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 内源性阿片系统与奖励、强化和激励作用密切相关 乙醇，阿片受体拮抗剂纳曲酮的既定临床疗效证明了这一点 纳美芬可减少乙醇摄入量、复发倾向和渴望。动物研究表明。 乙醇激活大脑内各种含有阿片肽的回路，包括大脑区域 最近，我们已经获得了多方面的证据。 表明乙醇激活下丘脑弓状核 (ArcN) 内的一部分神经元 表达阿片黑皮素原 (POMC)，产生多种生物活性神经肽，包括 - 使用膜片钳电生理学，我们观察到乙醇（5-40 mM）的浴应用。 类似地，使用 FosB 可以增加约 35% 记录的 ArcN POMC 神经元的放电频率。 通过免疫组织化学，我们证明了暴饮暴食的乙醇摄入大约激活了 ArcN 的一个子集 POMC 神经元，其中大部分合成 -内啡肽，而逆行追踪显示狂饮- 像乙醇摄入一样，主要激活投射到杏仁核的 ArcN POMC 神经元，激活的较少 令人惊讶的是，神经元投射到腹侧被盖区（VTA）或伏隔核（NAc）。 没有亚群划分的 ArcN POMC 神经元的调节对乙醇摄入没有影响。 我们推测这些效果的缺乏是由于许多 ArcN 激活的非特异性所致 观察到含有子电路的 POMC 神经元在暴饮暴食时的乙醇摄入量的基线性别差异，其中 雌性小鼠比雄性小鼠消耗更多的乙醇，我们观察到 ERα 是 与 ERα 或黄体酮相比，主要雌性激素受体位于 ArcN POMC 神经元上 总之，这些观察结果得出了我们的总体假设：ArcN POMC 神经元。 对中脑边缘奖赏系统区域的预测调节性别依赖性的暴饮暴食乙醇摄入量 主要通过 ERα 依赖机制来验证这一假设，我们制定了以下公式。 相互关联但独立的具体目标 在目标 1 中，我们将确定乙醇对 ArcN POMC 投射神经元的神经生理学特性 在目标 2 中，我们将确定以下因素的影响。 特定 ArcN POMC 传出投射神经元对暴饮暴食乙醇摄入的化学遗传学调节。 最后，在目标 3 中，我们将确定 ERα 对 POMC 神经元在调控暴饮暴食中的作用 这些研究将共同​​阐明具体的摄入量以及与中脑多巴胺神经元的潜在相互作用。 阿片类药物回路和机制调节暴饮暴食型乙醇摄入量，这将指导改善 用于治疗酒精使用障碍的神经调节和/或药理学方法。