Regulation of neuronal activity in the paraventricular thalamus by chronic morphine

慢性吗啡对室旁丘脑神经元活动的调节

• 批准号: 10470748
• 负责人: Vladislav Friedman
• 金额: $ 4.68万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-10 至 2026-08-09
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470748
• 关键词: Action Potentials; Address; Adverse effects; Affect; Agitation; Animal Behavior; Anxiety; Arousal; Behavior; Behavioral; Biological Assay; Brain region; CACNA1G gene; Canis familiaris; Chronic; Couples; Cre-LoxP; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Dorsal; Drug Addiction; Electrophysiology (science); Enkephalins; Exhibits; Fiber; Food; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Genetic; Glutamates; Hunger; Image; Immunohistochemistry; In Situ Hybridization; Infusion procedures; Ion Channel; Knock-out; Learning; Location; Mediating; Membrane; Messenger RNA; Microinjections; Morphine; Mus; Naloxone; Neurons; Neurosciences; Opioid; Opioid Receptor; Opioid agonist; Output; Palate; Pharmaceutical Preparations; Pharmacology; Photometry; Public Health; Receptor Activation; Regulation; Relapse; Research; Research Personnel; Rest; Rewards; Rodent; Role; Saline; Severities; Signal Transduction; Slice; Structure of paraventricular nucleus of thalamus; Symptoms; Techniques; Testing; Thalamic structure; Therapeutic; Tremor; United States; Up-Regulation; Viral; Withdrawal; Withdrawal Symptom; behavior test; behavioral phenotyping; channel blockers; desensitization; experimental study; in vivo; inward rectifier potassium channel; mu opioid receptors; neuroadaptation; novel; opioid abuse; opioid exposure; opioid mortality; opioid overdose; opioid use; opioid withdrawal; real time monitoring; training opportunity; voltage

Project Summary High rates of opioid abuse and overdose deaths represent a substantial public health issue in the United States. Avoidance of withdrawal symptoms is a primary driver of continued opioid use and overdose. Understanding the neuroadaptations induced by chronic opioid exposure holds great promise for the identification of novel and efficacious therapeutics. The paraventricular thalamic nucleus (PVT), located in the dorsal midline thalamus, encodes behavioral states relevant to drug addiction, including arousal, hunger, reward-seeking, and aversion. Recent studies have pointed a critical role of the PVT and its projections in regulating many behavioral effects of opioids. The Mu-opioid receptor (MOR) is expressed in many brain regions, which collectively mediate many cellular and behavioral effects of opioids. It remains unknown to what extent the MOR in the PVT contributes to morphine withdrawal-induced somatic signs. In addition, several important questions remain poorly understood. How is the MOR is activated in the PVT? How does chronic morphine exposure and subsequent withdrawal affect the action potential firing—the final output—of PVT neurons? To what extent do the changes in neuronal activity contribute to morphine withdrawal-induced somatic signs? Two Specific Aims are proposed to address these questions. In Aim I, I will determine the extent to which activation and desensitization of the MOR alters neuronal output of PVT neurons following morphine withdrawal. Slice electrophysiology and in vivo Ca2+ imaging with fiber photometry will be employed to address this question. In Aim II, I will use Cre-LoxP technique to selectively delete the MOR in the PVT and examine its impact on withdrawal-induced somatic signs. Additionally, I will test whether blocking withdrawal- induced increase in excitability in PVT neurons affects the aversive behavioral effects of morphine withdrawal. Completion of this project is expected to provide excellent training opportunities to learn a wide range of powerful techniques, including ex vivo slice electrophysiology, in vivo fiber photometry, in situ hybridization, immunohistochemistry, viral microinjection, pharmacology, and animal behavior assays. Further, the proposed research will deepen our understanding of cellular and circuit mechanisms underlying adverse effects of opioid withdrawal.

项目概要 阿片类药物滥用和过量死亡的高比例是美国的一个重大公共卫生问题 避免戒断症状是持续使用和过量服用阿片类药物的主要原因。 了解慢性阿片类药物暴露引起的神经适应为人类带来了巨大的希望 确定位于丘脑室旁核（PVT）的新颖且有效的治疗方法。 丘脑背侧中线，编码与毒瘾相关的行为状态，包括觉醒、饥饿、 最近的研究指出了 PVT 及其预测在这方面的关键作用。 Mu-阿片受体 (MOR) 在许多大脑中表达，调节阿片类药物的许多行为效应。 这些区域共同介导阿片类药物的许多细胞和行为效应，但目前尚不清楚。 PVT 中的 MOR 在多大程度上有助于吗啡戒断引起的躯体症状。 重要的问题仍然知之甚少。MOR 是如何在 PVT 中被激活的？ 吗啡暴露和随后的戒断会影响动作电位的激发（PVT 的最终输出） 神经元活动的变化在多大程度上有助于吗啡戒断诱导？ 提出了两个具体目标来解决这些问题。在目标 I 中，我将确定： MOR 的激活和脱敏在多大程度上改变了 PVT 神经元的神经输出 将采用切片电生理学和光纤光度测定法体内 Ca2+ 成像。 为了解决这个问题，在 Aim II 中，我将使用 Cre-LoxP 技术选择性地删除 PVT 中的 MOR，并 检查它对戒断引起的躯体症状的影响此外，我将测试是否阻止戒断-。 诱导的 PVT 神经元兴奋性增加会影响吗啡戒断的厌恶行为效应。 该项目的完成预计将为学习广泛的知识提供极好的培训机会 强大的技术，包括离体切片电生理学、体内纤维光度测定、原位杂交、 此外，还提出了免疫组织化学、病毒显微注射、药理学和动物行为测定。 研究将加深我们对阿片类药物不良反应背后的细胞和回路机制的理解 撤回。