Quiescent and Active Hippocampal Neural Stem Cells with Distinct Morphologies Respond Selectively to Physiological and Pathological Stimuli and Aging

Abstract

New neurons are generated in the adult hippocampus throughout life by neural stem/progenitor cells (NSCs), and neurogenesis is a plastic process responsive to external stimuli. We show that canonical Notch signaling through RBP-J is required for hippocampal neurogenesis. Notch signaling distinguishes morphologically distinct Sox2(+) NSCs, and within these pools subpopulations can shuttle between mitotically active or quiescent. Radial and horizontal NSCs respond selectively to neurogenic stimuli. Physical exercise activates the quiescent radial population whereas epileptic seizures induce expansion of the horizontal NSC pool. Surprisingly, reduced neurogenesis correlates with a loss of active horizontal NSCs in aged mice rather than a total loss of stem cells, and the transition to a quiescent state is reversible to rejuvenate neurogenesis in the brain. The discovery of multiple NSC populations with Notch dependence but selective responses to stimuli and reversible quiescence has important implications for the mechanisms of adaptive learning and also for regenerative therapy.

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

“…Additionally, a recent report from Varodayan et al [48] demonstrated that seizure leads to a shortening of the cell cycle in DG precursors, suggesting a link between G 1 phase length and seizureinduced proliferation. To address whether Cdk6 plays a role during seizure-induced proliferation, we injected kainic acid (KA) to WT and Cdk6 À/À animals and quantified precursor cell proliferation in the DG 72 hours later, with a protocol that was described previously [49,50]. Of note, we consistently observed a large overlap between Cdk4/6 and Ki-67 expression 72 hours after either NaCl or KA administration (Supporting Information Fig.…”

“…7A-7E). Because seizure has been demonstrated to initially trigger the proliferation of immature/noncommitted precursors [49,50], we then quantified the numbers of GFAP þ /Ki-67 þ and Sox2 þ /Ki-67 þ cells following KA injection. We observed a dramatic increase of the number of GFAP þ and Sox2 þ proliferating precursors, independently of the mouse genotype (Fig.…”

Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis

“…IdU was administered over 24 h diluted in drinking water at 0.92 mg/ml. These doses were based on equimolar doses of 50 mg/kg (Llorens‐Martin et al , 2010) and 0.8 mg/ml BrdU (Lugert et al , 2010), respectively.…”

Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age‐associated neurogenic decline

“…Aging is associated with reduced neurogenesis in the mouse SVZ and SGZ (Encinas et al., 2011; Enwere et al., 2004; Lugert et al., 2010; Luo, Daniels, Lennington, Notti & Conover, 2006), which might lead to decreased olfactory function and cognitive hippocampus‐dependent impairment (Goncalves et al., 2016; Lledo & Valley, 2016). This age‐associated neurogenic decline appears to be caused both by a depletion in the NSPC pool of the aged niche (Ahlenius, Visan, Kokaia, Lindvall & Kokaia, 2009; Bouab, Paliouras, Aumont, Forest‐Berard & Fernandes, 2011; Corenblum et al., 2016; Enwere et al., 2004; Luo et al., 2006; Maslov, Barone, Plunkett & Pruitt, 2004; Molofsky et al., 2006; Stoll et al., 2011) and by the decreased capacity of the remaining NSPCs to sustain proliferation and neuronal differentiation, as revealed by in vitro studies (Ahlenius et al., 2009; Apostolopoulou et al., 2017; Corenblum et al., 2016; Daynac, Morizur, Chicheportiche, Mouthon & Boussin, 2016; Daynac et al., 2014; L'Episcopo et al., 2013; Shi et al., 2017; Zhu et al., 2014).…”