Neuroplasticity of the Extended Amygdala CRF circuitry in alcohol dependence

酒精依赖中扩展杏仁核 CRF 回路的神经可塑性

• 批准号: 10077812
• 负责人: MARISA ROBERTO
• 金额: $ 39.94万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077812
• 关键词: Acute; Affect; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amygdaloid structure; Area; Behavior; Behavioral; CRF receptor type 1; Cell Nucleus; Cells; Characteristics; Chronic; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Dendritic Spines; Development; Electrophysiology (science); Emotional; Ethanol; Ethanol dependence; Female; Fluorescence-Activated Cell Sorting; Genes; Glutamates; Grant; Green Fluorescent Proteins; Impairment; In Situ Hybridization; Knowledge; Medial; Molecular; Molecular Profiling; Morphology; Mus; Neuronal Plasticity; Neurons; Neuropeptides; Phenotype; Physical shape; Physiological; Play; Population; Prefrontal Cortex; Property; Public Health; Regulation; Relapse; Role; Signal Transduction; Stress; Synapses; System; Systems Biology; Testing; Transgenic Mice; Viral; Viral Vector; alcohol abstinence; alcohol effect; alcohol response; alcohol use disorder; alcoholism therapy; anxiety-like behavior; anxiety-related behavior; cell type; drinking; drinking behavior; executive function; hippocampal pyramidal neuron; innovation; insight; interdisciplinary approach; male; mouse model; neuroadaptation; neurochemistry; patch clamp; promoter; receptor; recruit; response; sex; tool; transcriptome; transcriptomics; treatment strategy

Alcohol use disorder (AUD) is a major public health concern characterized by the loss of control over alcohol drinking and the emergence of negative emotionality during abstinence from alcohol. The transition to alcohol dependence is associated with the concomitant dysregulation of executive function by the medial prefrontal cortex (mPFC) and the recruitment of corticotropin releasing factor (CRF) and its CRF receptor 1 (CRF1) in the central nucleus of the amygdala (CeA), but much less is known about the role of CRF/CRF1 signaling in cortical areas. Critically, the development of new tools to access subpopulations of CRF1 neurons has facilitated our studies of function and connectivity of CRF/CRF1 systems. In the original grant, we use an innovative transgenic mouse models in which CRF1 expressing (CRF1+) neurons co-express green fluorescent protein (GFP) (CRF1:GFP mice) to understand the cell type-specific effects of acute and chronic alcohol in local and downstream CeA microcircuits. Preliminary data have revealed that the CRF1+ neurons are highly expressed in mPFC layer 2/3 and undergo specific neuroadaptations following chronic alcohol compared to unlabeled (CRF1-) neurons. Thus, in this renewal, we will continue to use CRF1:GFP and CRF1:Cre mice to characterize the electrophysiological, neurochemical and morphological properties of both CRF1+ and CRF1- neurons in the mPFC, and elucidate the role of mPFC CRF1+ circuitry in anxiety-like and drinking behaviors. Through a systems biology approach, we will delineate the CRF1-dependent effects of ethanol in mPFC, as well as amygdala-mPFC connectivity that may regulate ethanol dependence and withdrawal and contribute to associated anxiety-related behaviors. In addition, we will use fluorescence activated cell sorting (FACS) followed by whole transcriptome analysis to reveal molecular signatures and neuroadaptations of this specific CRF1 cortical population, which may identify new promising targets for treatment strategies for alcoholism.

酒精使用障碍（AUD）是一个主要的公共卫生问题，其特点是失去对酒精的控制 饮酒以及戒酒期间出现的负面情绪。这 向酒精依赖的转变与伴随的执行功能失调有关 通过内侧前额叶皮层 (mPFC) 和促肾上腺皮质激素释放因子 (CRF) 的募集 它的 CRF 受体 1 (CRF1) 位于杏仁核中央核 (CeA)，但人们对其知之甚少 CRF/CRF1 信号在皮质区域的作用。至关重要的是，开发新工具来访问 CRF1 神经元亚群促进了我们对 CRF/CRF1 功能和连接性的研究 系统。在最初的资助中，我们使用了一种创新的转基因小鼠模型，其中 CRF1 表达 (CRF1+) 神经元共表达绿色荧光蛋白 (GFP)（CRF1:GFP 小鼠） 了解急性和慢性酒精对局部和下游 CeA 的细胞类型特异性影响 微电路。初步数据显示，CRF1+神经元在mPFC中高表达 与未标记的相比，第 2/3 层在长期饮酒后经历特定的神经适应 (CRF1-) 神经元。因此，在本次更新中，我们将继续使用 CRF1:GFP 和 CRF1:Cre 小鼠 表征 CRF1+ 和 CRF1+ 的电生理学、神经化学和形态学特性 mPFC 中的 CRF1- 神经元，并阐明 mPFC CRF1+ 电路在焦虑样和 饮酒行为。通过系统生物学方法，我们将描述 CRF1 依赖性效应 mPFC 中乙醇的含量，以及可能调节乙醇依赖的杏仁核-mPFC 连接 和退缩并导致相关的焦虑相关行为。此外，我们将使用 荧光激活细胞分选（FACS），然后进行全转录组分析以揭示分子 该特定 CRF1 皮质群的特征和神经适应，可能会识别出新的 酒精中毒治疗策略的有希望的目标。