A molecularly defined D1 medium spiny neuron subtype negatively regulates cocaine addiction.
A molecularly defined D1 medium spiny neuron subtype negatively regulates cocaine addiction.
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DOI：
10.1126/sciadv.abn3552
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发表时间：
2022-08-12
期刊：
影响因子：
13.6
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中科院分区：
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--
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纹状体在调节与成瘾相关的行为方面起着关键作用。传统的二分法模型认为纹状体D1/D2中棘神经元(MSN)对成瘾相关行为进行正/负调节。然而，这一模型没有考虑纹状体神经元的异质性和功能的多样性，并且PAN-D1/D2群体以外的MSN亚型是否在药物成瘾中起着不同的作用尚不清楚。我们利用可卡因成瘾小鼠模型研究了速激肽2表达的D1MSN亚型(Tac2+)在啮齿动物和灵长类动物纹状体中的作用。我们发现，急性可卡因给药降低了Tac2神经元的活动，可卡因调节改变了与可卡因奖赏相关的神经元反应。此外，激活/抑制Tac2+神经元可减弱/促进可卡因诱导的条件性位置偏爱和可卡因静脉给药。此外，刺激Tac2+神经元NAC向下丘脑外侧投射抑制可卡因奖赏行为。我们的研究揭示了D1MSN在药物成瘾中的非常规负调控功能，这种功能以亚型和投影特异性的方式运作。我们确定了一个分子定义的D1MSN亚型在抑制可卡因奖赏和成瘾方面的非常规作用。
The striatum plays a critical role in regulating addiction-related behaviors. The conventional dichotomy model suggests that striatal D1/D2 medium spiny neurons (MSNs) positively/negatively regulate addiction-related behaviors. However, this model does not account for the neuronal heterogeneity and functional diversity of the striatum, and whether MSN subtypes beyond the pan-D1/D2 populations play distinct roles in drug addiction remains unknown. We characterized the role of a tachykinin 2–expressing D1 MSN subtype (Tac2+), present in both rodent and primate striatum, using cocaine addiction mouse models. We found that acute cocaine administration reduces Tac2 neuronal activity, and cocaine conditioning alters neuronal response related to cocaine reward contextual associations. In addition, activation/inhibition of Tac2+ neurons attenuates/promotes cocaine-induced conditioned place preference and cocaine intravenous self-administration. Furthermore, stimulation of the NAc-to-lateral hypothalamic projection of Tac2+ neurons suppresses cocaine reward behavior. Our study reveals an unconventional negative regulatory function of D1 MSNs in drug addiction that operates in a subtype- and projection-specific manner. We identified an unconventional role of a molecularly defined D1 MSN subtype in suppressing cocaine reward and addiction.
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