Prefrontal cortical microcircuit mechanisms for reciprocal interactions between arousal and ethanol consumption

唤醒和乙醇消耗之间相互作用的前额皮质微电路机制

• 批准号: 10567739
• 负责人: Rafiq Huda
• 金额: $ 57.22万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567739
• 关键词: Acute; Address; Affect; Alcohol consumption; Animal Model; Anterior; Arousal; Calcium; Cells; Color; Consumption; D Cells; Darkness; Data; Diameter; Disinhibition; Electrophysiology (science); Ethanol; Etiology; Female; Functional disorder; Head; Heavy Drinking; Hyperactivity; Image; Interneurons; Light; Link; Measurement; Measures; Mediating; Mus; Mydriasis; Neurons; Neurosecretory Systems; Output; Pathway interactions; Patients; Persons; Physiological; Play; Pre-Clinical Model; Prefrontal Cortex; Prevalence; Property; Pupil; Pyramidal Cells; Recording of previous events; Relapse; Role; Sex Differences; Shapes; Slice; Somatostatin; Stimulus; Stress; Sucrose; Synapses; Testing; Time; Vasoactive Intestinal Peptide; Work; alcohol abuse therapy; alcohol behavior; alcohol seeking behavior; alcohol use disorder; binge drinking; chronic alcohol ingestion; cingulate cortex; design; drinking; effective therapy; experimental study; hippocampal pyramidal neuron; in vivo; in vivo imaging; inhibitory neuron; machine vision; male; neural; neurobiological mechanism; neuronal circuitry; new therapeutic target; novel; optogenetics; pre-clinical; response; serial imaging; therapeutic target; therapeutically effective; two-photon

Project Summary/Abstract Alcohol use disorder (AUD) exacts a major personal, economical, and societal toll. Given its high lifetime prevalence, there is an urgent need to understand neurobiological mechanisms underlying AUD pathophysiology to develop effective therapeutic strategies. Dysfunction of stress-related neuroendocrine and autonomic arousal pathways are highly associated with alcohol-related behaviors. Repeated alcohol use increases arousal. Moreover, higher arousal levels in treatment-seeking AUD patients correlates with higher rates of relapse. These findings suggest reciprocal interactions between arousal and alcohol use, such that higher basal arousal promotes alcohol drinking, which further exacerbates arousal. A challenge in understanding the neurobiological mechanisms mediating interactions between arousal and drinking is the lack of preclinical animal models that allow quantification of drinking together with longitudinal measurements of arousal and neuronal activity. We addressed this by designing a voluntary ethanol consumption paradigm for head-fixed mice combined with two- photon calcium imaging for neuronal activity recordings and pupillometry for measuring arousal. Our preliminary experiments show that the anterior cingulate cortex (ACC) subdivision of the prefrontal cortex potently increases arousal. Basal levels of arousal and arousal-related ACC activity are correlated with the amount of ethanol consumption, suggesting that the ACC contributes to arousal modulation of drinking. Cortical activity is critically shaped by inhibition from local interneurons. The vasoactive intestinal polypeptide (VIP) expressing interneurons are particularly important as they inhibit other interneurons, leading to disinhibitory excitation of the ACC. We hypothesize that ACC VIP neurons are a key node for reciprocal interactions between arousal and ethanol consumption. In Aims 1 and 2, we test the hypothesis that VIP neuron-mediated disinhibition increases arousal and ethanol consumption. In Aim 3, we will determine if repeated ethanol consumption increases VIP-mediated disinhibition, leading to hyperarousal that further promotes drinking. We will test these hypotheses using a combination of advanced approaches including multicolor two-photon calcium imaging, multicolor optogenetics, machine vision-assisted closed-loop optogenetics, and ex-vivo slice electrophysiology. Together, these mechanistic studies will determine how VIP neurons both contribute to and are affected by drinking, establishing them as a key therapeutic target for modulating drinking driven by aberrant arousal.

项目摘要/摘要 酒精使用障碍（AUD）确切了一个主要的个人，经济和社会损失。鉴于它的一生 患病率迫切需要了解AUD病理生理学基础的神经生物学机制 制定有效的治疗策略。与压力有关的神经内分泌和自主神经功能障碍的功能障碍 途径与酒精相关的行为高度相关。反复使用饮酒会增加唤醒。 此外，寻求治疗的AUD患者较高的唤醒水平与复发率更高相关。这些 发现表明唤醒和酒精使用之间的相互相互作用，因此较高的基础唤醒 促进饮酒，这进一步加剧了唤醒。理解神经生物学的挑战 介导唤醒和饮酒之间相互作用的机制缺乏临床前动物模型 允许对饮酒以及唤醒和神经元活性的纵向测量进行定量。我们 通过设计一个自愿性乙醇消耗范式的头固定小鼠与两种形式结合 - 用于测量唤醒的神经元活性记录和瞳孔测定法的光子钙成像。我们的初步 实验表明，前额叶皮层的前扣带回皮层（ACC）细分有效地增加 唤醒。唤醒和唤醒相关的ACC活性的基础水平与乙醇的量相关 消费，表明ACC有助于唤醒饮酒的调节。皮质活动至关重要 由局部中间神经元的抑制作用。表达中间神经元的血管活性肠多肽（VIP） 特别重要，因为它们抑制其他神经元，从而导致对ACC的抑制激发。我们 假设ACC VIP神经元是唤醒和乙醇之间相互作用的关键节点 消耗。在目标1和2中，我们检验了VIP神经元介导的抑制作用的假设增加 和消耗乙醇。在AIM 3中，我们将确定重复的乙醇消耗是否增加了VIP介导的 抑制作用，导致超阳光进一步促进饮酒。我们将使用 高级方法的组合，包括多色双光子钙成像，多色光遗传学， 机器视觉辅助的闭环光遗传学和前体现场电生理学。在一起，这些 机械研究将确定VIP神经元如何构成饮酒和建立的影响 它们是调节异常唤醒驱动的饮酒的关键治疗靶标。