Defining the Role of D1 and D2 Medium Spiny Neurons in Relapse to Cocaine Seeking

定义 D1 和 D2 中型多棘神经元在可卡因寻求复发中的作用

• 批准号: 9162119
• 负责人: Erin Calipari
• 金额: $ 15.06万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9162119
• 关键词: Abstinence; Affect; Animals; Association Learning; Automobile Driving; Award; Behavior; Behavioral; Calcium; Cells; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Conditioned Reflex; Cues; Data; Decision Making; Development; Dopamine; Drug Addiction; Drug Controls; Drug abuse; Etiology; Extinction (Psychology); Family; Fiber; Functional disorder; Grant; Halorhodopsins; Human; Image; Intervention; Lead; Learning; Maps; Mediating; Mentors; Mentorship; Modeling; Molecular Target; Motivation; Mus; Neurobiology; Neurons; New York; Nucleus Accumbens; Opsin; Organism; Outcome; Output; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Photometry; Play; Population; Process; Public Health; Recruitment Activity; Relapse; Research; Rewards; Role; Self Administration; Signal Transduction; Specificity; Stimulus; Syndrome; Techniques; Time; Training; Transgenic Mice; Treatment outcome; United States; Withdrawal; Work; addiction; base; behavioral outcome; calcium indicator; cell type; classical conditioning; cocaine exposure; combat; drug craving; drug of abuse; experience; goal oriented behavior; improved; in vivo; innovation; medical schools; neurochemistry; neuromechanism; neurotransmission; novel; novel therapeutics; optogenetics; postsynaptic; prevent; programs; recombinase; relating to nervous system; response; selective expression; study population; synaptic function; tool; transmission process

Project Summary Learned associations between environmental contexts and experience are the basis of decision-making and allow organisms to guide behavior towards advantageous outcomes. Dysfunction in the neuronal processes that regulate these associations, especially in the nucleus accumbens (NAc), is a critical factor in the pathology of addiction. The NAc is a heterogeneous region primarily composed of two opposing cell types: D1 and D2 medium spiny projection neurons (MSNs). Optogenetic stimulation of these cells results in divergent behavioral outputs; thus, it is important to study these populations in isolation to understand the cell-type specific signals that underlie NAc-mediated learning processes. Under the primary mentorship of Dr. Eric Nestler and Dr. Paul Kenny at Icahn School of Medicine at Mount Sinai in New York, the Pathway to Independence Award will provide the opportunity to build on my expertise in cocaine self-administration and synaptic function while simultaneously developing my training and expertise in in vivo calcium imaging and optogenetics. In the mentored K-phase of this grant fiber photometry calcium imaging will be paired with cocaine self-administration in transgenic mouse lines that express Cre-recombinase in D1 or D2 MSN populations. These mice allow for cell-type specific expression of molecular targets, such as calcium indicators (GCaMP6f) and opsins (ChR2; NpHR). By expressing GCaMP6f in D1 or D2 MSNs, the temporally specific signals that mediate cue-induced cocaine seeking will be determined. Further, optogenetic stimulation and inhibition will allow for direct manipulation of these cells and the associated seeking behavior. The innovative combination of these tools will enable the mapping of how D1 and D2 MSNs encode cue information and concurrently establish causality. In the independent phase (R00), these cutting-edge techniques will be combined with the inducible ArcCreERT2 mice which express constructs (GCaMP6f/Opsins) selectively in cells that are activated by environmental stimuli during a temporally specific window. This will allow for the recording and manipulation of neuronal ensembles that are activated by cocaine or cocaine-paired cues to determine their role in drug seeking. Together, these data will elucidate the underlying neural processes that control associative learning and how cocaine exposure dysregulates MSN signaling to drive relapse following abstinence, which will expand our basic understanding of addiction and may lead to the development of novel therapeutic avenues. In summary, the research proposed in this Pathway to Independence Award will elucidate the neural mechanisms involved in addiction while simultaneously preparing me to develop a fully independent research program capable of integrating a wide range of circuit based and behavioral approaches to dissect the neurobiology of addiction. .

项目概要 环境背景和经验之间的习得关联是决策和决策的基础 允许有机体引导行为以获得有利的结果。神经元过程功能障碍 调节这些关联，特别是在伏隔核 (NAc) 中，是病理学的关键因素 的成瘾。 NAc 是一个异质区域，主要由两种相反的细胞类型组成：D1 和 D2 中型多刺投射神经元（MSN）。这些细胞的光遗传学刺激导致不同的行为 输出；因此，单独研究这些群体以了解细胞类型特异性信号非常重要 这是 NAc 介导的学习过程的基础。在 Eric Nestler 博士和 Paul 博士的主要指导下 纽约西奈山伊坎医学院的肯尼，独立之路奖将 提供机会利用我在可卡因自我管理和突触功能方面的专业知识，同时 同时发展我在体内钙成像和光遗传学方面的培训和专业知识。在 该补助金的指导 K 相纤维光度钙成像将与可卡因自我给药相结合 在 D1 或 D2 MSN 群体中表达 Cre 重组酶的转基因小鼠品系中。这些小鼠允许 分子靶标的细胞类型特异性表达，例如钙指示剂 (GCaMP6f) 和视蛋白 (ChR2； NpHR）。通过在 D1 或 D2 MSN 中表达 GCaMP6f，介导线索诱导的时间特异性信号 将确定可卡因寻求情况。此外，光遗传学刺激和抑制将允许直接 操纵这些细胞以及相关的寻找行为。这些工具的创新组合将 启用 D1 和 D2 MSN 如何编码提示信息并同时建立因果关系的映射。在 独立阶段（R00），这些尖端技术将与诱导型 ArcCreERT2 相结合 在被环境激活的细胞中选择性表达构建体（GCaMP6f/视蛋白）的小鼠 时间特定窗口期间的刺激。这将允许记录和操纵神经元 由可卡因或可卡因配对线索激活的整体，以确定其在寻求毒品中的作用。 这些数据将共同阐明控制联想学习的潜在神经过程以及如何控制联想学习。 接触可卡因会导致 MSN 信号失调，导致戒毒后复发，这将扩大我们的研究范围 对成瘾的基本了解，可能会导致新的治疗途径的发展。总之， 独立之路奖中提出的研究将阐明所涉及的神经机制 沉迷其中，同时准备开发一个完全独立的研究项目，能够 整合广泛的基于回路和行为的方法来剖析成瘾的神经生物学。 。