Department of Physiology and Pharmacology, The University of Western Ontario, London, ON N6A 5B7, Canada; Robarts Research Institute, The University of Western Ontario, London, ON N6A 5B7, Canada.
Graduate Program in Neuroscience, The University of Western Ontario, London, ON N6A 5B7, Canada.
Neuron. 2018 Jun 27;98(6):1256-1268.e4. doi: 10.1016/j.neuron.2018.05.027. Epub 2018 Jun 7.
Acetylcholine release in the prefrontal cortex (PFC), acting through muscarinic receptors, has an essential role in regulating flexible behavior and working memory (WM). General muscarinic receptor blockade disrupts PFC WM representations, while selective stimulation of muscarinic receptor subtypes is of great interest for the treatment of cognitive dysfunction in Alzheimer's disease. Here, we tested selective stimulation and blockade of muscarinic M1 receptors (M1Rs) in macaque PFC, during performance of a cognitive control task in which rules maintained in WM specified saccadic responses. We hypothesized that M1R blockade and stimulation would disrupt and enhance rule representation in WM, respectively. Unexpectedly, M1R blockade did not consistently affect PFC neuronal rule selectivity. Moreover, M1R stimulation suppressed PFC activity, and at higher doses, degraded rule representations. Our results suggest that, in primates, the deleterious effects of general muscarinic blockade on PFC WM activity are not mediated by M1Rs, while their overstimulation deteriorates PFC rule maintenance.
前额叶皮层（PFC）中的乙酰胆碱释放，通过毒蕈碱受体发挥作用，对于调节灵活行为和工作记忆（WM）具有重要作用。一般的毒蕈碱受体阻断会破坏 PFC WM 表现，而选择性刺激毒蕈碱受体亚型对于治疗阿尔茨海默病的认知功能障碍非常有意义。在这里，我们在猕猴 PFC 中测试了毒蕈碱 M1 受体（M1R）的选择性刺激和阻断，在执行认知控制任务期间，该任务规定 WM 中保持的规则指定了眼跳反应。我们假设 M1R 阻断和刺激分别会破坏和增强 WM 中的规则表示。出乎意料的是，M1R 阻断并没有一致地影响 PFC 神经元规则选择性。此外，M1R 刺激抑制了 PFC 活动，并且在较高剂量下，降低了规则表示。我们的结果表明，在灵长类动物中，一般毒蕈碱阻断对 PFC WM 活动的有害影响不是由 M1R 介导的，而过度刺激会恶化 PFC 规则维持。
