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

描述(申请人提供)：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。暴露在与药物相关的线索中是复发的风险因素，了解大脑如何处理这些线索可能会导致成瘾治疗。在这里，我研究了从腹侧钯(VP)到腹侧被盖区(VTA)的投射在大鼠自我给药/线索诱导的复吸恢复模型中的作用。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)和Opsins，前者在给予其他惰性药物(CNO)时抑制神经元活动，后者允许用光控制神经元活动。我发现这些预测来自于 在提示恢复期间，VP(RVP)到VTA的吻侧部分被激活，且基于DREADD的RVP及其VTA投射的失活特别阻止了这一行为。在这里，我探索了RVP-VTA投射介导线索恢复的机制，以及RVP输入如何调节VTA活动。在K99 AIMS中，我建议证实并扩展我的发现，即抑制RVP投射到VTA，特别是DREADD，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，以及抑制这一途径如何影响VTA神经元的活动。随着我在K99期间接受的电生理学和对大脑回路的光/药物遗传调制方面的训练，我将使用这些技术来进一步确定RVP-VTA回路在R00期间CUE恢复中的功能作用。首先，我将利用一种允许DREADD在多巴胺神经元中特异性表达的转基因大鼠株系，确定RVP投射到VTA是否需要多巴胺才能对恢复行为产生影响。接下来，我将使用抑制性光遗传学技术来研究RVP-VTA投射活动与恢复背景下的瞬时线索呈现之间的时间关系。我将确定RVP输入的阶段性激活、线索锁定激活还是强直激活是条件刺激引起恢复所必需的。因此，这些实验将表征新的、功能确定的RVP-VTA通路的机制，该通路在线索诱导复吸成瘾大鼠模型中恢复寻找可卡因的过程中起关键作用。

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.