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

项目摘要/摘要 上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。 暴露在与药物有关的线索中是复发的危险因素，并了解大脑如何处理 这些线索可能会导致成瘾疗法。在这里，我研究了腹侧苍白球投射的作用。 (VP)至腹侧被盖区(VTA)在大鼠自我给药/线索诱导的复吸模型中。我 将使用新的、基于病毒的方法来控制这一途径，包括设计受体(DREADD) 在给予其他惰性药物(CNO)时抑制神经元活动，以及允许控制 神经元在光的作用下活动。我发现从VP(RVP)的吻部到VTA的投射是 在提示恢复期间被激活，以及基于DREADD的RVP及其VTA预测的失活 明确阻止此行为。在这里，我探索了RVP-VTA投射调节线索的机制 恢复，以及RVP输入如何调节VTA活动。 在K99目标中，我建议证实并扩大我的发现，即抑制RVP投射到VTA 特别是在DREADDS中，特别是阻止提示恢复。接下来，我建议从电生理学的角度 研究VTA的RVP输入如何调节VTA多巴胺和非多巴胺神经元的放电，以及如何 抑制这一通路会影响VTA神经元的活动。 在我接受的电生理学和光/药物遗传大脑回路调制方面的训练 在K99期间，我将使用这些技术来进一步确定RVP-VTA电路的功能角色 在R00期间恢复提示。首先，我将确定RVP对VTA的预测是否需要 为了对恢复行为产生影响，使用允许表达多巴胺的转基因鼠系 DREADDS特别存在于多巴胺神经元中。接下来，我将考察RVP-VTA的时间关系 抑制光发生技术在恢复背景下对短时线索呈现的投射活动 技巧。我将确定RVP输入的阶段性激活、线索锁定激活还是强激性激活 条件性刺激引起复职所必需的。因此，这些实验将表征 新的、功能确定的RVP-VTA通路的机制，它在CUE诱导中起关键作用 在成瘾复吸大鼠模型中恢复寻找可卡因。

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.