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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

基本信息

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
项目类别：
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

项目摘要

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大流行大大加剧了过度饮酒的上升模式，特别是在女人身上。酗酒是最常见的过量饮酒模式，患情绪障碍和酒精使用障碍（AUD）的风险增加。社会大力支持缓冲对酒精的渴望和复发，但许多人显示减少社会奖励的价值和/或在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网络的能力。支持.因此，了解调节酒精对社会影响的神经生物学机制，行为需要为未来的治疗提供信息，旨在增强社会功能和减少复发。患者AUD在黑暗中喝酒（DiD）是研究电路和分子的一个强大的范例。酗酒对啮齿动物生理和行为的影响机制。此外，三室社会性模型允许询问社会奖励和社会认可行为，酒精消费。5-羟色胺（5-HT）受体在外侧缰核（LHb）中的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仍然高度不足。我最近发现DiD减少了社交活动，在禁欲期间雌性小鼠中选择性识别，以及LHb Gq-蛋白偶联基因缺失 5-羟色胺受体5 HT 2c部分地阻止了这种作用。我的初步数据显示酗酒消耗增强了内侧亚核含LHb 5 HT 2c神经元（LHb 5 HT 2c）的内在兴奋性。区域，5-HT在社会交往过程中释放到LHb 5 HT 2c上，并且Gi信号的急性参与 LHb 5 HT 2c可以使酒精引起的社会缺陷正常化。此外，DiD似乎可以调节多种5-HT受体亚型在LHb 5 HT 2c中共表达。这些数据表明，过度通过5-HT受体信号传导的失调激活LHb 5 HT 2c可能是酒精诱导的社会缺陷的基础。利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 LHb 5 HT 2c投射到DRN（5 HT 2cLHb-DRN）的翻译和生理景观，以及2）研究 5-HT受体亚型在5 HT 2cLHb-DRN中的遗传操作对神经元生理学的功能影响和DiD引起的社会行为失调总之，这些实验将确定酗酒对5 HT 2cLHb-DRN中分子和生理过程的影响，并确定新的机制这些神经元在禁欲期间促进社会功能障碍。此外，这个奖项将为我提供这些宝贵的技术和专业培训将有助于我向独立过渡。