Department of Integrated Biosciences, The University of Tokyo, Kashiwa, Chiba 277-8562, Japan.
Hippocampus. 2011 Apr;21(4):446-59. doi: 10.1002/hipo.20761.
Adult hippocampal neurogenesis contributes to the hippocampal circuit's role in cognitive functioning. New neurons are generated from hippocampal neural stem cells (NSCs) throughout life, but their generation is substantially diminished in aged animals due to a decrease in NSC proliferation. Because acetylcholine (ACh) is an important neurotransmitter released in the hippocampus during learning and exercise that is known to decrease with aging, we investigated whether aged NSCs can respond to ACh. In this study, we found that cholinergic stimulation has a positive effect on NSC proliferation in both young adult (8-12 weeks old) and aged mice (>2 years old). In fresh hippocampal slices, we observed a rapid calcium increase in NSCs in the dentate gyrus after muscarinic cholinergic stimulation, in both age groups. Furthermore, we found that the exercise-induced promotion of aged NSC proliferation was abrogated by the specific lesioning of the septal cholinergic system. In turn, cholinergic activation by either eserine (physostigmine) or donepezil treatment promoted the proliferation of NSCs in aged mice. These results indicate that NSCs respond to cholinergic stimulation by proliferating in aged animals. Physiological and/or pharmacological cholinergic stimulation(s) may ameliorate cognitive decline in aged animals, by supporting adult hippocampal neurogenesis.
成人海马神经发生有助于海马回路在认知功能中的作用。新的神经元由海马神经干细胞（NSC）在整个生命周期中产生，但由于 NSC 增殖减少，老年动物的产生大大减少。由于乙酰胆碱（ACh）是学习和运动期间在海马中释放的一种重要神经递质，已知其随年龄增长而减少，因此我们研究了老年 NSC 是否可以对 ACh 做出反应。在这项研究中，我们发现，在年轻成年（8-12 周龄）和老年小鼠（>2 岁）中，胆碱能刺激对 NSC 增殖具有积极影响。在新鲜的海马切片中，我们观察到在两组中，在齿状回的 NSCs 中，在毒蕈碱型胆碱能刺激后会迅速增加钙。此外，我们发现，通过特异性破坏隔区胆碱能系统，可以消除运动诱导的老年 NSC 增殖的促进作用。相反，通过毒扁豆碱（physostigmine）或多奈哌齐治疗进行胆碱能激活可促进老年小鼠 NSCs 的增殖。这些结果表明，NSC 通过在老年动物中增殖来对胆碱能刺激做出反应。生理和/或药理学的胆碱能刺激可能通过支持成年海马神经发生来改善老年动物的认知能力下降。
