Regulation of alcohol-induced social disturbances by lateral habenula serotonin receptors

外侧缰核血清素受体调节酒精引起的社交障碍

• 批准号: 10664291
• 负责人: Meghan Elizabeth Flanigan
• 金额: $ 10.79万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664291
• 关键词: 3-Dimensional; Abstinence; Acute; Address; Affective; Affinity Chromatography; Alcohol abuse; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcohols; Award; Back; Behavior; Behavioral; Brain; Buffers; COVID-19 pandemic; Cell Nucleus; Cell physiology; Cells; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Coupled; Darkness; Data; Development; Electrophysiology (science); Equilibrium; Female; Fiber; Foundations; Future; G alpha q Protein; Gene Expression; Generations; Genetic; Habenula; Heavy Drinking; Impairment; Individual; Lateral; Medial; Mediating; Modeling; Molecular; Mood Disorders; Mus; Neurons; Patients; Pattern; Persons; Phase; Photometry; Physiological; Physiological Adaptation; Physiological Processes; Physiology; Receptor Signaling; Recording of previous events; Regulation; Relapse; Research; Research Personnel; Rewards; Ribosomes; Risk; Rodent; Rodent Model; Role; Serotonin; Signal Transduction; Social Behavior; Social Behavior Disorders; Social Functioning; Social Interaction; Social Problems; Social support; Stimulus; Substance Use Disorder; Symptoms; System; Technical Expertise; Techniques; Testing; Training; Translating; Treatment outcome; Viral; Woman; alcohol abstinence; alcohol abuse therapy; alcohol craving; alcohol effect; alcohol exposure; alcohol relapse; alcohol use disorder; binge drinking; cell type; design; drinking; experience; experimental study; genetic manipulation; hindbrain; impaired driving performance; in vivo; knock-down; negative emotional state; neurobiological mechanism; neuronal excitability; neuroregulation; novel; overexpression; patch clamp; prevent; programs; receptor; receptor expression; response; serotonin receptor; sex; skills; social; social deficits; targeted treatment; tool; transcriptome sequencing; transcriptomics; translatome; virus genetics

The COVID-19 pandemic has greatly exacerbated rising patterns of excessive alcohol consumption, particularly in women. Binge alcohol drinking is the most common pattern of excessive alcohol drinking and is associated with increased risk of developing mood disorders and Alcohol Use Disorder (AUD). Social support strongly buffers against alcohol craving and relapse, yet many individuals display reduced valuation of social rewards and/or deficits in the processing of social stimuli following alcohol exposure and subsequent abstinence. This may compound interpersonal problems in people with AUD and limit their capacity to seek out or receive social support. Therefore, understanding the neurobiological mechanisms mediating alcohol’s effects on social behavior is required to inform future treatments aimed at enhancing social functioning and reducing relapse in patients with AUD. Drinking in the Dark (DiD) is a robust paradigm for investigating the circuit and molecular mechanisms of binge-like alcohol consumption on physiology and behavior in rodents. In addition, the 3-chamber sociability model permits the interrogation of both social reward and social recognition behaviors following alcohol consumption. Serotonin (5-Hydroxytryptamine, 5-HT) receptor signaling in the lateral habenula (LHb) has been implicated in the development of negative emotional states associated with abstinence from alcohol, but the LHb remains highly understudied in the context of AUD. I recently found that DiD reduced social recognition selectively in female mice during abstinence, and that genetic deletion of the LHb Gq-protein coupled serotonin receptor 5HT2c partially prevented this effect. My preliminary data suggests that binge alcohol consumption enhances the intrinsic excitability of LHb 5HT2c-containing neurons (LHb5HT2c) in the medial sub- region, that 5-HT is released onto LHb5HT2c during social interaction, and that acute engagement of Gi signaling in LHb5HT2c can normalize social deficits induced by alcohol. Moreover, DiD appears to modulate the expression of multiple 5-HT receptor subtypes co-expressed in LHb5HT2c. Together, these data suggest that excessive activation of LHb5HT2c via dysregulation of 5-HT receptor signaling may underlie social deficits induced by alcohol. Using these preliminary findings as a foundation for the current proposal, I will 1) characterize how DiD alters the translational and physiological landscape of LHb5HT2c projecting to the DRN (5HT2cLHb-DRN) and 2) investigate the functional impact of genetic manipulation of 5-HT receptor sub-types in 5HT2cLHb-DRN on neuronal physiology and DiD-induced dysregulation of social behavior. Together, these experiments will determine the effects of binge alcohol drinking on molecular and physiological processes in 5HT2cLHb-DRN and identify novel mechanisms by which these neurons promote social dysfunction during abstinence. Furthermore, this award will provide me with valuable technical and professional training that will facilitate my transition to independence.

COVID-19 大流行极大地加剧了过度饮酒的趋势，特别是 在女性中。酗酒是过量饮酒的最常见模式，并且与 患情绪障碍和酒精使用障碍 (AUD) 的风险增加。社会支持有力 缓冲酒精渴望和复发，但许多人表现出对社会奖励的重视程度降低 和/或酒精暴露和随后的戒酒后处理社会刺激的缺陷。这 可能会加剧 AUD 患者的人际关系问题，并限制他们寻求或接受社交活动的能力 支持。因此，了解调节酒精对社交影响的神经生物学机制 需要行为为未来旨在增强社会功能和减少复发的治疗提供信息 澳元患者。黑暗中饮酒（DiD）是研究电路和分子的强大范例 暴饮暴食对啮齿动物生理和行为的影响机制。此外，3室 社交模型允许对社会奖励和社会认可行为进行询问 饮酒量。外侧缰核 (LHb) 中的血清素（5-羟色胺，5-HT）受体信号传导 与戒酒相关的负面情绪状态的发展有关， 但在 AUD 的背景下，LHb 的研究仍然很少。我最近发现 DiD 减少了社交 雌性小鼠在禁欲期间选择性识别，并且 LHb Gq 蛋白偶联的基因删除 血清素受体 5HT2c 部分阻止了这种效应。我的初步数据表明酗酒 消耗增强了内侧亚区含有 LHb 5HT2c 的神经元 (LHb5HT2c) 的内在兴奋性 区域，5-HT 在社交互动过程中被释放到 LHb5HT2c 上，并且 Gi 信号传导的急剧参与 LHb5HT2c 中的 LHb5HT2c 可以使酒精引起的社交缺陷正常化。此外，DiD 似乎可以调节表达 LHb5HT2c 中共表达的多种 5-HT 受体亚型。总之，这些数据表明过度 通过 5-HT 受体信号传导失调激活 LHb5HT2c 可能是酒精引起的社交缺陷的基础。 使用这些初步发现作为当前提案的基础，我将 1) 描述 DiD 如何改变 LHb5HT2c 投射到 DRN (5HT2cLHb-DRN) 的翻译和生理景观以及 2) 研究 5HT2cLHb-DRN 中 5-HT 受体亚型的遗传操作对神经元生理学的功能影响 DiD 引起的社会行为失调。这些实验将共同确定以下效果： 酗酒对 5HT2cLHb-DRN 分子和生理过程的影响并确定新机制 这些神经元通过这些神经元在禁欲期间促进社会功能障碍。 Furthermore, this award will provide me 宝贵的技术和专业培训将有助于我过渡到独立。