Tian Guilian, Bartas Katrina, Hui May, Chen Lingxuan, Vasquez Jose J, Azouz Ghalia, Derdeyn Pieter, Manville Rían W, Ho Erick L, Fang Amanda S, Li Yuan, Tyler Isabella, Setola Vincent, Aoto Jason, Abbott Geoffrey W, Beier Kevin T
bioRxiv. 2024 May 30:2024.05.29.596557. doi: 10.1101/2024.05.29.596557.
The globus pallidus externus (GPe) is a central component of the basal ganglia circuit, receiving strong input from the indirect pathway and regulating a variety of functions, including locomotor output and habit formation. We recently showed that it also acts as a gatekeeper of cocaine-induced behavioral plasticity, as inhibition of parvalbumin-positive cells in the GPe (GPe ) prevents the development of cocaine-induced reward and sensitization. However, the molecular and circuit mechanisms underlying this function are unknown. Here we show that GPe cells control cocaine reward and sensitization by inhibiting GABAergic neurons in the substantia nigra pars reticulata (SNr ), and ultimately, selectively modulating the activity of ventral tegmental area dopamine (VTA ) cells projecting to the lateral shell of the nucleus accumbens (NAcLat). A major input to GPe cells is the indirect pathway of the dorsomedial striatum (DMS ), which receives DAergic innervation from collaterals of VTA →NAcLat cells, making this a closed-loop circuit. Cocaine likely facilitates reward and sensitization not directly through actions in the GPe, but rather in the upstream DMS, where the cocaine-induced elevation of DA triggers a depression in DMS cell activity. This cocaine-induced elevation in DA levels can be blocked by inhibition of GPe cells, closing the loop. Interestingly, the level of GPe cell activity prior to cocaine administration is correlated with the extent of reward and sensitization that animals experience in response to future administration of cocaine, indicating that GPe cell activity is a key predictor of future behavioral responses to cocaine. Single nucleus RNA-sequencing of GPe cells indicated that genes encoding voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability are downregulated in GPe cells following a single cocaine exposure, contributing to the elevation in GPe cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of (rosemary) extract, reduced GPe cell excitability and also impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its potential as a therapeutic to counteract psychostimulant use disorder. Our findings illuminate the molecular and circuit mechanisms by which the GPe orchestrates brain-wide changes in response to cocaine that are required for reward, sensitization, and self-administration behaviors.
苍白球外部（GPe）是基底神经节回路的核心组成部分，接收来自间接通路的强烈输入并调节多种功能，包括运动输出和习惯形成。我们最近发现，它还充当可卡因诱导的行为可塑性的守门人，因为抑制GPe中表达小白蛋白的细胞（GPe ）可防止可卡因诱导的奖赏和敏化的发展。然而，这种功能背后的分子和回路机制尚不清楚。在这里，我们表明GPe 细胞通过抑制黑质网状部（SNr ）中的GABA能神经元来控制可卡因奖赏和敏化，最终选择性地调节投射到伏隔核外侧壳（NAcLat）的腹侧被盖区多巴胺（VTA ）细胞的活动。GPe 细胞的一个主要输入是背内侧纹状体（DMS ）的间接通路，该通路从VTA →NAcLat细胞的侧支接收多巴胺能神经支配，形成一个闭环回路。可卡因可能不是直接通过在GPe中的作用来促进奖赏和敏化，而是在其上游的DMS中，在那里可卡因诱导的多巴胺升高会引发DMS 细胞活动的抑制。这种可卡因诱导的多巴胺水平升高可以通过抑制GPe 细胞来阻断，从而关闭这个回路。有趣的是，在给予可卡因之前GPe 细胞的活动水平与动物对未来给予可卡因所经历的奖赏和敏化程度相关，这表明GPe 细胞活动是未来对可卡因行为反应的关键预测指标。对GPe细胞进行单核RNA测序表明，在单次接触可卡因后，编码控制细胞内在兴奋性的电压门控钾通道KCNQ3和KCNQ5的基因在GPe 细胞中下调，导致GPe 细胞兴奋性升高。使用小分子肌醇六磷酸（迷迭香叶提取物的一种关键精神活性成分）急性激活包含KCNQ3和/或KCNQ5的通道，可降低GPe 细胞的兴奋性，并损害可卡因奖赏、敏化和自愿性可卡因摄取，表明其作为对抗精神兴奋剂使用障碍疗法的潜力。我们的研究结果阐明了GPe协调全脑对可卡因反应变化的分子和回路机制，这些变化是奖赏、敏化和自我给药行为所必需的。
