Regulation of binge-like ethanol intake by arcuate POMC projection neurons

弓形 POMC 投射神经元对暴饮暴食乙醇摄入的调节

• 批准号: 10594822
• 负责人: M. FOSTER OLIVE
• 金额: $ 33.76万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-10 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594822
• 关键词: Agonist; Alcohol abuse; Alcohol consumption; Amygdaloid structure; Animals; Bathing; Brain; Cannulas; Cells; Consumption; Development; Electric Capacitance; Electrophysiology (science); Endorphins; Estradiol; Ethanol; Female; Frequencies; Genes; Genetic; Glutamates; Goals; Hormone Receptor; Hypothalamic structure; Immunohistochemistry; Infusion procedures; Intake; Label; Legal; Mediating; Medical; Membrane Potentials; Midbrain structure; Morphology; Motivation; Mus; Naltrexone; Nature; Neurons; Neuropeptides; Nucleus Accumbens; Opioid; Opioid Antagonist; Opioid Peptide; Peptides; Phenotype; Physiological; Pro-Opiomelanocortin; Procedures; Progesterone Receptors; Property; Regulation; Relapse; Research; Rewards; Role; Sex Differences; Site; Societies; Structure of nucleus infundibularis hypothalami; System; Testing; Ventral Tegmental Area; Viral Vector; alcohol abuse therapy; alcohol effect; alcohol use disorder; clinical efficacy; cost; craving; design; designer receptors exclusively activated by designer drugs; dopaminergic neuron; endogenous opioids; female sex hormone; implantation; improved; male; nalmefene; neural circuit; neurochemistry; neuronal excitability; neurophysiology; neuroregulation; novel; patch clamp; pharmacologic; public health relevance; receptor; retrograde transport; reward circuitry; sex; socioeconomics

ABSTRACT The endogenous opioid system is strongly implicated in the rewarding, reinforcing, and motivational effects of ethanol, as evidenced by the established clinical efficacy of the opioid receptor antagonists naltrexone and nalmefene in reducing ethanol intake, relapse propensity, and craving. Animal studies have demonstrated that ethanol activates various opioid peptide-containing circuits within the brain, including regions of the mesocorticolimbic reward circuitry and amygdala. Recently we have generated multiple lines of evidence indicating that ethanol activates a subset of neurons within the arcuate nucleus (ArcN) of the hypothalamus expressing pro-opiomelanocortin (POMC), which gives rise to numerous bioactive neuropeptides including - endorphin. Using patch clamp electrophysiology, we observed that bath application of ethanol (5-40 mM) increases the firing frequency of ~35% of recorded ArcN POMC neurons. Similarly, using FosB immunohistochemistry, we demonstrated that binge-like ethanol intake activates approximately a subset of ArcN POMC neurons, the majority of which synthesize -endorphin vs. -MSH. Retrograde tracing revealed binge- like ethanol intake primarily activates ArcN POMC neurons projecting to the amygdala, with fewer activated neurons projecting to the ventral tegmental area (VTA) or nucleus accumbens (NAc). Surprisingly, chemogenetic modulation of ArcN POMC neurons without subpopulation delineation had no effect on ethanol intake. However, we speculate that these lack of effects were due to the non-specific nature of activation of a number of ArcN POMC neuron containing subcircuits. Baseline sex differences in binge-like ethanol intake were observed, where female mice consumed significantly more ethanol than their male counterparts, and we observed that ER is the primary female sex hormone receptor located on ArcN POMC neurons as compared to ER or progesterone receptors. Together, these observations have led to our overarching hypothesis that ArcN POMC neuron projections to regions of the mesolimbic reward system regulate binge-like ethanol intake in a sex-dependent manner primarily via ER dependent mechanisms. To test this hypothesis, we have formulated the following inter-related yet independent Specific Aims. In Aim 1, we will determine the effects of ethanol on the neurophysiological properties of ArcN POMC projection neurons. In Aim 2, we will determine the effects of chemogenetic modulation of specific ArcN POMC efferent projection neurons on binge-like ethanol intake. Finally, in Aim 3, we will determine the role of ER on POMC neurons in the regulation of binge-like ethanol intake and potential interactions with midbrain dopamine neurons. Together, these studies will elucidate specific opioid circuits and mechanisms regulating binge-like ethanol intake, which will guide the improvement of neuromodulatory and/or pharmacological approaches for the treatment of alcohol use disorders.

抽象的 内源性阿片类药物系统与奖励，增强和动机作用有关 乙醇，如阿片受体拮抗剂Naltrexone和 纳米芬（Nalmefene）减少乙醇摄入量，救济改善和渴望。动物研究表明 乙醇激活大脑中各种含阿片类肽的电路，包括 中皮层奖励电路和杏仁核。最近我们产生了多种证据 表明乙醇激活下丘脑的弧形核（ARCN）内神经元的子集 表达促蛋白聚糖素（POMC），引起许多生物活性神经肽，包括- 内啡肽。使用斑块夹电生理学，我们观察到乙醇的浴施用（5-40 mm） 将记录的ARCN POMC神经元的发射频率增加约35％。同样，使用FOSB 免疫组织化学，我们证明了暴饮暴食的乙醇摄入量大约激活了ARCN的子集 POMC神经元，其中大多数合成-内啡肽与-MSH。逆行追踪显示了Benge- 像乙醇摄入量一样激活投射到杏仁核的ARCN POMC神经元，激活较少 投射到腹侧对接区域（VTA）或伏隔核（NAC）的神经元。令人惊讶的是，化学生成 没有亚群描述的ARCN POMC神经元的调节对乙醇摄入没有影响。然而， 我们推测这些缺乏效果是由于许多ARCN激活的非特异性性质 含有亚电路的POMC神经元。观察到狂风样乙醇摄入的基线性别差异，其中 雌性小鼠的乙醇比男性多得多，我们观察到Er是 与ER或孕酮相比 受体。总之，这些观察结果导致了我们的总体假设，即ARCN POMC神经元 在中性脱脂奖励系统的项目中，调节性别依赖性的狂饮般的乙醇摄入量 通过依赖机制的主要方式。为了检验这一假设，我们已经制定了以下内容 相互关联但独立的特定目的。在AIM 1中，我们将确定乙醇对 ARCN POMC投影神经元的神经生理特性。在AIM 2中，我们将确定 特异性ARCN POMC有效投影神经元在暴饮暴食样乙醇摄入量的化学发生调节。 最后，在AIM 3中，我们将确定ER在pOMC神经元中的作用在狂饮样乙醇中 与中脑多巴胺神经元的摄入量和潜在相互作用。这些研究将共同​​阐明特定 阿片类电路和机制，以策略类似暴饮暴食的乙醇摄入量，这将指导改善 用于治疗酒精使用障碍的神经调节和/或药理方法。