Neural microcircuit selection by astrocyte signaling following cocaine exposure

项目总结/摘要 开发有效的药物成瘾疗法的一个重要障碍是药物诱导的神经元可塑性 可能仅限于大脑奖励区域内的离散神经元群体。驱动选择的过程 从更大的可用神经元库中提取特定细胞的方法尚不清楚。我们的长期目标是确定 组装中型多刺神经元（MSN）微电路的机制，这些微电路是行为表达的基础， 可卡因寻找和服用在这个应用中，我们的目标是确定可卡因相关的神经适应 依赖于星形胶质细胞信号。我们提出一个假设，即星形胶质细胞的信号招募离散 MSNs的亚群内的神经核（NAc）壳，以促进神经元和行为 可塑性与可卡因自我管理的大鼠。这一假设得到了我们初步的支持。 并发表了其他团体的数据和研究。追求这一假设的理由是，尽管 越来越多的认识，星形胶质细胞积极调节神经元的活动，很少有人知道的作用， 星形胶质细胞协调局部回路，更不用说可卡因对局部回路的调节。上 基于大量的初步数据，我们将在三个具体目标中检验我们的中心假设：1）表征 星形胶质细胞信号传导对MSN微电路中可卡因诱导的NMDA受体（NMDAR）可塑性的影响。 2)表征星形胶质细胞信号传导对可卡因诱导的AMPA受体（AMPAR）可塑性的影响， 同步活动的MSN。3)确定星形胶质细胞同步化神经元活动的后果， 可卡因寻找和服用在第一个目标中，我们将使用神经元反应的一个独特特征， 星形胶质细胞衍生的信号，慢内向电流（SICs），以检验可卡因诱导的可塑性的假设， 突触外NMDAR，以前与可卡因接触有关，仅限于NAc外壳MSN显示SIC 事件第二个目标是建立在将NMDAR介导的信号传导与神经元的可塑性联系起来的经典知识上。 突触AMPAR和目前的证据表明，NMDAR介导的SICs共同发生在神经元 亚群在这个目标中，我们将确定可卡因诱导的突触AMPAR信号的可塑性是否 仅限于由星形胶质细胞来源的信号同步的NAc壳MSNs亚群。第三个目标， 我们将检验星形胶质细胞驱动的神经元同步化的促进和抑制将， 分别促进和抑制可卡因寻求行为。这种方法很重要，因为它改善了 我们识别负责特定行为反应的细胞群的能力。这种能力对于 有针对性的治疗方法。我们的方法是创新的，因为：它考虑了一个新的假设， 星形胶质细胞作为可卡因相关神经元微电路选择的积极参与者，它促进发育 新的病毒工具来识别这种微电路，它试图确定可卡因诱导的新机制。 神经胶质可塑性这些研究的完成将扩大对神经胶质细胞之间关系的理解， 信号传导，个体神经元兴奋性，局部网络功能和行为结果 可卡因成瘾

Project Summary/Abstract A significant obstacle to developing effective drug addiction therapies is that drug-induced neuronal plasticity may be restricted to discrete neuronal populations within brain reward areas. The processes driving selection of specific cells from a larger pool of available neurons are not clear. Our long-term goal is to identify the mechanisms that assemble medium spiny neuron (MSN) microcircuits underlying behavioral expression of cocaine seeking and taking. In this application, our objective is to identify cocaine-related neuronal adaptations that depend on astrocytic signaling. We propose a hypothesis that astrocytic signals recruit discrete subpopulations of MSNs within the nucleus accumbens (NAc) shell to facilitate neuronal and behavioral plasticity associated with cocaine self-administration in the rat. This hypothesis is supported by our preliminary and published data and studies from other groups. The rationale for pursuing this hypothesis is that despite a growing recognition that astrocytes actively modulate neuronal activity, little is known about the role of astrocytes in coordination of local circuits and even less about regulation of local circuits by cocaine. On the basis of substantial preliminary data we will test our central hypothesis in three specific aims: 1) Characterize the impact of astrocyte signaling on cocaine-induced NMDA receptor (NMDAR) plasticity in MSN microcircuits. 2) Characterize the impact of astrocyte signaling on cocaine-induced AMPA receptor (AMPAR) plasticity in synchronously active MSNs. 3) Identify the consequences of astrocyte-synchronized neuronal activity on cocaine seeking and taking. In the first aim, we will use a unique characteristic of neuronal response to astrocyte-derived signals, slow inward currents (SICs), to test the hypothesis that cocaine-induced plasticity of extrasynaptic NMDARs, previously linked to cocaine exposure, is restricted to NAc shell MSNs displaying SIC events. The second aim is built on classical knowledge linking NMDAR-mediated signaling to plasticity of synaptic AMPARs and current evidence indicating that NMDAR-mediated SICs co-occur in neuronal subpopulations. In this aim, we will determine whether cocaine-induced plasticity of synaptic AMPAR signaling is restricted to subpopulations of NAc shell MSNs synchronized by astrocyte-derived signals. In the third aim, we will test the hypothesis that facilitation and inhibition of astrocyte-driven neuronal synchronization will, respectively, facilitate and inhibit cocaine-seeking behaviors. The approach is significant because it improves our ability to identify cell populations responsible for specific behavioral responses. This ability is critical for targeted therapeutic approaches. Our approach is innovative because: it considers a novel hypothesis of astroglia as active participants in selection of cocaine-relevant neuronal microcircuits, it facilitates development of novel viral tools to identify such microcircuits, and it seeks to identify novel mechanisms of cocaine-induced neuroglial plasticity. Completion of these studies will expand understanding of the relationship between glial signaling, individual neuron excitability, local network function, and behavioral outcomes in the context of cocaine addiction.