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

项目总结/摘要 杏仁核是编码“效价”的大脑结构之一，定义为主观价值 分配给影响后续行为的感官刺激。中央杏仁核（CeA）已经出现， 作为一个重要的大脑区域，积极处理各种动机，包括与价相关的学习， 行为。最先进的遗传学和光遗传学技术揭示了CeA内的微电路 在食欲和厌恶的动机状态下具有不同的功能， 投射到许多大脑区域，这些区域的功能与积极和消极的功能密切相关。 化合价虽然已经取得了重大进展，但仍不清楚不同的细胞类型是否 有助于行为调节与一个单一的价，积极或消极的，或是否有些细胞 以一种依赖于国家的方式对两者作出贡献。一个候选的单细胞类型的CeA处理中， 两者都是表达促肾上腺皮质激素释放因子（CRF）的神经元。在负效价中，CeA-CRF的作用 神经元在恐惧和焦虑已被确定，他们被认为是调节恐惧的表达和 恐惧的可扩展性。有趣的是，CeA-CRF神经元的激活被报道为强化，这表明 CeA-CRF神经元也参与正效价。处理两种化合价的可能方式是通过 一种情感状态依赖的方式;这种状态是基于先前经验的效价来设定的。 因此，先前已经报道了CRF的状态依赖性作用，将CRF注入到 在幼稚状态下的丘脑核（NAc）正在加强;然而，由于先前的厌恶经历， 将CRF输注到NAc中将食欲状态逆转为厌恶状态。根据这些观察， 我建议，两种经验的顺序（积极的其次是消极的或消极的其次是 正）导致偏向的状态依赖性，其有利于CeA-CRF朝向 初步经验。我将从三个不同的层次（行为、神经元和神经 电路）。这项拟议中的研究将为如何处理不同的情绪效价提供新的见解 以及这种处理过程如何影响动机行为。我将接受广泛的培训， 分子，遗传和成像技术，这将使我能够揭示CeA-CRF神经元是如何 双向影响奖励寻求行为的状态依赖的方式，并阐明 这些调节的机制。

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.