Stressing the Importance of Cholinergic Interneurons in Striatal Function.
Stressing the Importance of Cholinergic Interneurons in Striatal Function.
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DOI：
10.1002/mds.28869
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Gittis AH
中科院分区：
文献类型：
--
作者：
Albaugh DL;Gittis AH
当病理性应激源威胁细胞健康和功能时，整合应激反应（ISR）可能被招募作为救援反应。ISR是一种进化上保守的信号通路，广泛抑制蛋白质合成，同时也触发选择转录因子的翻译，一旦压力使蛋白质组处于不平衡状态，ISR就有效地充当翻译重置按钮1。也许并不奇怪，ISR的激活发生在各种神经病理学中，包括运动障碍，如肌张力障碍2.Writing在Science，Helseth，Hernanel-Martinez和同事现在已经确定了组成性ISR信号在纹状体胆碱能中间神经元（CINS）的正常生理和功能中的惊人新作用3。该团队开发了一种遗传编码的生物传感器，称为“SPOTlight”，可用于识别具有活跃ISR信号的细胞。SPOTlight通过两种荧光团报告ISR信号传导，这两种荧光团根据真核起始因子2 α（eIF 2 α）的磷酸化状态相互排斥地表达。由于eIF 2 α的磷酸化是ISR的组成部分，因此两个SPOTlight荧光团的相对表达在单细胞水平上报告了ISR信号状态。当SPOTlight在小鼠大脑中表达时，ISR标记的神经元稀疏地分布在异质区域和细胞类型中，这表明在健康大脑中存在随机的低水平ISR诱导。在纹状体中发现了一个例外，其中ISR传感器均匀地强烈标记了CIN。这一意想不到的发现提出了组成型ISR信号传导有助于正常CIN功能的可能性。虽然它们是纹状体中的一种罕见细胞类型，但CIN在纹状体微电路中起着关键作用，部分原因是它们与中纹状体多巴胺系统的强大和相互作用4。CIN表达D2多巴胺受体（D2 R），并且D2 R激动剂的应用通常降低自发性CIN放电率。然而，当作者使用药理学或遗传学方法抑制ISR信号传导时，后者选择性地在CIN中，D2 R激动剂增加CIN放电。CINs的激活可以通过位于纹状体多巴胺能末梢上的胆碱能受体驱动纹状体多巴胺释放。一致地，CIN ISR信号传导的破坏导致纹状体细胞外多巴胺水平被D2 R激动剂放大，而不是钝化。最后，作者将这些发现联系在一起，证明了学习运动技能的表现，纹状体CIN-多巴胺相互作用可能密切参与的过程，通过抑制CIN ISR信号传导而被削弱。
When pathological stressors threaten cellular health and function, the integrated stress response (ISR) may be recruited as a rescue response. An evolutionarily conserved signaling pathway, the ISR broadly dampens protein synthesis while also triggering translation of select transcription factors, effectively serving as a translational reset button once stressors have set the proteome into disequilibrium1. Perhaps not surprisingly, activation of the ISR occurs in a variety of neuropathologies, including movement disorders such as dystonia2.Writing in Science, Helseth, Hernandez-Martinez and colleagues have now identified a surprising new role for constitutive ISR signaling in the normal physiology and function of striatal cholinergic interneurons (CINs) 3. The team developed a genetically-encoded biosensor, termed “SPOTlight”, that could be used to identify cells with active ISR signaling. SPOTlight reports ISR signaling by means of two fluorophores which are expressed with mutual exclusivity depending upon the phosphorylation status of eukaryotic initiation factor 2 alpha (eIF2α). Because phosphorylation of eIF2α is an integral component of the ISR, relative expression of the two SPOTlight fluorophores reports the ISR signaling state on a single-cell level. When SPOTlight was expressed in the brains of mice, ISR-labeled neurons were sparsely distributed across heterogenous regions and cell types, suggesting stochastic, low-level ISR induction in the healthy brain. An exception was discovered in the striatum, where CINs were uniformly strongly labeled by the ISR sensor. This unexpected finding raised the possibility that constitutive ISR signaling contributes to normal CIN function. Although they are a rare cell type in striatum, CINs play pivotal roles in the striatal microcircuitry, in part due to their powerful and reciprocal interactions with the mesostriatal dopamine system4. CINs express the D2 dopamine receptor (D2R), and application of D2R agonists normally lowers spontaneous CIN firing rates. However, when the authors inhibited ISR signaling, using either pharmacologic or genetic approaches, the latter selectively in CINs, a D2R agonist increased CIN firing. Activation of CINs can drive striatal dopamine release through cholinergic receptors located on striatal dopaminergic terminals. Consistently, disruption of CIN ISR signaling resulted in an amplification, rather than blunting, of striatal extracellular dopamine levels by a D2R agonist. Lastly, the authors tied these findings together in demonstrating that performance of a learned motor skill, a process in which striatal CIN-dopamine interactions may be intimately involved, is invigorated by inhibition of CIN ISR signaling.
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影响因子：
16.2
作者：
Rittiner JE;Caffall ZF;Hernández-Martinez R;Sanderson SM;Pearson JL;Tsukayama KK;Liu AY;Xiao C;Tracy S;Shipman MK;Hickey P;Johnson J;Scott B;Stacy M;Saunders-Pullman R;Bressman S;Simonyan K;Sharma N;Ozelius LJ;Cirulli ET;Calakos N
通讯作者：
Calakos N
DOI：
10.1111/ejn.13638
发表时间：
2018-05
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Tanimura A;Pancani T;Lim SAO;Tubert C;Melendez AE;Shen W;Surmeier DJ
通讯作者：
Surmeier DJ
DOI：
10.1126/science.aat5314
发表时间：
2020-04-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Costa-Mattioli M;Walter P
通讯作者：
Walter P
影响因子：
3
作者：
Threlfell S;Cragg SJ
通讯作者：
Cragg SJ
DOI：
10.1126/science.abe1931
发表时间：
2021-04-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Helseth AR;Hernandez-Martinez R;Hall VL;Oliver ML;Turner BD;Caffall ZF;Rittiner JE;Shipman MK;King CS;Gradinaru V;Gerfen C;Costa-Mattioli M;Calakos N
通讯作者：
Calakos N