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

酒精暴露对孤束核 CRF 1 神经元的生理影响

• 批准号: 10537984
• 负责人: Sema Quadir
• 金额: $ 6.72万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537984
• 关键词: Acute; Affect; Age; Alcohol consumption; Alcohols; Amygdaloid structure; Area; Behavior; Brain; Brain Stem; CRF receptor type 1; Cell Nucleus; Cells; Chronic; Closure by clamp; Clozapine; Consumption; Corticotropin-Releasing Hormone; Data; Desire for food; Disease; Eating; Electrophysiology (science); Emotional; Enterobacteria phage P1 Cre recombinase; Ethanol; Female; Genes; Genetic Polymorphism; Goals; Heavy Drinking; High Prevalence; Hypothalamic structure; Intake; Lead; Mediating; Membrane; Modeling; Monitor; Neurobiology; Neuronal Plasticity; Neurons; Neuropeptides; Outcome; Oxides; Partner in relationship; Peptides; Persons; Pharmaceutical Preparations; Physiological; Prefrontal Cortex; Property; Rattus; Recording of previous events; Relapse; Reporter; Research; Respiration; Risk; Role; Signal Transduction; Slice; Stress; Structure; Synaptic Transmission; System; Testing; Therapeutic; Viral; Water consumption; Withdrawal; Work; addiction; alcohol consequences; alcohol effect; alcohol exposure; alcohol use disorder; anxiety-like behavior; base; binge drinking; chronic alcohol ingestion; designer receptors exclusively activated by designer drugs; drinking; drinking water; experimental study; feeding; gastrointestinal function; heart function; hypothalamic-pituitary-adrenal axis; improved; male; negative emotional state; neural circuit; neuroadaptation; neurobiological mechanism; neurotransmission; promoter; receptor; response; sex; stress reactivity; transmission process; treatment strategy; vector control; voltage clamp

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.

摘要 酒精使用障碍(AUD)是一种高度流行的慢性复发性障碍，其特征是 酒精(乙醇)摄入，无法控制消费，以及戒酒期间的负面情绪。 这些行为是通过细胞和电路的适应来调节的，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，一种在大脑中广泛释放的多肽，对压力做出反应。CRF通过CRF1的信号转导 受体(CRF1)与应激反应增强、焦虑样行为和过度饮酒有关。 事实上，Crhr1(编码CRF1的基因)的多态与酗酒、情绪化、 以及开发澳元的风险。大多数关于AUDS和CRF1的研究都集中在 前额叶皮质和杏仁核，而脑干等其他区域的研究要少得多。设于 在延髓尾侧，孤束核(NTS)是一个自主中枢，含有丰富的 CRF1受体。虽然长期饮用乙醇已被证明能增加NTS神经元的活动，但几乎没有 已知特定NTS亚群在这一效应中的作用，最明显的是CRF1神经元。在这 建议用雄性和雌性CRF1：CRE：td番茄大鼠和已建立的自愿无水乙醇模型 摄取结合细胞电生理方法。在目标1中，我将确定急性 乙醇对雌雄CRF1：Cre：td番茄CRF1NTS神经元兴奋性和突触传递的影响 老鼠。在目标2中，我将研究雄性CRF1NTS神经元兴奋性和突触传递的变化 雌性CRF1：CRE：td番茄大鼠慢性自愿饮用乙醇。在目标3中，我将研究 CRF1NTS神经元化学操作对男性和女性自愿饮用乙醇的影响 CRF1：CRE：td番茄大鼠。总之，这些实验将揭示CRF1NTS神经元是如何区分的 受到急性和慢性乙醇暴露的影响，以及CRF1NTS神经元如何促进饮酒。 总而言之，这些研究的结果将促进我们对 酒精暴露对脑干中特定亚群的影响以及这些亚群对 与澳元相关的行为。