Early environment and the neurobiology of depression

早期环境和抑郁症的神经生物学

• 批准号: 6752130
• 负责人: RONALD S. DUMAN
• 金额: $ 3.37万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-15 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6752130
• 关键词: apoptosis; brain derived neurotrophic factor; cAMP response element binding protein; cyclic AMP; depression; developmental neurobiology; early experience; gene expression; genetically modified animals; hippocampus; immunocytochemistry; in situ hybridization; laboratory mouse; northern blottings; parent deprivation; psychosocial separation; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant) Depression is a stress-related heterogeneous disorder. The mechanisms underlying the pathogenesis of depression and the therapeutic actions of antidepressant treatments are as yet not well understood. Understanding the factors that contribute to the generation of individual differences in vulnerability to depressive disorders is of critical importance. One hypothesis is that early life events result in persistent alterations in the nervous system thus contributing to the programming of individual differences in vulnerability to adult psychopathology. The specific pathways that are influenced by early life events and their role in setting up individual differences in adult vulnerability is not as yet clearly characterized. The cyclic AMP cascade, the transcription factor cAMP response element binding protein (CREB), and the neurotrophin, Brain derived neurotrophic factor (BDNF) have been implicated in the pathophysiology and treatment of depression. The role of the cAMP-CREB cascade and the neurotrophin BDNF in the effects of early-life events is relatively unexplored. The influence of early life events, namely maternal separation and postnatal handling in rodent models, on CREB and BDNF and the role of the cAMP-CREB cascade and BDNF in contributing to the actions of early life events are the main thrust of this collaborative FIRCA project. Approaches used to address the role of these molecules will capitalize on the use of pharmacological agents, viral expression of molecules and transgenic/deletion mouse mutants. We will ask whether regulation of these molecules influences the effects of maternal separation and postnatal handling on (1) gene expression (2) hippocampal progenitor proliferation (3) apoptosis in the hippocampus and (4) behavioral models such as forced swim test and open-field test. The above studies will provide insights into whether the cAMP-CREB cascade and BDNF are sensitive to early-life events and will address whether alterations in these pathways contribute to the generation of individual differences in neural systems thus providing a substrate for altered vulnerability to stress-related disorders such as depression. The proposed project will be executed in collaboration with Dr. Vidita Vaidya at TIFR, India and the research is an extension of the parent NIH grant # RO1 MH45481.

描述（由申请人提供） 抑郁症是一种与压力相关的异质性疾病。抑郁症的发病机制和抗抑郁药物的治疗作用尚不清楚。了解导致抑郁症易感性个体差异的因素至关重要。一种假设是，早期生活事件会导致神经系统的持续改变，从而导致个体差异对成人精神病理学的脆弱性的影响。受早期生活事件影响的具体途径及其在建立成人脆弱性个体差异中的作用尚未明确描述。环 AMP 级联、转录因子 cAMP 反应元件结合蛋白 (CREB) 和神经营养蛋白、脑源性神经营养因子 (BDNF) 与抑郁症的病理生理学和治疗有关。 cAMP-CREB ​​级联和神经营养素 BDNF 在早期生命事件影响中的作用相对尚未被探索。早期生命事件，即啮齿动物模型中的母体分离和产后处理，对 CREB ​​和 BDNF 的影响以及 cAMP-CREB ​​级联和 BDNF 在促进早期生命事件的作用中的作用是该合作 FIRCA 项目的主要推动力。用于解决这些分子作用的方法将利用药理制剂、分子的病毒表达和转基因/缺失小鼠突变体。我们将询问这些分子的调节是否会影响母体分离和产后处理对（1）基因表达（2）海马祖细胞增殖（3）海马细胞凋亡和（4）行为模型（例如强迫游泳测试和旷场测试）的影响。上述研究将深入了解 cAMP-CREB ​​级联和 BDNF 是否对早期生命事件敏感，并将解决这些途径的改变是否有助于神经系统个体差异的产生，从而为改变对抑郁症等压力相关疾病的脆弱性提供基础。拟议的项目将与印度 TIFR 的 Vidita Vaidya 博士合作执行，该研究是 NIH 母基金 # RO1 MH45481 的延伸。