Early environment and the neurobiology of depression

描述(由申请人提供) 抑郁症是一种与压力相关的异质性障碍。抑郁症的发病机制和抗抑郁治疗的治疗作用尚不清楚。了解导致抑郁障碍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变化，从而导致对成人精神疾病易感性的个体差异的编程。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不清楚。CAMP级联反应、转录因子cAMP反应元件结合蛋白(CREB)和神经营养因子、脑源性神经营养因子(BDNF)参与抑郁症的病理生理和治疗。CAMP-CREB级联反应和神经营养因子BDNF在早期生活事件的影响中的作用还相对未被探讨。早期生活事件，即啮齿动物模型中的母体分离和出生后处理，对CREB和BDNF的影响，以及cAMP-CREB级联和BDNF在促进早期生活事件的行动中的作用是这一合作FIRCA项目的主旨。解决这些分子作用的方法将利用药理学试剂、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出生后处理对(1)基因表达、(2)海马祖细胞增殖、(3)海马区细胞凋亡和(4)行为模型(如强迫游泳试验和旷场试验)的影响。上述研究将提供关于cAMP-CREB级联和BDNF是否对早期生命事件敏感的见解，并将解决这些通路的变化是否有助于神经系统中个体差异的产生，从而为抑郁症等应激相关疾病的易感性变化提供底物。拟议的项目将与印度TIFR的Vidita Vaidya博士合作执行，该研究是NIH母公司#RO1 MH45481赠款的延伸。

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.