Sensitive Periods, Brain Development and Depression

描述（由申请人提供）：早期遭受虐待是抑郁症发展的主要风险因素。在过去的几年里，我们和其他人已经证明，童年时期的虐待与大脑结构的改变有关。最近，我们假设不同的大脑区域有自己的神经发育敏感期，当它们最容易受到早期压力的影响时，并发表了第一批支持这些假设的初步发现。特别是，我们发现海马、胼胝体和额叶皮层分别在3-5岁、9=10岁和14-16岁时最脆弱。此外，我们假设虐待的精神后遗症至少部分取决于与区域敏感期相关的压力源的时间。这个研究项目的目的是确定这些区域神经发育敏感期的初步发现是否可以复制，扩展到男性和其他形式的逆境，除了儿童性虐待。其次，我们将验证我们的假设，即存在离散的敏感期，当遭受虐待或损失与患抑郁症的风险最大相关时。进一步，我们将验证抑郁症发展的敏感期与左海马和部分前额叶皮层的易感性窗口重叠的假设，并将确定其他大脑区域是否有易感性窗口与抑郁症的敏感期重叠。接下来，我们将测试遗传因素增加抑郁症风险的假设，部分是通过放大和延长抑郁症的敏感期。最后，我们将验证这样的假设，即早期暴露于可耐受的压力源将有助于接种未暴露的儿童宿主，如果他们随后在敏感期暴露于可耐受的压力源，则不会发展为抑郁症。此外，促进神经发生、促进强烈自尊感或提供支持性社会网络的经历将有助于预防暴露的宿主出现抑郁症。这些假设将在从社区招募的600个人（20-25岁，约50%为男性）的样本中进行测试。每个童年阶段遭受虐待和损失的程度和时间将使用改进的童年不良经历评分进行回顾性量化。将通过体积T1和T2扫描和扩散张量图像评估其中200名受试者的神经发育敏感期。这一信息将极大地增强我们对重度抑郁症的起源和病因的理解，并可能为设计预防或预防抑郁症发展的计划提供必要的关键见解。

DESCRIPTION (provided by applicant): Exposure to early abuse is a major risk factor for the development of depression. Over the last several years we, and others, have shown that childhood abuse is associated with alterations in brain structure. Recently, we hypothesized that different brain regions have their own individual neurodevelopmental sensitive periods when they are maximally susceptible to the effects of early stress, and have published the first preliminary findings that support these hypotheses. In particular, we found that the hippocampus, corpus callosum and frontal cortex were maximally vulnerable at 3-5, 9=10 and 14-16 years of age, respectively. In addition we hypothesized that the psychiatric sequela of abuse would depend, at least in part, on the timing of the stressor in relation to regional sensitive periods. The aims of this program of research is to ascertain if these preliminary findings of regional neurodevelopmental sensitive periods can be replicated, extended to males and to other forms of adversity besides childhood sexual abuse. Second, we will test our hypothesis that there are discrete sensitive periods when exposure to abuse or loss is maximally associated with risk for developing depression. Further, we will test the hypothesis that sensitive periods for the development of depression overlap with windows of vulnerability for left hippocampus and portions of prefrontal cortex, and will also ascertain if other brain regions have windows of vulnerability that overlap with the sensitive period for depression. Next we will test the hypothesis that hereditary factors increase risk for depression, in part, by amplifying and extending the sensitive period for depression. Finally, we will test the hypotheses that early exposure to tolerable stressors will help to inoculate unexposed child hosts from developing depression if they are subsequently exposed during the sensitive period. Further, experiences that foster neurogenesis, facilitate strong feelings of self-esteem or provide a supportive social network will help to preempt the emergence of depression in exposed hosts. These hypotheses will be tested in a sample of 600 individuals (20-25 years of age, ~50% male) recruited from the community. Degree and timing of developmental exposure to abuse and loss across each childhood stage will be quantified retrospectively using a modified Adverse Childhood Experience score. Neurodevelopmental sensitive periods will be evaluated in 200 of these subjects from volumetric T1 and T2 scans and diffusion tensor images. This information will greatly enhance our understanding of the genesis and etiology of major depression and may provide critical insights necessary to design programs to prevent or preempt the development of depressive disorders.