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 early life experience of traumatic stress. 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. Stress experienced during the rodent equivalent of human adolescence leads to long- term changes in the structure and function of mPFC. However, it remains unclear how stress affects specific mPFC neurons and circuits, or what role these substrates play in pathological emotional responses. The long- term goal of this project is to identify mPFC neurons that are activated by adolescent traumatic stress and to test the hypothesis that these cells undergo persistent functional changes that underlie increased adult anxiety. During the exploratory phase of this award, we will implement a viral genetic system to tag stress-activated neurons so that they can be identified and manipulated in adulthood, a technique that has never before been applied within the context of early-life stress. In conjunction with this approach, we will utilize optogenetics to activate or inhibit stress-activated neurons in adult animals to establish their role in anxiety-related behaviors. In addition, electrophysiological recordings will be obtained from these cells to investigate whether emotional dysfunction correlates with changes in their synaptic physiology. These experiments could establish a novel paradigm for isolating brain plasticity that underlies specific behavioral outcomes of stress, which would be major advance toward more precise and effective therapies. Further analysis of the circuit, synaptic and molecular properties of stress-activated neurons could uncover specific mechanisms for pathology that might evade detection with traditional approaches.
The goal of this proposal is to define specific cellular and circuit mechanisms of plasticity resulting from early life traumatic stress. The results of these studies will help improve our understanding of how early life experience leads to adult emotional dysfunction.
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