Dysfunction of ventrolateral striatal dopamine receptor type 2-expressing medium spiny neurons impairs instrumental motivation.
Dysfunction of ventrolateral striatal dopamine receptor type 2-expressing medium spiny neurons impairs instrumental motivation.
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DOI：
10.1038/ncomms14304
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发表时间：
2017-02-01
影响因子：
16.6
通讯作者：
Tanaka KF
中科院分区：
文献类型：
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作者：
Tsutsui-Kimura I;Takiue H;Yoshida K;Xu M;Yano R;Ohta H;Nishida H;Bouchekioua Y;Okano H;Uchigashima M;Watanabe M;Takata N;Drew MR;Sano H;Mimura M;Tanaka KF
动机受损存在于各种神经系统疾病中，这表明动机下降是由神经系统在各种回路中的广泛功能障碍引起的。基于证据表明，受损的动机是一个主要的症状，在早期阶段的亨廷顿氏病，当多巴胺受体2型表达纹状体中型多刺神经元（D2-MSNs）特别受到影响，我们假设，这些神经元的退化将是一个关键节点调节动机状态。使用渐进的、时间可控的白喉毒素介导的细胞消融/功能障碍技术，我们发现腹外侧纹状体（VLS）内D2-MSNs的功能丧失足以减少目标导向行为，而不会损害奖励偏好或自发行为。此外，VLS D2-MSN的光遗传学抑制和消融分别引起目标导向行为的短暂和慢性减少。我们的数据表明，包含VLS D2-MSN的电路控制有动机的行为，并且VLS D2-MSN功能丧失可能是神经退行性疾病中动机缺陷的原因。表达D2受体的中型多刺神经元（D2-MSN）被认为抑制目标导向行为。在这里，作者专门在腹外侧纹状体中消融D2-MSN，并发现令人惊讶的是，它导致小鼠目标导向动机的减少。
Impaired motivation is present in a variety of neurological disorders, suggesting that decreased motivation is caused by broad dysfunction of the nervous system across a variety of circuits. Based on evidence that impaired motivation is a major symptom in the early stages of Huntington's disease, when dopamine receptor type 2-expressing striatal medium spiny neurons (D2-MSNs) are particularly affected, we hypothesize that degeneration of these neurons would be a key node regulating motivational status. Using a progressive, time-controllable, diphtheria toxin-mediated cell ablation/dysfunction technique, we find that loss-of-function of D2-MSNs within ventrolateral striatum (VLS) is sufficient to reduce goal-directed behaviours without impairing reward preference or spontaneous behaviour. Moreover, optogenetic inhibition and ablation of VLS D2-MSNs causes, respectively, transient and chronic reductions of goal-directed behaviours. Our data demonstrate that the circuitry containing VLS D2-MSNs control motivated behaviours and that VLS D2-MSN loss-of-function is a possible cause of motivation deficits in neurodegenerative diseases. D2 receptor-expressing medium spiny neurons (D2-MSNs) are thought to suppress goal-directed behaviours. Here authors ablate D2-MSNs specifically in the ventrolateral striatum, and find that surprisingly, it leads to a reduction in goal-directed motivation in mice.