Physiological consequences of alcohol exposure on CRF 1 neurons in the nucleus tractus solitarius

摘要 酒精使用障碍（AUD）是一种高度流行的慢性复发性疾病，其特征在于增加的酒精使用障碍。 酒精（EtOH）摄入，无法控制消费，以及戒断期间的负面情绪状态。 这些行为是由细胞和电路适应介导的，这可能导致神经元的变化。 结构和功能。一个关键的神经适应涉及促肾上腺皮质激素释放因子（CRF）的激活 系统，一种肽广泛释放在整个大脑中，以应对压力。通过CRF 1的CRF信号传导 CRF1受体与应激反应性增加、焦虑样行为和过量饮酒有关。 事实上，Crhr1（编码CRF1的基因）的多态性与酗酒、情绪化、 开发AUD的风险。大多数关于AUD和CRF 1的研究都集中在 前额皮质和杏仁核，而其他区域如脑干的研究则少得多。位于 在延髓尾侧，孤束核（NTS）是一个自主神经中枢，含有丰富的 CRF1受体。虽然慢性乙醇饮用已被证明可以增加NTS神经元的活性，但几乎没有。 已知特定NTS亚群的作用，最明显的是CRF1神经元，在这种作用中。在这 建议，我们将使用雄性和雌性CRF1：cre：tdTomato大鼠并建立自愿EtOH模型 摄入结合细胞电生理学方法。在目标1中，我将确定急性 乙醇对雄性和雌性CRF1：cre：td番茄CRF1 NTS神经元兴奋性和突触传递的影响 大鼠目的2：研究雄性大鼠CRF1NTS神经元兴奋性和突触传递的变化 和雌性CRF1：cre：tdTomato大鼠在慢性自愿EtOH饮用后。在目标3中，我将研究 CRF1NTS神经元的化学遗传操作对男女自愿乙醇饮酒的影响 CRF1：cre：tdTomato大鼠。总之，这些实验将揭示CRF1NTS神经元是如何与 受急性和慢性EtOH暴露以及CRF1NTS神经元如何促进饮酒的影响。 总的来说，这些研究的结果将促进我们对性别特异性后果的理解， 酒精暴露对脑干中定义的亚群的影响以及这些亚群如何有助于 与AUD相关的行为。

Abstract Alcohol use disorder (AUD) is a highly prevalent chronically relapsing disorder characterized by increased alcohol (EtOH) intake, inability to control consumption, and a negative emotional state during withdrawal. These behaviors are mediated by cellular and circuit adaptations, which can lead to changes in neuronal structure and function. One key neuroadaptation involves activation of the corticotropin releasing factor (CRF) system, a peptide released widely throughout the brain in response to stress. CRF signaling through the CRF1 receptor (CRF1) is associated with increased stress reactivity, anxiety-like behavior, and excessive drinking. Indeed, polymorphisms in Crhr1 (the gene encoding CRF1) are associated with binge drinking, emotionality, and risk for developing an AUD. A majority of the research concerning AUDs and CRF1 has focused on the prefrontal cortex and amygdala, while other areas such as the brainstem are much less well-studied. Located in the caudal medulla, the nucleus tractus solitarius (NTS) is an autonomic center containing an abundance of CRF1 receptors. While chronic EtOH drinking has been shown to increase activity of NTS neurons, little is known about the role of specific NTS subpopulations, most notably CRF1 neurons, in this effect. In this proposal, we will use male and female CRF1:cre: tdTomato rats and established models of voluntary EtOH intake combined with a cellular electrophysiological approach. In Aim 1, I will determine the effects of acute EtOH on excitability and synaptic transmission in CRF1NTS neurons from male and female CRF1:cre: tdTomato rats. In Aim 2, I will examine the changes in excitability and synaptic transmission in CRF1NTS neurons in male and female CRF1:cre: tdTomato rats following chronic voluntary EtOH drinking. In Aim 3, I will examine the effect of chemogenetic manipulation of CRF1NTS neurons on voluntary EtOH drinking in male and female CRF1:cre: tdTomato rats. Together, these experiments will reveal how CRF1NTS neurons are differentially impacted by acute and chronic EtOH exposure and how CRF1NTS neurons contribute to alcohol drinking. Collectively, the results of these studies will advance our understanding of the sex-specific consequences of alcohol exposure on defined subpopulations in the brainstem and how those subpopulations contribute to behaviors associated with AUD.