Alcohol-induced changes in stress-related neuropeptide circuitry

酒精引起的压力相关神经肽回路的变化

基本信息

批准号：
10509944
负责人：
Beverly Reyes
金额：
$ 39.77万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10509944
关键词：
Adverse effects Agonist Alcohol abuse Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcohols American Amygdaloid structure Animal Model Anxiety Anxiety Disorders Arousal Behavior Control Behavioral Biological Markers Blood alcohol level measurement Brain Injuries Cell Nucleus Chronic Clinical Confocal Microscopy Consumption Corticosterone Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Development Diagnosis Emotions Exhibits Exposure to Female Frequencies Genetic Goals Health High Prevalence Immunoelectron Microscopy Immunohistochemistry Intake Investigation Link Mediating Mediator Medical Modeling Molecular Neurobiology Neurons Neuropeptides Norepinephrine Pathway interactions Phenotype Presynaptic Terminals Prevalence Prosencephalon Rattus Receptor Signaling Regulation Relapse Reporting Research Resolution Rodent Role Sex Differences Signal Transduction Societies Source Stress Synapses System Testing Tracer Viral Withdrawal Woman Work alcohol abuse therapy alcohol consequences alcohol effect alcohol exposure alcohol use disorder anxiety reduction anxiety-like behavior biological adaptation to stress chronic alcohol ingestion cost drinking drinking behavior drug of abuse experimental study field study genetic approach individualized medicine locus ceruleus structure male men nerve supply neural circuit neuropeptide Y norepinephrine system novel opioid exposure pharmacologic receptor sex trafficking transmission process

项目摘要

ABSTRACT Alcohol use disorders (AUDs) are serious medical conditions that afflict approximately 17 million Americans and cost the U.S. $400 billion annually. Whereas men are diagnosed twice as frequently as women, a greater vulnerability to adverse effects of alcohol occurs in women. Despite the sex differences in prevalence and effects of AUD, the factors mediating the sex differences in the effects of alcohol use are not fully understood. Animal models showed an escalation of alcohol drinking from baseline in male rodents while higher baseline drinking was evident in female rodents. Withdrawal from chronic alcohol exposure induced a greater anxiety in male compared to female. Research is needed on the neural circuitry underlying sex differences to advance the field of alcohol neurobiology. AUD development involves the actions of critical neuropeptides in the central nucleus of the amygdala (CeA), including corticotropin-releasing factor (CRF) and neuropeptide Y (NPY). CRF is an excitatory stress neuropeptide that orchestrates stress responses, while NPY may act as an inhibitory or excitatory neuropeptide. The CeA ubiquitously receives NPY-ergic afferents and is enriched with CRF neurons. Alcohol exposure and withdrawal reduced the NPY signaling in the CeA while alcohol withdrawal increased CRF levels in the CeA. We have shown that CRF neurons in the CeA project to the locus coeruleus (LC), a major source of norepinephrine (NE) to the forebrain. The CRF CeA-LC pathway relays emotion-related information. We propose that the specific NPY CRF-CeA LC pathway mediates sex differences in alcohol drinking and anxiety-like behavior following withdrawal. The goal of the proposed work is to test the overarching hypothesis that the specific NPY CRF-CeA LC-NE pathway mediates sex differences in alcohol drinking and anxiety-like behavior during withdrawal. We will use a well-established rodent alcohol model, the intermittent-access ethanol drinking (IED) paradigm. In this model, females initially consume more alcohol than males, while males escalate intake, resulting in matched intake in males and females following 30 days of drinking. We will use IED to test circuit and molecular mechanisms mediating alcohol effects on alcohol drinking and anxiety-like behavior. We will integrate pharmacological, chemogenetics, behavioral, and cellular approaches including immunohistochemistry, immunoelectron microscopy and tract tracing. AIM 1 tests the hypothesis that CRF- containing neurons contacted by NPY in the CeA project to the LC-NE system, and that withdrawal from chronic alcohol exposure alters the NPY-CRF synaptic organizations in male and female rats. Aim 2 tests the hypothesis that Y1r agonism within the CRF-CeA neurons that project to LC will reverse the elevated alcohol drinking and anxiety-like behavior during alcohol withdrawal in male and female rats. Elucidating sex differences in the peptidergic interactions in the CeA that impact NE transmission under alcohol withdrawal, and the role of NPY in modulating the LC-NE via the amygdalar CRF circuitry has significant clinical implications in developing individualized therapies and novel targets for the treatment of AUDs.

抽象的酒精使用障碍 (AUD) 是一种严重的疾病，困扰着大约 1700 万美国人，每年花费 4000 亿美元。尽管男性被诊断的频率是女性的两倍，但男性的诊断率更高女性容易受到酒精的不利影响。尽管患病率和影响存在性别差异对于澳元而言，调节饮酒影响中性别差异的因素尚不完全清楚。动物模型显示，雄性啮齿类动物的饮酒量较基线有所增加，而基线饮酒量较高在雌性啮齿动物中很明显。戒断长期饮酒会导致男性更加焦虑与女性相比。需要对性别差异背后的神经回路进行研究以推进该领域的发展酒精神经生物学。 AUD 的发展涉及中央核中关键神经肽的作用杏仁核 (CeA)，包括促肾上腺皮质激素释放因子 (CRF) 和神经肽 Y (NPY)。 CRF 是一个兴奋性应激神经肽协调应激反应，而 NPY 可能充当抑制性或抑制性应激神经肽。兴奋性神经肽。 CeA 无处不在地接收 NPY 能传入神经，并且富含 CRF 神经元。酒精暴露和戒断减少了 CeA 中的 NPY 信号传导，而酒精戒断则增加了 CRF CeA 中的水平。我们已经证明，CeA 中的 CRF 神经元投射到蓝斑 (LC)，蓝斑是一个主要的神经元。前脑去甲肾上腺素（NE）的来源。 CRF CeA-LC 通路传递情绪相关信息。我们提出特定的 NPY CRF-CeA LC 通路介导饮酒和饮酒的性别差异戒断后的焦虑样行为。拟议工作的目标是检验总体假设特定的 NPY CRF-CeA LC-NE 通路介导饮酒和焦虑样症状的性别差异戒断期间的行为。我们将使用成熟的啮齿动物酒精模型，即间歇性获取乙醇饮酒（简易爆炸装置）范例。在这个模型中，女性最初比男性消耗更多的酒精，而男性则逐渐增加摄入量，导致饮酒 30 天后男性和女性的摄入量相匹配。我们将使用IED来测试介导酒精对饮酒和焦虑样行为的影响的电路和分子机制。我们将整合药理学、化学遗传学、行为学和细胞方法，包括免疫组织化学、免疫电子显微镜和纤维追踪。 AIM 1 检验 CRF- 的假设包含由 CeA 中的 NPY 接触的神经元投射到 LC-NE 系统，并且从慢性酒精暴露会改变雄性和雌性大鼠的 NPY-CRF 突触组织。目标 2 检验假设投射到 LC 的 CRF-CeA 神经元内的 Y1r 激动作用将逆转饮酒量增加和雄性和雌性大鼠酒精戒断期间的焦虑样行为。阐明性别差异 CeA 中的肽能相互作用影响酒精戒断下的 NE 传输，以及 NPY 的作用通过杏仁核 CRF 电路调节 LC-NE 对开发具有重要的临床意义 AUD 治疗的个体化疗法和新靶点。