Glial-mediated synaptic remodeling in drug addiction

胶质细胞介导的毒瘾突触重塑

• 批准号: 9897513
• 负责人: Yan Dong
• 金额: $ 51.85万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897513
• 关键词: AMPA Receptors; Adult; Amphetamines; Anatomy; Astrocytes; Behavior; Behavioral; Brain; Brain region; Cells; Cellular biology; Chronic; Cocaine; Coupled; Cues; Dendritic Spines; Development; Dopamine D1 Receptor; Dopamine D2 Receptor; Drug Addiction; Drug Exposure; Drug Modelings; Electrophysiology (science); Ensure; Equilibrium; Excitatory Synapse; Exposure to; Foundations; Functional disorder; Gene Transfer; Generations; Genetic; Goals; Heroin; Knockout Mice; Knowledge; Laboratories; Mediating; Modeling; Molecular; Morphine; Mus; Neuroglia; Neurons; Nucleus Accumbens; Nutritional Support; Opioid; Outcome; Pathway interactions; Phagocytes; Pharmaceutical Preparations; Pharmacology; Physiological; Play; Process; Prosencephalon; Proteins; RNA Interference; Relapse; Role; Self Administration; Signal Transduction; Slice; Structure; Synapses; Synaptic Transmission; Testing; Thrombospondins; Transgenic Mice; Vertebral column; Viral; Withdrawal; Work; addiction; base; brain volume; cell type; cocaine exposure; confocal imaging; density; drug craving; drug of abuse; drug relapse; experimental study; in vivo; interdisciplinary approach; mouse model; neurotransmission; optogenetics; postnatal; postsynaptic; presynaptic; prevent; public health relevance; receptor; success; synaptogenesis; targeted treatment; thrombospondin 2; tool; virus genetics

 DESCRIPTION (provided by applicant): In many brain regions, glial cells substantially outnumber nerve cells, but their role in physiological and pathophysiological conditions remains poorly understood. Astrocytes are the most widely distributed glia with intimate anatomical interactions with excitatory synapses. Recent studies reveal that, in addition to providing structural and nutritional support, astrocytes dictate synapse formation and subsequent synapse refinement- elimination in the developing CNS. Our preliminary results show that, after chronic exposure to cocaine or morphine, some of these glia-based developmental mechanisms re-emerge in the adult nucleus accumbens (NAc), a forebrain region essential for addiction-related behavioral abnormalities. These drug-induced, glia- mediated synaptic remodeling processes may profoundly rewire the neurocircuits involving the NAc, and critically contribute to the pathophysiology of drug addiction. Focusing on this unique angle, the objectives of this application are: 1) To characterize the molecular and cellular mechanisms underlying glia-mediated synaptogenesis and synaptodegeneration in the NAc in mice after cocaine or morphine self-administration and withdrawal; 2) To determine the circuitry consequences of drug-induced, glia-mediated synaptic remodeling, particularly, how NAc excitatory synapses are refashioned in cocaine- and morphine-exposed mice by glia- mediated synaptogenesis or synaptodegeneration; and 3) To determine the behavioral consequences of drug- induced, glia-mediated synapse and circuitry remodeling using the mouse model of incubation of cue-induced drug craving, a drug relapse model that depends on NAc excitatory circuits. To achieve these goals, we will use a multidisciplinary approach, across the Dong and Nestler laboratories, including confocal imaging, slice electrophysiology, optogenetics, in vivo viral-mediated gene transfer, RNA interference, transgenic mouse lines, and mouse models of drug self-administration. By targeting the previously unexplored glia-mediated synapse and circuitry remodeling in drug-exposed mice, the proposed experiments promise to open new avenues toward understanding cellular and circuitry mechanisms underlying drug addiction and providing new strategies for anti-addiction treatments.

 描述（由适用提供）：在许多大脑区域，神经胶质细胞基本上是外部数神经细胞，但它们在物理和病理生理条件中的作用仍然很少。星形胶质细胞是分布最广泛的胶质细胞，与兴奋性突触具有紧密的解剖相互作用。最近的研究表明，除了提供结构和营养支持外，星形胶质细胞还决定了发育中心的中枢神经系统中突触的形成和随后的突触细化。我们的初步结果表明，在长期暴露于可卡因或吗啡后，这些基于神经胶质的发育机制中的一些重新出现在成人核伏隔（NAC）中，这是成瘾相关行为异常必不可少的前脑区域。这些药物诱导的，胶质介导的突触重塑过程可能会深刻地重新连接涉及NAC的神经回路，并严重有助于药物成瘾的病理生理学。该应用程序的目的关注这个独特的角度：1）表征可卡因或吗啡自给症和吗啡自我给药和戒断后NAC中神经胶质介导的突触发生的分子和细胞机制； 2）确定药物诱导的，神经胶质介导的突触重塑的电路后果，特别是如何通过神经胶质介导的突触发生或突触播种机在可卡因和吗啡暴露的小鼠中重塑NAC兴奋性突触； 3）为了确定使用小鼠孵育提示诱导的药物渴望的小鼠模型，为了确定药物诱导的，神经胶质介导的突触和回路重塑，这是一种依赖于NAC兴奋性电路的药物继电器模型。为了实现这些目标，我们将在整个Dong和Nestler实验室中使用多学科的方法，包括共聚焦成像，切片电生理学，光遗传学，体内病毒介导的基因转移，RNA干扰，转基因小鼠系和药物自我施用的小鼠模型。通过靶向先前意外的神经胶质介导的突触和电路重塑，拟议的实验有望开放新的途径，以理解药物成瘾的细胞和电路机制，并为抗活化治疗提供新的策略。