Orchestrating state-dependent modulation of motivations in central amygdala CRF neurons

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PROJECT SUMMARY/ABSTRACT The amygdala is one of the brain structures that encode ‘valence’, defined as the subjective value allocated to sensory stimuli that influences consequential behavior. The central amygdala (CeA) has emerged as an important brain region for actively processing diverse motivations, including valence-related learning and behaviors. State-of-the-art techniques in genetics and optogenetics have revealed microcircuits within the CeA that have heterogeneous functions in appetitive and aversive motivational states, as well as long-range projections to numerous brain regions whose functions are closely related to both positive and negative valences. Although significant progress has been made, it remains unclear whether distinct cell types contribute to behavioral regulation related to a singular valence, positive or negative, or whether some cells contribute to both in a state-dependent manner. One candidate of single cell type in the CeA processing in both is the corticotropin-releasing factor (CRF)-expressing neurons. In negative valence, the role of CeA-CRF neurons in fear and anxiety has been identified, and they are thought to regulate the fear expression and the scalability of fear. Interestingly, activation of CeA-CRF neurons was reported as reinforcing, which suggests that CeA-CRF neurons are also involved in positive valence. A possible way of processing both valences is via an affective state-dependent manner; where the state is set based on the valence of previous experience. Accordingly, state-dependent actions of CRF have been previously reported, with the infusion of CRF into the nucleus accumbens (NAc) in a naïve state being reinforcing; however, with a previous aversive experience, infusion of CRF into the NAc inverses the appetitive state into an aversive state. Based on these observations, I propose that the order of two experiences (positive followed by negative or negative followed by positive) results in a biased state dependence that favors valence coding by CeA-CRF towards the initial experience. I will examine this hypothesis at three different levels (behavioral, neuronal, and neural circuit). The proposed research will provide new insights into how different emotional valances are processed by the same neurons and how this processing affects motivated behaviors. I will receive extensive training in molecular, genetic, and imaging techniques that will allow me to reveal how CeA-CRF neurons have bidirectional influences over reward-seeking behavior in a state-dependent manner and to elucidate the mechanisms underlying these modulations.