Neuroplasticity of the Extended Amygdala CRF circuitry in alcohol dependence

酒精使用障碍（AUD）是一个主要的公共卫生问题，其特征是对酒精的失控。 饮酒和戒酒期间出现的负面情绪。的 向酒精依赖的转变与伴随的执行功能失调有关 通过内侧前额叶皮质（mPFC）和促肾上腺皮质激素释放因子（CRF）的募集， 它的CRF受体1（CRF 1）位于杏仁核中央核（CeA），但对它的研究知之甚少。 CRF/CRF 1信号在皮质区的作用。至关重要的是，开发新的工具， CRF 1神经元的亚群为我们研究CRF/CRF 1的功能和连接提供了便利 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CRF 1 表达（CRF 1+）神经元共表达绿色荧光蛋白（GFP）（CRF 1：GFP小鼠）， 了解急性和慢性酒精在局部和下游CeA中的细胞类型特异性影响 微型电路初步数据显示，CRF 1+神经元在mPFC中高度表达， 与未标记的相比，在慢性酒精后，第2/3层经历特定的神经适应 （CRF 1-）神经元。因此，在这次更新中，我们将继续使用CRF 1：GFP和CRF 1：Cre小鼠， 表征CRF 1+和CRF 2+的电生理学、神经化学和形态学特性。 CRF 1-神经元的mPFC，并阐明mPFC CRF 1+电路在焦虑样和 饮酒行为。通过系统生物学的方法，我们将描绘CRF 1依赖的影响， 以及杏仁核-mPFC连接，可能调节乙醇依赖 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 这个特定的CRF 1皮质群体的特征和神经适应，这可能会发现新的 酒精中毒治疗策略的有希望的目标。

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.