State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; Brain and Behavior Discovery Institute, Department of Neurology, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA 30912, USA.
Brain and Behavior Discovery Institute, Department of Neurology, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA 30912, USA.
Curr Biol. 2017 Sep 11;27(17):2640-2646.e4. doi: 10.1016/j.cub.2017.07.021. Epub 2017 Aug 17.
Acetylcholine in the neocortex is critical for executive function [1-3]. Degeneration of cholinergic neurons in aging and Alzheimer's dementia is commonly treated with cholinesterase inhibitors [4-7]; however, these are modestly effective and are associated with side effects that preclude effective dosing in many patients [8]. Electrical activation of the nucleus basalis (NB) of Meynert, the source of neocortical acetylcholine [9, 10], provides a potential method of improving cholinergic activation [11, 12]. Here we tested whether NB stimulation would improve performance of a working memory task in a nonhuman primate model. Unexpectedly, intermittent stimulation proved to be most beneficial (60 pulses per second, for 20 s every minute), whereas continuous stimulation often impaired performance. Pharmacological experiments confirmed that the effects depended on cholinergic activation. Donepezil, a cholinesterase inhibitor, restored performance in animals impaired by continuous stimulation but did not improve performance further during intermittent stimulation. Intermittent stimulation was rendered ineffective by either nicotinic or muscarinic receptor antagonists. In the months after stimulation began, performance also improved in sessions without stimulation. Our results reveal that intermittent NB stimulation can improve working memory, a finding that has implications for restoring cognitive function in aging and Alzheimer's dementia.
大脑皮层中的乙酰胆碱对于执行功能至关重要[1-3]。衰老和阿尔茨海默病中胆碱能神经元的退化通常用胆碱酯酶抑制剂来治疗[4-7]；然而，这些药物的效果有限，且存在副作用，这使得许多患者无法有效用药[8]。梅内特核（Meynert 的基底核）的电激活是大脑皮层乙酰胆碱的来源[9,10]，为改善胆碱能激活提供了一种潜在的方法[11,12]。在这里，我们测试了 NB 刺激是否会改善非人类灵长类动物模型的工作记忆任务的表现。出乎意料的是，间歇性刺激被证明是最有益的（每秒 60 脉冲，每分钟 20 秒），而连续刺激往往会损害表现。药理实验证实，这些效果取决于胆碱能的激活。多奈哌齐，一种胆碱酯酶抑制剂，恢复了连续刺激导致的动物表现受损，但在间歇性刺激期间并没有进一步提高表现。烟碱或毒蕈碱受体拮抗剂使间歇性刺激无效。在刺激开始后的几个月里，即使没有刺激，动物的表现也会在随后的会议中得到改善。我们的结果表明，间歇性 NB 刺激可以改善工作记忆，这一发现对于恢复衰老和阿尔茨海默病的认知功能具有重要意义。
