Dopamine D2 receptors in discrimination learning and spine enlargement
Dopamine D2 receptors in discrimination learning and spine enlargement
复制标题
DOI：
10.1038/s41586-020-2115-1
复制
发表时间：
2020-03-18
期刊：
影响因子：
64.8
通讯作者：
Yagishita, Sho
中科院分区：
文献类型：
--
作者：
Iino, Yusuke;Sawada, Takeshi;Yagishita, Sho
通过检测纹状体中表达多巴胺D2受体的神经元的多巴胺下降，可用于改进由多巴胺D1受体介导的广义奖励条件反射。多巴胺D2受体（D2 R）在纹状体中密集表达，并与精神分裂症等神经精神疾病有关（1，2）。多巴胺的高亲和力结合表明，D2 Rs在惩罚学习过程中检测到多巴胺浓度的短暂降低（多巴胺下降）（3-5）。然而，D2 R依赖行为的性质和细胞基础尚不清楚。在这里，我们表明，音调奖励条件反射诱导显着的刺激泛化的方式，依赖于多巴胺D1受体（D1 Rs）在小鼠的脑桥核（NAc），和歧视学习细化的条件反射使用多巴胺浸渍。在NAc切片中，D2 Rs检测到一个狭窄的多巴胺下降（短至0.4 s），以解除腺苷A（2A）受体（A（2A）R）介导的D2 R表达的多刺投射神经元（D2-SPN）树突棘的扩大。可塑性相关的信号传导的钙/钙调蛋白依赖性蛋白激酶II和A（2A）Rs在NAc的歧视学习。相比之下，消退学习不涉及多巴胺下降或D2-SPN。用甲基苯丙胺治疗，它会使多巴胺信号失调，损害辨别学习和脊柱扩大，这些损害被D2 R拮抗剂逆转。我们的数据表明，D2 Rs细化D1 Rs介导的广义奖励学习。
Detection of dopamine dips by neurons that express dopamine D2 receptors in the striatum is used to refine generalized reward conditioning mediated by dopamine D1 receptors.Dopamine D2 receptors (D2Rs) are densely expressed in the striatum and have been linked to neuropsychiatric disorders such as schizophrenia(1,2). High-affinity binding of dopamine suggests that D2Rs detect transient reductions in dopamine concentration (the dopamine dip) during punishment learning(3-5). However, the nature and cellular basis of D2R-dependent behaviour are unclear. Here we show that tone reward conditioning induces marked stimulus generalization in a manner that depends on dopamine D1 receptors (D1Rs) in the nucleus accumbens (NAc) of mice, and that discrimination learning refines the conditioning using a dopamine dip. In NAc slices, a narrow dopamine dip (as short as 0.4 s) was detected by D2Rs to disinhibit adenosine A(2A) receptor (A(2A)R)-mediated enlargement of dendritic spines in D2R-expressing spiny projection neurons (D2-SPNs). Plasticity-related signalling by Ca2+/calmodulin-dependent protein kinase II and A(2A)Rs in the NAc was required for discrimination learning. By contrast, extinction learning did not involve dopamine dips or D2-SPNs. Treatment with methamphetamine, which dysregulates dopamine signalling, impaired discrimination learning and spine enlargement, and these impairments were reversed by a D2R antagonist. Our data show that D2Rs refine the generalized reward learning mediated by D1Rs.