A thalamic input to the nucleus accumbens mediates opiate dependence.
A thalamic input to the nucleus accumbens mediates opiate dependence.
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DOI：
10.1038/nature16954
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发表时间：
2016-02-11
期刊：
影响因子：
64.8
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Zhu Y;Wienecke CF;Nachtrab G;Chen X
长期使用阿片类药物会导致阿片类药物依赖，其特征是在戒毒后产生极不愉快的身体和情感感受。药物的奖赏效应和避免戒断症状的愿望都会刺激持续的药物使用，而伏隔核(NAC)对这两个过程都很重要。虽然对NAC的多个输入调节奖赏，但对NAC回路背后的戒断知之甚少。在这里，我们认为丘脑室旁核(PVT)是NAC的重要输入，介导阿片类药物戒断诱导的体征和厌恶记忆的表达。PVT到NAC通路的活性是调节行为厌恶的必要条件和充分条件。选择性地沉默这一途径可以消除两种不同的阿片类药物戒断小鼠模型的厌恶症状。慢性吗啡暴露通过突触插入缺乏GluA2的AMPA受体，选择性地增强PVT和D2受体表达的中棘神经元(D2-MSN)之间的兴奋性传递。值得注意的是，在体内，光遗传去增强恢复了PVT→D2-MSNS突触的正常传递，并有力地抑制了吗啡戒断症状。这些结果将PVT→NAc回路中吗啡诱发的通路和细胞类型特异性可塑性与阿片依赖联系起来，并表明重新编程该回路有望用于阿片成瘾的治疗。
Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both rewarding effects of drug and the desire to avoid withdrawal symptoms motivate continued drug use, and the nucleus accumbens (NAc) is important for orchestrating both processes. While multiple inputs to the NAc regulate reward, little is known about the NAc circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus (PVT) as a prominent input to the NAc mediating the expression of opiate withdrawal induced physical signs and aversive memory. Activity in the PVT to NAc pathway is necessary and sufficient to mediate behavioral aversion. Selectively silencing this pathway abolishes aversive symptoms in two different mouse models of opiate withdrawal. Chronic morphine exposure selectively potentiates excitatory transmission between the PVT and D2-receptor-expressing medium spiny neurons (D2-MSNs) via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at PVT→D2-MSNs synapses and robustly suppresses morphine withdrawal symptoms. These results link morphine-evoked pathway- and cell type-specific plasticity in the PVT→NAc circuit to opiate dependence, and suggest that reprogramming this circuit holds promise for treating opiate addiction.