Cellular substrates of early life trauma

大多数精神疾病在早期发病的几率最高，目前估计 每五个青少年中就有一个会发展成这种情况，一直持续到成年。导致这种情况的一个主要风险因素 精神障碍是童年经历的创伤。在与这些事件关系最密切的大脑区域中 条件是内侧前额叶皮质(MPFC)，它形成了一个突触网络，在 情绪调节。在相当于人类青春期的发育阶段，啮齿动物表现出 对压力诱导的行为表型的易感性增加，这些表型类似于人类的情况，如焦虑 并伴随着mPFC结构和功能的长期变化。 成人期。然而，目前还不清楚是否有独特的机制赋予不成熟的人对压力的敏感性。 动物，或成人与小鼠暴露在压力下后立即发生的过程。长期的 该项目的目标是揭示创伤如何直接影响mPFC神经元，描绘底物和 这些影响的机制，并了解导致的异常功能特性。尤其是，我们的 初步数据表明，青春期早期是去甲肾上腺素依赖抑制的敏感期。 MPFC的活性和兴奋性，在创伤应激过程中参与这一过程会导致长时间的- 威胁回避的持续增加，这是人类焦虑的一个潜在相关性。我们将史无前例地 在行为自由的小鼠身上进行纵向钙成像，以测量这些生理效应以及 发出异常回避行为信号的mPFC活动的变化。细胞和突触机制 低兴奋性将通过电生理记录加以阐明。最后，我们将使用时间特定的 光遗传学操作以测试在特定投射路径内恢复mPFC活性是否 足以逆转创伤相关的表型。我们希望建立这一全面的范例 应激易感性，我们可以揭示可能导致高应激率的生物因素 儿童时期因精神障碍而发病。

Most psychiatric conditions have their highest incidence of onset in early life, and it is currently estimated that one in five adolescents will develop such a condition that persists into adulthood. A major risk factor for such disorders is the experience of childhood trauma. Among the brain regions most highly implicated in these conditions is the medial prefrontal cortex (mPFC), which forms a synaptic network that plays important roles in emotional regulation. During a developmental stage equivalent of human adolescence, rodents exhibit heightened susceptibility to stress-induced behavioral phenotypes that resemble human conditions like anxiety and depression, and that are accompanied by long-term changes in the structure and function of mPFC in adulthood. However, it remains unclear whether unique mechanisms confer susceptibility to stress in immature animals, or what processes immediately ensue upon exposure to stress in adults versus mice. The long-term goal of this project is to reveal how trauma impacts directly on mPFC neurons, delineate substrates and mechanisms in these effects, and understand the abnormal functional properties that result. In particular, our preliminary data suggest that early adolescence is a sensitive period for noradrenaline-dependent suppression of mPFC activity and excitability, and that engagement of this process during traumatic stress leads to a long- lasting increase in threat avoidance, a potential correlate of human anxiety. We will make unprecedented use of longitudinal calcium imaging in freely behaving mice to measure these physiological effects as well as changes in mPFC activity that signal abnormal avoidance behaviors. Cellular and synaptic mechanisms for hypoexcitability will be elucidated by electrophysiological recordings. Finally, we will use temporally specific optogenetic manipulations to test whether recovering mPFC activity within specific projection pathways is sufficient to reverse trauma-related phenotypes. We hope that be establishing this comprehensive paradigm of stress susceptibility, we can shed light on biological factors that potentially contribute to a high rate of childhood onset for psychiatric disorders.