Lv Xiaohui, Dickerson Jonathan W, Rook Jerri M, Lindsley Craig W, Conn P Jeffrey, Xiang Zixiu
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
Neuropharmacology. 2017 May 15;118:209-222. doi: 10.1016/j.neuropharm.2017.03.017. Epub 2017 Mar 20.
The dorsolateral striatum is critically involved in movement control and motor learning. Striatal function is regulated by a variety of neuromodulators including acetylcholine. Previous studies have shown that cholinergic activation excites striatal principal projection neurons, medium spiny neurons (MSNs), and this action is mediated by muscarinic acetylcholine subtype 1 receptors (M) through modulating multiple potassium channels. In the present study, we used electrophysiology techniques in conjunction with optogenetic and pharmacological tools to determine the long-term effects of striatal cholinergic activation on MSN intrinsic excitability. A transient increase in acetylcholine release in the striatum by optogenetic stimulation resulted in a long-lasting increase in excitability of MSNs, which was associated with hyperpolarizing shift of action potential threshold and decrease in afterhyperpolarization (AHP) amplitude, leading to an increase in probability of EPSP-action potential coupling. The M selective antagonist VU0255035 prevented, while the M selective positive allosteric modulator (PAM) VU0453595 potentiated the cholinergic activation-induced persistent increase in MSN intrinsic excitability, suggesting that M receptors are critically involved in the induction of this long-lasting response. This M receptor-dependent long-lasting change in MSN intrinsic excitability could have significant impact on striatal processing and might provide a novel mechanism underlying cholinergic regulation of the striatum-dependent motor learning and cognitive function. Consistent with this, behavioral studies indicate that potentiation of M receptor signaling by VU0453595 enhanced performance of mice in cue-dependent water-based T-maze, a dorsolateral striatum-dependent learning task.
背外侧纹状体在运动控制和运动学习中起着关键作用。纹状体功能受多种神经调质调节，包括乙酰胆碱。先前的研究表明，胆碱能激活可兴奋纹状体主要投射神经元——中型多棘神经元（MSNs），且这种作用是通过毒蕈碱型乙酰胆碱1型受体（M1）调节多个钾通道介导的。在本研究中，我们结合电生理学技术以及光遗传学和药理学工具，来确定纹状体胆碱能激活对MSN内在兴奋性的长期影响。通过光遗传学刺激使纹状体中乙酰胆碱释放短暂增加，导致MSN兴奋性持久增加，这与动作电位阈值的超极化偏移和后超极化（AHP）幅度的降低有关，从而导致兴奋性突触后电位-动作电位耦合概率增加。M1选择性拮抗剂VU0255035可阻止这种增加，而M1选择性正变构调节剂（PAM）VU0453595则增强胆碱能激活诱导的MSN内在兴奋性的持续增加，这表明M1受体在诱导这种持久反应中起关键作用。MSN内在兴奋性这种依赖M1受体的持久变化可能对纹状体处理过程产生重大影响，并可能为纹状体依赖性运动学习和认知功能的胆碱能调节提供一种新机制。与此一致的是，行为学研究表明，VU0453595增强M1受体信号传导可提高小鼠在基于线索的水基T迷宫中的表现，这是一种背外侧纹状体依赖性学习任务。
