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: 8488038
• 负责人: Stephen Vincent Mahler
• 金额: $ 12.01万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8488038
• 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; Palladium; Pathway interactions; Pattern; Peptides; Pharmaceutical Preparations; Pharmacogenetics; Presynaptic Terminals; Process; Proteins; Rattus; Relapse; Resolution; Risk Factors; Role; Self Administration; Specificity; Stimulus; Substantia nigra structure; Synapsins; Techniques; Testing; Training; Transgenic Organisms; Ventral Tegmental Area; Viral; addiction; base; career; dopaminergic neuron; neuronal cell body; novel; optogenetics; promoter; public health relevance; receptor; research study; response

DESCRIPTION (provided by applicant): 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 palladium (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.

描述（由申请人提供）：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，我研究的作用，从腹侧钯（VP）腹侧被盖区（VTA）在大鼠自我管理/线索诱导的复发模型的预测。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（DREADDs），当给予惰性药物（CNO）时，它会抑制神经元的活动，以及视蛋白，它允许用光来控制神经元的活动。我发现， VP（RVP）至VTA吻侧部分在线索恢复期间被激活，且RVP及其VTA投射的基于DREADD的失活特异性地阻断该行为。在这里，我探讨的机制，RVP-VTA预测调解线索恢复，以及如何RVP输入调制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，特别是DREADD，特别会阻止线索恢复。接下来，我建议电生理研究如何RVP输入腹侧被盖区调制放电腹侧被盖区多巴胺和非多巴胺神经元，以及如何抑制这一途径影响腹侧被盖区神经元的活动。 随着我在K99期间接受的脑回路电生理学和光学/药物遗传学调制的培训，我将采用这些技术来进一步确定R 00期间RVP-VTA回路在线索恢复中的功能作用。首先，我将确定是否RVP预测腹侧被盖区需要多巴胺，以恢复行为的影响，使用转基因大鼠行允许表达的DREADDs，特别是在多巴胺神经元。接下来，我将使用抑制性光遗传学技术来检查RVP-VTA投射活动与恢复背景下的瞬时线索呈现的时间关系。我将确定是否相位，线索锁定激活或紧张性激活的RVP输入是必要的条件刺激，以引起恢复。因此，这些实验将表征新的功能鉴定的RVP-VTA途径的机制，其在成瘾复发的大鼠模型中关键地参与可卡因寻求的线索诱导的恢复。