Cellular substrates of early life trauma

大多数精神疾病在生命早期发病率最高，目前估计， 五分之一的青少年会患上这种疾病，并持续到成年。一个主要的风险因素， 是童年创伤的经历。在与这些最密切相关的大脑区域中， 条件是内侧前额叶皮层（mPFC），它形成了一个突触网络，在大脑中起着重要作用。 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敏感性增加，这些表型类似于人类的状况，如焦虑 和抑郁症，并伴随着mPFC的结构和功能的长期变化， 成年然而，目前还不清楚是否独特的机制赋予不成熟的应激敏感性， 动物，或者在成年人与小鼠中暴露于压力后立即发生的过程。长期 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， 这些影响的机制，并了解导致的异常功能特性。特别是我们 初步数据表明，青春期早期是去甲肾上腺素依赖性抑制的敏感期 的mPFC活动和兴奋性，这一过程的参与，在创伤性应激导致长期- 威胁回避的持续增加，这是人类焦虑的潜在相关因素。我们将前所未有地利用 纵向钙成像在自由行为的小鼠，以测量这些生理效应，以及 mPFC活动的变化，信号异常回避行为。细胞和突触机制 低兴奋性将通过电生理记录来阐明。最后，我们将使用时间特定的 光遗传学操作，以测试在特定投射途径内恢复mPFC活性是否 足以逆转创伤相关的表型。我们希望建立这种全面的模式， 压力敏感性，我们可以揭示生物因素，可能有助于高利率， 儿童期精神疾病发作。

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.