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

协调中央杏仁核 CRF 神经元的状态依赖性动机调节

基本信息

批准号：
10624231
负责人：
Mi-Seon Kong
金额：
$ 7.43万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624231
关键词：
Address Affect Affective Amygdaloid structure Anxiety Appetitive Behavior Behavior Behavioral Brain Brain region Cells Code Corticotropin-Releasing Hormone Decision Making Dependence Desire for food Development Emotional Fright Genetic Genetic Techniques Imaging Techniques Incentives Infusion procedures Learning Light Link Mediating Mediator Molecular Motivation Negative Valence Neurons Nucleus Accumbens Output Physiological Play Positive Valence Process Regulation Reporting Research Rewards Role Stimulus Structure System Techniques Testing Tetanus Toxin Thalamic structure Training behavioral outcome behavioral response cell type designer receptors exclusively activated by designer drugs directed attention experience experimental study in vivo calcium imaging innovation insight motivated behavior mouse genetics neural circuit neuronal circuitry optogenetics response sensory stimulus tool

项目摘要

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.

项目概要/摘要杏仁核是编码“价”的大脑结构之一，“价”被定义为主观价值分配给影响后续行为的感觉刺激的中央杏仁核（CeA）已经出现。作为积极处理各种动机的重要大脑区域，包括与价相关的学习和最先进的遗传学和光遗传学技术揭示了 CeA 内的微电路。在食欲和厌恶动机状态以及远程状态下具有异质功能对许多大脑区域的预测，这些区域的功能与积极和消极密切相关尽管已经取得了重大进展，但仍不清楚不同的细胞类型是否存在差异。有助于与单价（正价或负价）相关的行为调节，或者某些细胞是否在 CeA 处理中，单细胞类型的一种候选者以状态依赖的方式对两者做出贡献。两者都是表达促肾上腺皮质激素释放因子 (CRF) 的神经元，CeA-CRF 的作用为负价。恐惧和焦虑的神经元已经被识别出来，并且它们被认为可以调节恐惧的表达和恐惧的表达。据报道，恐惧的可扩展性是增强的，这表明 CeA-CRF 神经元的激活。 CeA-CRF 神经元也参与正价态的处理，一种可能的方式是通过情感状态依赖方式；状态是根据先前经验的效价设定的。因此，之前已经报道了 CRF 的状态依赖性作用，将 CRF 输注到处于幼稚状态的伏隔核（NAc）正在增强；然而，由于之前有过厌恶的经历，根据这些观察，将 CRF 输注到 NAc 中可将食欲状态逆转为厌恶状态。我建议两种经历的顺序（正面接着负面，或者负面接着负面）正）导致偏态状态依赖性，有利于 CeA-CRF 的价态编码我将从三个不同的层面（行为层面、神经层面和神经层面）检验这个假设。拟议的研究将为如何处理不同的情绪价提供新的见解。由相同的神经元进行处理，以及这种处理如何影响动机行为，我将接受广泛的培训。分子、遗传和成像技术将使我能够揭示 CeA-CRF 神经元如何以状态依赖的方式对寻求奖励行为进行双向影响，并阐明这些调制背后的机制。