Astrocyte-mediated regulation of cocaine-generated synapses during cocaine seeking

摘要：物质使用障碍（SUD）是一种复杂的情感和动机障碍， 治疗至今。目前，美国正处于SUD流行之中， 和代际界限。SUD的一个特别阴险的组成部分是复发，这是一个强大的 禁欲期间寻求毒品的动机。线索诱导的药物寻找是一种复发的啮齿动物模型， 其中在不存在药物的情况下呈现药物相关线索以触发可量化的寻找行为。 成瘾研究将觅药行为，如线索诱导的自我觅药， 可卡因给药（SA）改变了延髓核（NAc）的功能。专注于NAC， 广泛的研究已经检查了GABA能的、中等多棘神经元（MSN）中的药物诱导的适应， 其是NAc的主要细胞类型（~90%）和主要功能输出。相比之下， 了解神经胶质细胞，如星形胶质细胞，如何塑造药物相关行为。星形胶质细胞与 这使得它们能够直接监控和调节突触传递。星形胶质细胞突触 联合（称为三联突触）在经验依赖性突触中起着关键作用。 与学习和记忆相关的适应性。因此，本申请的目的是表征如何 星形胶质细胞调节NAc壳（NAcSh）中的突触动力学，进而调节线索诱导的可卡因 在小鼠SA模型中寻找。先前的研究结果表明，重新接触可卡因相关的线索重新沉默 可卡因产生的NAcSh突触，一个过程，这有助于不稳定的线索相关 可卡因记忆在线索再暴露诱导的记忆提取。初步结果表明， 在戒断（WD）过程中，功能性星形胶质细胞活性对于线索诱导的可卡因再沉默是必要的， 在NAcSh中产生突触，并且与可卡因奖励相关的线索增加星形胶质细胞的活性， 纳希这些初步结果将星形胶质细胞活性与可卡因产生的沉默的动态状态联系起来。 突触，并导致我的假设，星形胶质细胞调节线索诱导的可卡因突触适应- 在NAcSh中产生突触，这反过来又调节线索诱导的可卡因寻求可卡因WD。我会 通过追求两个目标来检验这个假设。Aim 1将测试星形胶质细胞活性增加是否足以重新激活 在WD期间使可卡因产生的NAcSh突触沉默。目标2将扩大初步数据， 证明了WD期间功能性星形胶质细胞活性对于线索诱导的突触再沉默的必要性， 使用具有增加的时间精确性的药理学和病毒工具来抑制星形胶质细胞活性 就在提示重新曝光之前。预期成果将提供一个全面的了解， NAcSh通过整合星形胶质细胞调节药物诱导的行为，从而揭示NAcSh星形胶质细胞是关键 细胞基质靶向药物的经验，以重塑行为。这种潜在的概念扩展可能 提供了新的角度来了解细胞和电路机制的基础药物寻求和复发。

Abstract: Substance use disorder (SUD) is a complex emotional and motivational disorder with no effective treatment thus far. Currently, the United States is in the midst of a SUD epidemic that defies socioeconomic and generational boundaries. A particularly insidious component of SUD is relapse, which is the strong motivational drive to seek drugs during abstinence. Cue-induced drug seeking is a rodent model of relapse, wherein a drug-associated cue is presented in the absence of the drug to trigger quantifiable seeking behavior. Addiction research attributes drug-seeking behaviors, such as cue-induced drug-seeking following self- administration (SA) of cocaine, to altered function of the nucleus accumbens (NAc). Focusing on the NAc, extensive studies have examined drug-induced adaptations in GABAergic, medium-spiny neurons (MSNs), which are the majority cell type (~90%) and principal functional output of the NAc. In contrast, much less is known about how glial cells, such as astrocytes, shape drug-related behaviors. Astrocytes closely associate with synapses, allowing them to directly monitor and regulate synaptic transmission. The astrocyte-synapse association (referred to as the tripartite synapse) plays a key role in experience-dependent synaptic adaptations associated with learning and memory. Thus, the objective of this application is to characterize how astrocytes regulate synaptic dynamics in the NAc Shell (NAcSh), which, in turn, regulate cue-induced cocaine seeking in the mouse SA model. Prior results show that re-exposure to cocaine-associated cues re-silences cocaine-generated NAcSh synapses, a process which contributes to the destabilization of cue-associated cocaine memories upon cue re-exposure-induced memory retrieval. Preliminary results demonstrate that functional astrocyte activity during withdrawal (WD) is necessary for the cue-induced re-silencing of cocaine- generated synapses in the NAcSh, and that cues associated with cocaine reward increase astrocyte activity in the NacSh. These preliminary results link astrocyte activity to the dynamic state of cocaine-generated silent synapses and lead to my hypothesis that astrocytes regulate the cue-induced synaptic adaptations of cocaine- generated synapses in the NAcSh which, in turn, regulate cue-induced cocaine seeking after cocaine WD. I will test this hypothesis by pursuing two aims. Aim 1 will test the sufficiency of increased astrocyte activity to re- silence cocaine-generated NAcSh synapses during WD. Aim 2 will expand preliminary data, which demonstrates the necessity of functional astrocyte activity during WD for cue-induced synaptic re-silencing, by using pharmacological and viral tools with increased temporal precision to suppress astrocyte activity immediately prior to cue re-exposure. The expected outcome will provide a holistic understanding of how the NAcSh regulates drug-induced behaviors by incorporating astroglia, thus revealing NAcSh astroglia as key cellular substrates targeted by drug experience to reshape behaviors. This potential conceptual expansion may provide novel angles to understand the cellular and circuit mechanisms underlying drug seeking and relapse.