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

可卡因寻找过程中星形胶质细胞介导的可卡因生成突触的调节

• 批准号: 10606141
• 负责人: Alexander Zinsmaier
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606141
• 关键词: AMPA Receptors; Abstinence; Acute; Addictive Behavior; Anatomy; Astrocytes; Behavior; Brain Diseases; Cocaine; Cocaine withdrawal; Complex; Cues; Data; Disease; Drug Targeting; Emotional; Epidemic; Exposure to; Generations; Glutamates; In Vitro; Knowledge; Learning; Link; Mediating; Memory; Modeling; Monitor; Motivation; Mus; Neuroglia; Neurons; Nucleus Accumbens; Outcome; Output; Permeability; Pharmaceutical Preparations; Play; Prevalence; Process; Regulation; Relapse; Research; Retrieval; Rodent; Rodent Model; Role; Self Administration; Shapes; Signal Transduction; Substance Use Disorder; Synapses; Synaptic Transmission; Testing; Therapeutic; Thrombospondins; Transgenic Mice; United States; Up-Regulation; Viral; Virus; Withdrawal; addiction; cell type; cellular targeting; cocaine exposure; cocaine relapse; cocaine reward; cocaine seeking; cocaine self-administration; designer receptors exclusively activated by designer drugs; drug abstinence; drug induced behavior; drug seeking behavior; drug withdrawal; effective therapy; experience; experimental study; improved; in vivo; memory consolidation; memory retrieval; novel; pharmacologic; prevent; recruit; socioeconomics; tool; transmission process

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.

摘要：物质使用障碍（SUD）是一种复杂的情绪和动机障碍，目前尚无有效的治疗方法。 治疗至今。目前，美国正处于 SUD 流行之中，这种流行病违背了社会经济的发展规律。 和代际界限。 SUD 的一个特别阴险的组成部分是复发，这是强烈的 戒断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， 其中在没有药物的情况下呈现与药物相关的提示以触发可量化的寻求行为。 成瘾研究归因于寻求药物的行为，例如以下自我暗示诱导的寻求药物： 施用（SA）可卡因，以改变伏隔核（NAc）的功能。专注于 NAc， 广泛的研究检查了药物诱导的 GABA 能中棘神经元 (MSN) 的适应， 它们是 NAc 的大多数细胞类型 (~90%) 和主要功能输出。相比之下，就少了很多 了解神经胶质细胞（例如星形胶质细胞）如何形成与药物相关的行为。星形胶质细胞密切相关 与突触，使它们能够直接监测和调节突触传递。星形胶质细胞突触 关联（称为三方突触）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。因此，本应用的目的是描述如何 星形胶质细胞调节 NAc Shell (NAcSh) 中的突触动力学，进而调节提示诱导的可卡因 在小鼠SA模型中寻找。先前的结果表明，重新接触与可卡因相关的线索会重新沉默 可卡因产生的 NAcSh 突触，这个过程会导致线索相关的不稳定 可卡因记忆是根据线索重新暴露引起的记忆检索。初步结果表明 戒断期间（WD）的功能性星形胶质细胞活性对于提示诱导的可卡因重新沉默是必要的。 在 NAcSh 中产生突触，与可卡因奖励相关的线索会增加星形胶质细胞的活性 纳克什。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：星形胶质细胞调节可卡因的提示诱导的突触适应 NAcSh 中产生突触，进而调节提示诱导的可卡因寻找可卡因 WD。我会 通过追求两个目标来检验这个假设。目标 1 将测试增加的星形胶质细胞活性是否足以重新 WD 期间沉默可卡因产生的 NAcSh 突触。目标 2 将扩展初步数据，其中 证明了 WD 期间功能性星形胶质细胞活性对于提示诱导的突触重新沉默的必要性，通过 使用具有更高时间精度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。预期结果将提供对如何 NAcSh 通过整合星形胶质细胞来调节药物诱导的行为，从而揭示 NAcSh 星形胶质细胞是关键 药物经验针对细胞底物重塑行为。这种潜在的概念扩展可能 提供新的角度来理解药物寻找和复发背后的细胞和回路机制。