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

基本信息

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
项目类别：
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

项目摘要

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，青春期代表了增加对抑郁症发展的脆弱性，特别是对治疗的抑郁症。此外，沮丧的青少年的治疗选择比成人更有限，青春期的抑郁症会增加整个生命周期中吸烟，肥胖，滥用药物，失业和抑郁症的风险。这些结果可能与逆境一样的影响，例如社会隔离或压力激素暴露对前额叶皮层，仅在青春期结束时达到完整的结构成熟度。我们和其他人假设，当逆境皮质与明显的青春期神经可塑性相吻合时，逆境对前额叶皮层内细胞结构的长期影响可能会被夸大，从而可能会产生添加，持久，甚至永久的后果。但是，经验证据是有限的，因为对在典型的，较少的病态情况下协调结构成熟的生物事件的行为影响知之甚少。为了填补当前知识的这一空白，我们将首先隔离早期逆境对深层前额叶皮质神经元结构的神经生物学后果。我们将分别使用为男性和女性青少年开发的两种抑郁症模型，并利用体内和体内成像。这是至关重要的，因为青少年急性抑郁症在女性中更为普遍，但女性人口仍然严重研究。接下来，为了测试针对前额叶皮质细胞细化的分子机制的治疗干预措施的潜力，我们将筛选两种对肌动蛋白细胞骨架调节剂作用的药理化合物，测量其抗抑郁药样的功效。我们旨在阻止早期逆境的长期行为后果。最后，由于抑郁症会减轻奖励的敏感性，破坏了实现目标至关重要的决策过程，并减少了执行日常任务的动机，因此，作为最后一个目标，我们将使用病毒介导的基因沉默和修改的手术脱节技术来同时隔离目标的动力学动力学。我们将重点关注于产后结构改进至关重要的分子相互作用：脑衍生的神经营养因子与高亲和力TRKB受体的结合以及P120RASGAP-P190RHOGAP信号传导复合物的形成。该提案独特地适合NIMH大脑计划：使用各种实验方法，并利用由该领域的顾问组成的咨询委员会，我们将在早期逆境之后绘制细胞和行为结果的轨迹；我们将完善研究研究研究的新型治疗方法；我们将隔离精神病核心成分的发育和分子机制。