症和决策的个体因素

• 批准号: 8711565
• 负责人: Shannon Leigh Gourley
• 金额: $ 43.89万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711565
• 关键词: Actins; Adolescence; Adolescent; Adult; Advisory Committees; Affinity; Amygdaloid structure; Antidepressive Agents; Attenuated; Behavior; Behavioral; Binding; Biological; Brain-Derived Neurotrophic Factor; Cellular Structures; Complex; Confocal Microscopy; Corticosterone; Cytoskeleton; Decision Making; Dedications; Dendritic Spines; Depressed mood; Development; Doctor of Philosophy; Epidemiology; Event; Exposure to; Failure; Female; Female Adolescents; Foundations; Funding; Gene Silencing; Gene Transfer; Gene-Modified; Goals; Guanosine Triphosphate Phosphohydrolases; Hormones; Image; Imaging Techniques; In Vitro; Infusion procedures; Knowledge; Life; Long-Term Effects; Longevity; Male Adolescents; Measures; Mediating; Mental Depression; Mental Health; Mental disorders; Mission; Modeling; Molecular; Molecular Mechanisms of Action; Molecular Target; Motivation; Mus; National Institute of Mental Health; Neuraxis; Neurobiology; Neuronal Plasticity; Neurons; Neurotoxins; Neurotrophic Tyrosine Kinase Receptor Type 2; Obesity; Operative Surgical Procedures; Outcome; Pediatrics; Pharmacological Treatment; Population; Prefrontal Cortex; Primates; Process; Property; Psychiatry; Psychopathology; Qualifying; Recurrence; Research; Research Priority; Resistance; Rewards; Risk; Rodent; Rodent Model; Role; Safety; Signal Transduction; Smoking; Social isolation; Structure; Substance abuse problem; Techniques; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Unemployment; United States National Institutes of Health; Viral; Woman; adolescent-onset depression; base; critical period; depressive symptoms; in vivo; in vivo imaging; interest; latrunculin A; male; medical schools; mouse model; novel; p120 GTPase Activating Protein; postnatal; professor; programs; public health relevance; relating to nervous system; research study; social stress; treatment strategy

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.

描述（由申请人提供）：流行病学证据表明，青春期是一个易患抑郁症的时期，特别是难以治疗的抑郁症。此外，青少年抑郁症的治疗选择比成年人更有限，青少年抑郁症的发作增加了吸烟、肥胖、药物滥用、失业和抑郁症在整个生命周期中复发的风险。这些结果可能与逆境的影响有关——比如社会孤立或压力激素暴露——对前额皮质的影响，前额皮质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，逆境对前额皮质细胞结构的长期影响可能会被夸大，当它与青春期显著的神经可塑性同时发生时，可能因此产生附加的、持续的，甚至可能是永久的后果。然而，经验证据是有限的，因为在典型的，更不用说病理的情况下，对协调青春期结构成熟的生物事件的行为影响知之甚少。为了填补目前知识的空白，我们将首先分离出早期生活逆境对深层前额皮质神经元结构的神经生物学后果。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。这是至关重要的，因为青春期出现的抑郁症在女性中更为常见，而女性群体的研究仍然严重不足。接下来，为了测试针对前额皮质细胞细化的分子机制的治疗干预的潜力，我们将筛选两种作用于肌动蛋白细胞骨架调节剂的药理化合物，测量它们的抗抑郁样功效。我们的目标是阻止早年逆境的长期行为后果。最后，由于抑郁症减弱了奖励敏感性，扰乱了完成目标所必需的决策过程，并减少了执行日常任务的动机，我们将作为最后的目标，使用病毒介导的基因沉默和改良的手术断开技术来同时分离目标导向行动选择的分子和神经解剖学机制。我们将重点关注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受体的结合和p120RasGAP-p190RhoGAP信号复合物的形成。这一建议特别适合NIMH BRAINS项目：使用多种实验方法，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；我们将在未充分研究的人群中完善新的抑郁症精神病理学治疗方法；我们将分离精神疾病核心成分的发育和分子机制。