Alcohol-induced epigenetic reprogramming of PPAR-α affects allopregnanolone biosynthesis

酒精诱导的 PPAR-α 表观遗传重编程影响异孕酮生物合成

• 批准号: 10658534
• 负责人: GRAZIANO PINNA
• 金额: $ 35.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658534
• 关键词: Acute; Affect; Agonist; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Allopregnanolone; Amygdaloid structure; Anabolism; Anti-Anxiety Agents; Anxiety; Area; Autopsy; Basic Science; Biological Assay; Brain; Cause of Death; Cerebellum; Cholesterol; Chromatin Remodeling Factor; Chronic; Cytosine; DNA; DNA Methylation; DNA Modification Methylases; Dorsal; Down-Regulation; Enzymes; Epigenetic Process; Estrous Cycle; Ethanol; Ethanol dependence; FDA approved; Female; Fenofibrate; Gene Expression; Genes; Hippocampus; Human; Hydroxysteroid Dehydrogenases; Impairment; Isomerism; Link; Mass Fragmentography; Measures; Medial; Methods; Methyl-CpG-Binding Protein 2; Methylation; Mixed Function Oxygenases; Modeling; Modification; Molecular; Mood Disorders; Neurobiology; Neurons; Nuclear Receptors; Nucleus Accumbens; Oxidoreductase; PPAR alpha; Pathway interactions; Peroxisome Proliferators; Phenotype; Prefrontal Cortex; Pregnanolone; Pregnenolone; Progesterone; Proteins; Publishing; Rattus; Regulation; Rodent; Rodent Model; Signal Transduction; Stress; Symptoms; Withdrawal; Withdrawal Symptom; alcohol effect; alcohol exposure; alcohol reward; alcohol use disorder; antagonist; anxiety-like behavior; anxious behavior; biological adaptation to stress; chromatin immunoprecipitation; comorbidity; demethylation; emotional behavior; epigenetic regulation; improved; mRNA Expression; male; neural; neuropsychiatric disorder; neurosteroids; palmidrol; pharmacologic; protein expression; receptor; transcription factor; transcriptomics; translational impact; translational model; vapor

Abstract. The neural substrates underlying alcohol use disorder (AUD), remain poorly understood in part due to lack of translational models that recapitulate phenotypes from the human condition. Biosynthesis of the GABAergic neurosteroid, allopregnanolone (Allo) in corticolimbic neurons, regulates stress sensitivity and induces a potent anxiolytic action. In a rodent model of chronic intermittent ethanol (CIE) exposure, decreased expression of Allo biosynthetic enzymes, 5α-reductase type I (5α-RI) and 3α-hydroxy-steroid dehydrogenase (3α-HSD) is associated with Allo level downregulation in the hippocampus (HIP) and cerebellum. Consistently, in AUD postmortem brain, cerebellum Allo levels and neurosteroidogenic proteins and enzymes, such as the translocator protein (TSPO), 5α-RI and 3α-HSD expression decreased in association with aberrant epigenetic marks. Alcohol-induced epigenetic modifications (e.g., DNA hyper/hypomethylation) on transcriptomics and their impact on neurosteroidogenic gene expression, neurosteroid levels, and anxiety are poorly understood. Allo biosynthesis can be upregulated in brain areas that modulate anxiety and alcohol reward by stimulating the epigenetically modifiable nuclear receptor, peroxisome proliferator-regulated receptor (PPAR)-α by the endogenous modulator, palmitoylethanolamide (PEA). Intriguingly, chronic alcohol exposure decreases PPAR- α expression, while stimulation of PPAR-α by PEA decreases both anxiety and alcohol intake. The molecular mechanisms underlying these effects remain unclear. Our preliminary and published results suggest that alcohol-induced aberrant regulation of PPAR-α may affect anxiety via decreasing Allo content. Hypothesis: Chronic alcohol exposure alters methylation/demethylation dynamics that downregulate corticolimbic PPAR-α expression and allopregnanolone biosynthesis, and elevated anxiety. In male and female rats, we will: (AIM 1) Examine the effect of 14-day CIE exposure (EtOH), ethanol acute (24h, W24h) and protracted (7 days, W7d) withdrawal on the epigenetic regulation of PPAR-α expression and downstream effects on neurosteroidogenic enzyme expression; (AIM 2) Investigate the effects of CIE exposure and ethanol acute and protracted withdrawal on the brain content of Allo; and (AIM 3) Study the pharmacoepigenetics of PEA and fenofibrate on Allo biosynthesis and anxiety after CIE exposure and acute and protracted ethanol withdrawal. This study may unveil CIE-induced neurobiological alterations and suggest treatment targets for alcohol withdrawal symptoms.

摘要：酒精使用障碍（AUD）的神经基础仍然知之甚少，部分原因是。 缺乏概括人类生物合成表型的翻译模型。 GABA 能神经类固醇，皮质边缘神经元中的四氢孕酮 (Allo)，可调节应激敏感性和 在慢性间歇性乙醇（CIE）暴露的啮齿动物模型中，诱导有效的抗焦虑作用。 同种异体生物合成酶、I 型 5α-还原酶 (5α-RI) 和 3α-羟基类固醇脱氢酶的表达 (3α-HSD) 与海马 (HIP) 和小脑中的 Allo 水平下调相关。 AUD 死后大脑、小脑 Allo 水平以及神经类固醇生成蛋白和酶，例如 易位蛋白 (TSPO)、​​5α-RI 和 3α-HSD 表达下降与异常表观遗传相关 酒精诱导的转录组学表观遗传修饰（例如 DNA 高/低甲基化）和 它们对神经类固醇生成基因表达、神经类固醇水平和焦虑的影响知之甚少。 同种异体生物合成可以在通过刺激调节焦虑和酒精奖赏的大脑区域上调 表观遗传修饰核受体，过氧化物酶体增殖物调节受体（PPAR）-α 内源性调节剂棕榈酰乙醇酰胺 (PEA) 有趣的是，长期接触酒精会降低 PPAR-。 α 表达，而 PEA 刺激 PPAR-α 会降低焦虑和酒精摄入量。 我们的初步和已发表的结果表明，这些影响的机制尚不清楚。 酒精引起的 PPAR-α 异常调节可能通过降低 Allo 含量来影响焦虑。 慢性酒精暴露会改变甲基化/去甲基化动力学，从而下调皮质边缘 PPAR-α 在雄性和雌性大鼠中，我们将：（AIM 1） 检查 14 天 CIE 暴露 (EtOH)、急性乙醇（24 小时，第 24 小时）和长期乙醇暴露（第 7 天，第 7 天）的影响 撤回 PPAR-α 表达的表观遗传调控及其对神经类固醇生成的下游影响 酶表达；（AIM 2）研究 CIE 暴露和乙醇急性和长期的影响 戒断对 Allo 脑含量的影响；以及 (AIM 3) 研究 PEA 和非诺贝特对大脑的药物表观遗传学 同种异体生物合成和 CIE 暴露以及急性和长期乙醇戒断后的焦虑。 揭示 CIE 引起的神经生物学改变，并提出酒精戒断症状的治疗目标。