Cholinergic activation of hippocampal neural stem cells in aged dentate gyrus

Abstract

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.

Role of Adult Hippocampal Neurogenesis in Cognition in Physiology and Disease: Pharmacological Targets and Biomarkers

“…Acetylcholine neurotransmission appears to be deregulated with age and in Alzheimer's disease, conditions with reduction in both neurogenesis and cognitive capacity. Notably, pharmacological modulation of the cholinergic activity in aged or stressed animals promotes NSCs' proliferation and corrects cognitive alterations (Itou et al 2011;Veena et al 2011b). The dopaminergic system has been shown to affect proliferation and differentiation of neural progenitor cells during embryonic development and in both adult neurogenic zones.…”

Development of glutamatergic innervation during maturation of adult-born neurons

“…Selective lesioning of the cholinergic system in the basal forebrain reduces proliferation of neuronal progenitor cells (Ma et al, 2000;Zhou et al, 2004;Mohapel et al, 2005). In both young and aged mice, focal application of ACh induces rapid calcium responses in Type 1 and Type 2 cells, suggesting that endogenous ACh might regulate stem cell activity by acting directly on proliferating cells (Itou et al, 2011). As mentioned above,Type 1 cells give rise to Type 2 cells that lack dendritic and axonal processes but may have short plump horizontal processes of unknown function.…”

Effects of treadmill exercise on the LiCl-induced conditioned taste aversion in rats

“…Itou et al have reported positive effects of exercise on neural stem cells in the hippocampus [21]. Exercise-induced activation of cholinergic neurons has been implicated as a stimulus for hippocampal neurogenesis derived from neural stem cells in the dentate gyrus of mice over the age of 2 years [21].…”

“…Itou et al have reported positive effects of exercise on neural stem cells in the hippocampus [21]. Exercise-induced activation of cholinergic neurons has been implicated as a stimulus for hippocampal neurogenesis derived from neural stem cells in the dentate gyrus of mice over the age of 2 years [21]. Others report that exercise-induced increases in the synthesis of dihydrotestosterone caused by mild treadmill running are responsible for increased neurogenesis of hippocampal neurons in adult rats [22].…”