Glial-mediated synaptic remodeling in drug addiction

 描述（由申请人提供）：在许多脑区，神经胶质细胞的数量大大超过神经细胞，但它们在生理和病理生理条件下的作用仍然知之甚少。星形胶质细胞是分布最广泛的神经胶质细胞，与兴奋性突触有密切的解剖学相互作用。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发育中CNS中突触的形成和随后的突触细化-消除。我们的初步研究结果表明，在长期暴露于可卡因或吗啡后，这些基于胶质细胞的发育机制中的一些重新出现在成年人的延髓核（NAc）中，这是成瘾相关行为异常所必需的前脑区域。这些药物诱导的、胶质细胞介导的突触重塑过程可能深刻地重新连接涉及NAc的神经回路，并对药物成瘾的病理生理学起关键作用。1）研究可卡因或吗啡自身给药和戒断后小鼠NAc中胶质细胞介导的突触发生和突触变性的分子和细胞机制; 2）为了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，在可卡因和吗啡暴露的小鼠中NAc兴奋性突触如何通过胶质细胞介导的突触发生或突触变性而重新形成;和3）确定药物诱导的行为后果，神经胶质介导的突触和电路重塑使用的小鼠模型的孵化线索诱导的药物渴求，药物复发模型，依赖于NAc兴奋性电路。为了实现这些目标，我们将使用跨Dong和Nestler实验室的多学科方法，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，转基因小鼠品系和药物自我给药的小鼠模型。通过靶向药物暴露小鼠中以前未探索的神经胶质介导的突触和电路重塑，拟议的实验有望为理解药物成瘾的细胞和电路机制开辟新的途径，并为抗成瘾治疗提供新的策略。

 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.