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.

Adult hippocampal neural stem cells can be activated by hippocampal neural activities. When focal cerebral ischemia, known as middle cerebral artery occlusion (MCAO), occurs, neural stem cells are activated to promote their proliferation. However, the mechanism by which these cells are activated is still unclear. Here, we indicate the involvement of metabotropic glutamate receptor 5 (mGluR5) signaling in neural stem cells in their activity-related proliferation after MCAO. We found mGluR5 molecules on neural stem cells by using calcium imaging. We detected the activation of neural stem cells by adding the mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine. On a hippocampal slice, the activation of neural stem cells to promote their proliferation was initiated by theta-burst electrical stimulation at the perforant pathway, and this activation was significantly blocked by an mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP). In addition to this, the injection of the blood-brain barrier-permeable mGluR5 agonist 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide into live mice promoted the proliferation of neural stem cells. Moreover, in vivo theta-burst electrical stimulation induced proliferation of neural stem cells. A chronic field recording study showed that the activity of the hippocampal formation was elevated after MCAO. Finally, we observed that the mGluR5 antagonist MPEP significantly blocked the stimulated proliferation of neural stem cells induced by MCAO, by blocking mGluR5 signaling. Our results suggest that glutamates released by the elevated neural activities after MCAO may trigger mGluR5 signaling in neural stem cells to promote their proliferation.

Hippocampal neurogenesis is accelerated during the elevation of hippocampal neural activities under both physiological and pathophysiological conditions. One of these conditions, middle cerebral artery occlusion (MCAO), induces both the hyperactivities of hippocampal network and the elevation of neural stem cell (NSC) proliferation. However, the causal relationship between the elevated activity and the elevation of NSC proliferation is still unclear. In this study, to block the elevation of hippocampal activity after MCAO in mice, we utilized a typical γ-aminobutyric acid type A (GABAA ) receptor active modulator, diazepam. With MCAO mice treated with diazepam, we observed complete disappearance of the elevation of hippocampal activity. Additionally, the diazepam treatment blocked the elevation of NSC proliferation after MCAO. From this result, it is speculated that the increased NSC proliferation is blocked by the suppression of elevated neural activity. However, diazepam might have effects other than the suppression of hippocampal activity, so we performed additional experiment and found that diazepam did not affect the number of bromodeoxyuridine-positive cells under the normal condition, whereas the GABA agonist pentobarbital stimulated NSC/neural progenitor cell proliferation and differentiation. Next, we evaluated the expression of the diazepam-binding inhibitor (DBI) protein and found that the cells expressed DBI in soma and on the surface of cell membrane. From these observations, we can propose that diazepam blocks the elevation of hippocampal activity and also NSC proliferation after MCAO.

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