Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota.
Department of Neurologic Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota; Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota.
Biol Psychiatry. 2020 Nov 15;88(10):797-808. doi: 10.1016/j.biopsych.2020.04.023. Epub 2020 May 6.
Habitual reward-seeking behavior is a hallmark of addictive behavior. The role of the dorsomedial striatum (DMS) in regulating goal-directed reward-seeking behavior has been long appreciated. However, it remains unclear how the astrocytic activities in the DMS differentially affect the behavioral shift.
To investigate the astrocytic activity-driven neuronal synaptic events and behavioral consequences, we chemogenetically activated astrocytes in the DMS using GFAP promoter-driven expression of hM3Dq, the excitatory DREADDs (designer receptors exclusively activated by designer drugs). First, we confirmed the chemogenetically induced cellular activity in the DMS astrocytes using calcium imaging. Then, we recorded electrophysiological changes in the synaptic activity of the two types of medium spiny neurons (MSNs): direct and indirect pathway MSNs. To evaluate the behavioral consequences, we trained mice in nose-poking operant chambers that developed either habitual or goal-directed reward-seeking behaviors.
The activation of DMS astrocytes reduced the frequency of spontaneous excitatory postsynaptic currents in the direct pathway MSNs, whereas it increased the amplitude of the spontaneous excitatory postsynaptic currents and decreased the frequency of spontaneous inhibitory postsynaptic currents in the indirect pathway MSNs. Interestingly, astrocyte-induced DMS neuronal activities are regulated by adenosine metabolism, receptor signaling, and transport. Importantly, mice lacking an astrocytic adenosine transporter, ENT1 (equilibrative nucleoside transporter 1; Slc29a1), show no transition from habitual to goal-directed reward-seeking behaviors upon astrocyte activation, while restoring ENT1 expression in the DMS facilitated this transition.
Our findings reveal that DMS astrocyte activation differentially regulates MSNs' activity and facilitates shifting from habitual to goal-directed reward-seeking behavior.
习惯性的奖励寻求行为是成瘾行为的一个标志。背内侧纹状体（DMS）在调节目标导向的奖励寻求行为中的作用早已被人们所认识。然而，目前尚不清楚 DMS 中的星形胶质细胞活动如何差异地影响行为转变。
为了研究星形胶质细胞活动驱动的神经元突触事件和行为后果，我们使用 GFAP 启动子驱动 hM3Dq 的表达，即兴奋性 DREADD（专门被设计药物激活的设计受体），化学遗传学激活 DMS 中的星形胶质细胞。首先，我们使用钙成像来确认 DMS 星形胶质细胞中的化学遗传诱导的细胞活动。然后，我们记录了两种类型的中间神经元（MSNs）：直接和间接通路 MSNs 的突触活动的电生理变化。为了评估行为后果，我们在鼻戳操作性条件反射室中对老鼠进行训练，使老鼠形成习惯性或目标导向的奖励寻求行为。
DMS 星形胶质细胞的激活降低了直接通路 MSNs 中自发性兴奋性突触后电流的频率，而增加了间接通路 MSNs 中自发性兴奋性突触后电流的幅度，并降低了自发性抑制性突触后电流的频率。有趣的是，星形胶质细胞诱导的 DMS 神经元活动受腺苷代谢、受体信号和转运调节。重要的是，缺乏星形胶质细胞腺苷转运体 ENT1（平衡核苷转运体 1；Slc29a1）的小鼠在星形胶质细胞激活后不会从习惯性奖励寻求行为转变为目标导向奖励寻求行为，而在 DMS 中恢复 ENT1 表达则促进了这种转变。
我们的发现表明，DMS 星形胶质细胞的激活差异调节 MSNs 的活动，并促进从习惯性奖励寻求行为转变为目标导向奖励寻求行为。
