Role of Ventral Pallidum Projection to VTA in Reinstatement of Cocaine Seeking

腹侧苍白球投射至 VTA 在恢复可卡因寻求中的作用

• 批准号: 8990066
• 负责人: Stephen Vincent Mahler
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8990066
• 关键词: Affect; Agonist; Animals; Axon; Axonal Transport; Behavior; Bilateral; Brain; Brain region; Cells; Chronic; Clozapine; Cocaine; Cues; Data; Disease; Dopamine; Dose; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Exposure to; Future; Globus Pallidus; Health; Human; Infusion procedures; Lead; Learning; Light; Link; Mediating; Mediator of activation protein; Mental disorders; Microinjections; Modeling; Nature; Neurons; Opsin; Oxides; Pathway interactions; Pattern; Peptides; Pharmaceutical Preparations; Pharmacogenetics; Presynaptic Terminals; Process; Proteins; Rattus; Relapse; Risk Factors; Role; Self Administration; Specificity; Stimulus; Substantia nigra structure; Synapsins; Techniques; Testing; Training; Transgenic Organisms; Ventral Tegmental Area; Viral; abstracting; addiction; base; career; dopaminergic neuron; neuronal cell body; novel; optogenetics; promoter; receptor; research study; response; temporal measurement

Project Summary/Abstract Addiction is a major health concern, and its chronic relapsing nature is perhaps its most insidious aspect. Exposure to drug-associated cues is a risk factor for relapse, and understanding how the brain processes these cues may lead to addiction therapies. Here, I examine the role of projections from the ventral pallidum (VP) to ventral tegmental area (VTA) in a rat self-administration/cue-induced reinstatement model of relapse. I will employ novel, viral-based means of controlling this pathway, including designer receptors (DREADDs) that inhibit neuronal activity when an otherwise inert drug (CNO) is administered, and opsins, which allow control of neuronal activity with light. I have found that projections from the rostral portion of VP (RVP) to VTA are activated during cued reinstatement, and that DREADD-based inactivation of RVP and its VTA projections specifically block this behavior. Here, I explore the mechanisms by which RVP-VTA projections mediate cued reinstatement, and how RVP inputs modulate VTA activity. In the K99 Aims, I propose confirming and extending my findings that inhibiting RVP projections to VTA in particular with DREADDs specifically blocks cued reinstatement. Next, I propose electrophysiologically examining how RVP inputs to VTA modulate firing of VTA dopamine and non-dopamine neurons, and how inhibiting this pathway affects VTA neuronal activity. With the training in electrophysiology and opto/pharmacogenetic modulation of brain circuits I receive during the K99 period, I will employ these techniques to further determine the functional roles of the RVP-VTA circuit in cued reinstatement during the R00 period. First, I will determine whether RVP projections to VTA require dopamine in order to have effects on reinstatement behavior, using a transgenic rat line allowing expression of DREADDs specifically in dopamine neurons. Next, I will examine the temporal relationship of RVP-VTA projection activity to transient cue presentations in the reinstatement context using inhibitory optogenetic techniques. I will determine whether phasic, cue-locked activation, or tonic activation of RVP inputs is necessary for conditioned stimuli to elicit reinstatement. These experiments will therefore characterize the mechanisms of the novel, functionally-identified RVP-VTA pathway, which is crucially involved in cue-induced reinstatement of cocaine seeking in a rat model of relapse in addiction.

项目总结/摘要 成瘾是一个主要的健康问题，其慢性复发的性质可能是其最阴险的方面。 暴露于药物相关的线索是复发的风险因素，了解大脑如何处理 这些线索可能会导致成瘾治疗。在这里，我检查的作用，预测从腹侧苍白球 (VP)腹侧被盖区（VTA）在大鼠自我管理/线索诱导复发模型。我 将采用新的，基于病毒的手段来控制这一途径，包括设计受体（DREADD）， 当施用惰性药物（CNO）时抑制神经元活性，以及视蛋白，其允许控制 光下的神经元活动。我发现从VP的吻侧部分（RVP）到VTA的投影是 在提示恢复过程中激活，并且基于DREADD的RVP及其VTA投射的失活 专门阻止这种行为。在这里，我探讨了RVP-VTA投射介导线索的机制， 恢复，以及RVP输入如何调节VTA活动。 在K99目标中，我建议确认和扩展我的发现，即抑制RVP投射到VTA， 尤其是DREADDs会特别阻碍线索恢复。接下来，我提出电生理学 研究RVP输入到VTA如何调节VTA多巴胺和非多巴胺神经元的放电，以及如何 抑制该途径影响VTA神经元活性。 随着在电生理学和脑回路的光/药物遗传学调制的培训，我在 在K99期间，我将使用这些技术来进一步确定RVP-VTA电路的功能作用 在R 00期间的提示恢复。首先，我将确定RVP预测到VTA是否需要 多巴胺，以便对恢复行为产生影响，使用允许表达 尤其是多巴胺神经元。接下来，我将研究RVP-VTA的时间关系 使用抑制性光遗传学在恢复背景下对瞬时线索呈现的投射活性 技术.我将确定RVP输入的相位、线索锁定激活或强直激活是否是 是条件刺激诱发复原所必需的因此，这些实验将表征 新的，功能鉴定的RVP-VTA途径的机制，这是关键参与线索诱导的 在成瘾复发的大鼠模型中恢复可卡因寻求。