Sound of silent synapses from the addicted hippocampus.
Sound of silent synapses from the addicted hippocampus.
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沉迷的海马体发出无声的突触声。
DOI：
10.1038/s41386-018-0142-5
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Dong,Yan
中科院分区：
文献类型：
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作者：
Koya,Eisuke;Dong,Yan
在发育中的大脑中富集，大多数沉默突触是不成熟的突触能突触，其含有稳定的NMDA受体（NMDAR）和AMPA受体（AMPAR），AMPA受体（AMPAR）要么不存在，要么高度不稳定，因此是AMPAR沉默的[1]。它们作为神经元之间的初始连接，形成新的神经回路。在发育过程中，一些沉默的突触经历经验依赖性成熟，通过招募或稳定AMPAR来巩固突触连接。先前的研究表明，在成年啮齿动物中，非偶然的可卡因注射在延髓核（NAc）中产生沉默突触[2，3]，这是一个涉及与成瘾相关的动机学习和记忆的大脑区域[4]。随后的研究表明，可卡因自我管理产生沉默的突触在杏仁核和前额叶皮质投射到NAc，随后由AMPAR插入介导的成熟可卡因戒断后。这种沉默的突触介导的回路重塑有助于线索诱导的可卡因渴望的孵化[5，6]，这是线索诱导的可卡因在戒断后寻求的时间依赖性增强[7]。这些结果表明，可卡因重新激活成年大脑中沉默的突触介导的发育机制，以重塑关键的大脑回路并促进成瘾相关行为[4]。因此，出现了几个问题：（1）是沉默的突触为基础的电路重塑机制，只有可卡因或其他滥用药物，以重新定义电路的属性？(2)药物经验是否会在除NAc以外的其他脑区引起沉默的突触介导回路重塑？（3）除了由线索-药物关联控制的行为外，沉默的突触介导的回路重塑是否参与成瘾的其他标志性特征？在这一期的《神经精神药理学》中，Beroun et al. [8]勇敢地回答了这些问题。他们采用了一种延长的酒精摄入程序，包括训练小鼠在90天内自我饮酒。然后，他们将酒精暴露的小鼠分为“上瘾”和“上瘾”。使用五个DSM-IV酒精依赖标准（美国精神病学协会，2000年）：（1）在自由获取期间的高饮酒水平;（2）饮酒动机高;（3）尽管酒精不可用，但持续寻求酒精;（4）酒精提示暴露诱导寻求酒精;（5）戒断后复发期间过度饮酒。得分在前35%的小鼠被定义为标准“阳性”，表现出两个或更多个阳性标准的小鼠被认为是“成瘾”。使用这种临床相关的动物模型，他们对齿状回（DG）中的颗粒细胞进行了电生理和形态学研究，齿状回是一个奖励相关区域，其在成瘾中的作用尚未得到充分研究。通过抑制性（hM 4Di）DREADDs的化学遗传学操作，他们证明了在长期接触酒精后，DG颗粒神经元的抑制以持久（7天）的方式增加了饮酒和寻求，这表明DG颗粒神经元的兴奋减少促进了酒精滥用。然后，作者研究了沉默的突触内的DG颗粒细胞的贯穿路径的动态变化。在酒精自我给药期间，成瘾和非成瘾小鼠的沉默突触水平都有所增加，但在酒精戒断后下降到基础水平。值得注意的是，90分钟后线索诱导的酒精寻求戒断，成瘾小鼠表现出更高水平的沉默突触相比，非成瘾小鼠，这表明增强的兴奋性突触在DG颗粒细胞成瘾小鼠迅速...
Enriched in the developing brain, most silent synapses are immature glutamatergic synapses that contain stable NMDA receptors (NMDARs) with AMPA receptors (AMPARs) that are either absent or highly labile, and thus are AMPAR-silent [1]. They serve as initial connections between neurons to form new neural circuits. During development, some silent synapses undergo experience-dependent maturation by recruiting or stabilizing AMPARs to consolidate synaptic connections. Prior studies have revealed in adult rodents that non-contingent cocaine injections generate silent synapses in the nucleus accumbens (NAc)[2, 3], a brain region implicated in motivational learning and memory relevant to addiction [4]. Subsequent studies demonstrated that cocaine self-administration generates silent synapses in the amygdalar and prefrontal cortical projections to the NAc, followed by AMPAR insertion-mediated maturation after cocaine withdrawal. This silent synapse-mediated circuit remodeling contributes to incubation of cue-induced cocaine craving [5, 6], a time-dependent enhancement of cue-induced cocaine seeking after withdrawal [7]. These results suggest that cocaine re-activates silent synapse-mediated developmental mechanisms in the adult brain to remodel critical brain circuits and promote addictionrelated behaviors [4]. As such, several questions arise:(1) Is silent synapse-based circuit remodeling a mechanism only employed by cocaine or also by other abused drugs to redefine circuit properties?;(2) Does drug experience induce silent synapsemediated circuit remodeling in other brain regions apart from the NAc?; and (3) in addition to behaviors controlled by cue-drug associations, is silent synapse-mediated circuit remodeling involved in other hallmark features of addiction? In this issue of Neuropsychopharmacology, Beroun et al.[8] heroically addressed these questions. They employed an extended alcohol intake procedure involving training mice for alcohol selfadministration over 90 days. They then categorized the alcoholexposed mice into “addicted” vs.“non-addicted” using five DSM-IV criteria for alcohol dependence (American Psychiatric Association 2000):(1) high drinking levels during free access;(2) high motivation to drink;(3) persistent alcohol seeking despite alcohol unavailability;(4) alcohol cue exposure induced alcohol seeking;(5) excessive alcohol consumption during relapse after withdrawal. Mice that scored in the upper 35% were defined to be ‘positive’for a criterion, and mice that exhibited two or more positive criteria were considered ‘addicted’. Using this clinically relevant animal model, they performed electrophysiological and morphological investigations on granule cells in the dentate gyrus (DG), a reward-relevant region whose role in addiction remains underexplored. By chemogenetic manipulations via inhibitory (hM4Di) DREADDs, they demonstrated that after extended access to alcohol, inhibition of DG granule neurons increased both alcohol drinking and seeking in an enduring (7 days) manner, indicating that a decreased excitation of DG granule neurons promotes alcohol abuse. The authors then examined the dynamic changes of silent synapses within the perforant path to DG granule cells. Silent synapse levels increased in both addicted and non-addicted mice during alcohol self-administration, but declined to basal levels after alcohol withdrawal. Strikingly, 90 min following cue-induced alcohol seeking after withdrawal, addicted mice exhibited higher levels of silent synapses compared to non-addicted mice, suggesting an enhanced capability of excitatory synapses at DG granule cells in addicted mice to rapidly …