Beta-arrestin 1 regulation of reward-motivated behaviors and glutamatergic function.
Beta-arrestin 1 regulation of reward-motivated behaviors and glutamatergic function.
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DOI：
10.1371/journal.pone.0185796
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Walwyn W
中科院分区：
文献类型：
--
作者：
Mittal N;Minasyan A;Romaneschi N;Hakimian JK;Gonzalez-Fernandez G;Albert R;Desai N;Mendez IA;Schallert T;Ostlund SB;Walwyn W
两种高度同源的非视觉抑制蛋白，β-抑制蛋白1和2，在中枢神经系统中普遍表达，但对它们不同作用的认识是有限的。虽然β-arrestin 2（β arr 2）与奖励相关的学习和行为的几个方面有关，但对β-arrestin 1（β arr 1）的行为功能知之甚少。使用缺乏β arr 1的小鼠，我们专注于这种支架和信号转导蛋白在奖励动机行为和纹状体神经元功能中的作用。我们发现，β arr 1基因敲除小鼠在获得可卡因自我给药和消除这种行为方面都较慢。他们还表现出在自然食物奖励支持的学习任务中的缺陷，这表明奖励处理的一般改变。然后，我们检查了幼稚动物伏隔核（NAc）壳的WT和KO中型多刺神经元（MSN）中的多巴胺能突触强度，以及接受可卡因自我给药的动物。在未处理KO与WT MSN中发现AMPA/NMDA（A/N）比值增加，且相对缺乏富含GluN 2B的NMDAR。将Lim结构域激酶（LIMK 1）（磷酸化和灭活cofilin的激酶）应用于这些细胞，表明β arr 1和LIMK都调节A/N比和GluN 2B-NMDAR。在WT MSN中，辅酶A自身给药增加了A/N比和GluN 2B-NMDAR，尽管在KO MSN中A/N比也增加了，但这伴随着更少的GluN 2B-NMDAR和钙渗透性AMPAR的出现。最后，为了检查在KO小鼠中观察到的奖励处理中基础GluN 2B-NMDAR减少的后果，我们将GluN 2B拮抗剂艾芬地尔长期输注到WT小鼠的NAc壳中。这种干预大大减少了食物动机的行为。这些发现共同确定了β arr 1在调节特定奖励动机行为和神经元功能中的一个先前未知的作用。
The two highly homologous non-visual arrestins, beta-arrestin 1 and 2, are ubiquitously expressed in the central nervous system, yet knowledge of their disparate roles is limited. While beta-arrestin 2 (βarr2) has been implicated in several aspects of reward-related learning and behavior, very little is known about the behavioral function of beta-arrestin 1 (βarr1). Using mice lacking βarr1, we focused on the role of this scaffolding and signal transduction protein in reward-motivated behaviors and in striatal glutamatergic function. We found that βarr1 KO mice were both slower in acquiring cocaine self-administration and in extinguishing this behavior. They also showed deficits in learning tasks supported by a natural food reward, suggesting a general alteration in reward processing. We then examined glutamatergic synaptic strength in WT and KO medium spiny neurons (MSNs) of the Nucleus Accumbens (NAc) shell in naïve animals, and from those that underwent cocaine self-administration. An increase in the AMPA/NMDA (A/N) ratio and a relative lack of GluN2B-enriched NMDARs was found in naïve KO vs WT MSNs. Applying Lim Domain Kinase (LIMK1), the kinase that phosphorylates and inactivates cofilin, to these cells, showed that both βarr1 and LIMK regulate the A/N ratio and GluN2B-NMDARs. Cocaine self-administration increased the A/N ratio and GluN2B-NMDARs in WT MSNs and, although the A/N ratio also increased in KO MSNs, this was accompanied by fewer GluN2B-NMDARs and an appearance of calcium-permeable AMPARs. Finally, to examine the consequences of reduced basal GluN2B-NMDARs in reward-processing seen in KO mice, we chronically infused ifenprodil, a GluN2B antagonist, into the NAc shell of WT mice. This intervention substantially reduced food-motivated behavior. Together these findings identify a previously unknown role of βarr1 in regulating specific reward-motivated behaviors and glutamatergic function.
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影响因子：
16.2
作者：
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通讯作者：
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影响因子：
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