Neurogenesis in the adult mammalian brain occurs
Neurogenesis in the adult mammalian Avasimibe occurs throughout life and has been clearly demonstrated at two locations under physiological conditions: the SVZ of the lateral ventricle and the subgranular zone (SGZ) of the DG in the hippocampus (Alvarez-Buylla and Lim, 2004). Several studies have shown that hippocampal neurogenesis is regulated by both physiological and pathological activities at different stages, including (1) proliferation of NPCs, (2) fate determination and differentiation of NPCs, and (3) survival, maturation, and integration of newborn neurons (Zhao et al., 2008). Furthermore, each of these stages is subject to regulation by numerous intrinsic and extrinsic factors (Suh et al., 2009). Genetic and environmental factors that affect adult hippocampal neurogenesis also cause alteration in cognitive performance, suggesting roles for adult hippocampal neurogenesis in learning and memory (Zhao et al., 2008). Our results showed that VPA-treated mice have a decreased level of postnatal neurogenesis in the hippocampus, which correlates with their poor performance in learning and memory tests. We have shown here and elsewhere (Hsieh et al., 2004; Jessberger et al., 2007) that VPA can reduce the proliferation of NPCs, and this reduction, together with the enhancement of neurogenesis, probably led to the depletion of the NPC pool in VPA-treated mice. It is possible that this depletion caused a slower differentiation of the residual NPCs in order to maintain required number of NPC pool during life. This possibility is an interesting avenue to be explored in the future.
In accordance with previous studies (van Praag et al., 1999a, 1999b), we found that voluntary running augments hippocampal neurogenesis of both MC- and VPA-treated mice, and it restores learning and memory deficiencies in VPA-treated mice. A previous report has shown the same restoration of decreased hippocampal neurogenesis and learning deficits in aged rodents by voluntary running (van Praag et al., 2005), although the precise molecular mechanisms responsible for voluntary running-induced neurogenesis remain undetermined (Deng et al., 2010). Here, we propose that at least the increase expression level of Bdnf, and the reduction of activated microglia may contribute to the restoration of impaired hippocampal neurogenesis and neuronal morphology in the DG of VPA-treated mice after voluntary running. However, future exploration is necessary to reveal the direct connection between the increase expression level of Bdnf and the reduction of microglia and its activated form in the hippocampus after voluntary running.
Acknowledgments We thank Y. Bessho, T. Matsui, Y. Nakahata, J. Kohyama, T. Takizawa, M. Namihira, S. Katada, and T. Imamura for valuable discussions. We also thank I. Smith for critical reading of the manuscript. We are very grateful to M. Tano for her excellent secretarial assistance and other laboratory members for discussion and technical help. This research was supported in part by the NAIST Global COE Program (Frontier Biosciences: Strategies for survival and adaptation in a changing global environment) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT); a Grant-in-Aid for Scientific Research on Innovative Area: Neural Diversity and Neocortical Organization from MEXT; Health Sciences Research Grants from the Ministry of Health, Labour and Welfare, Japan; Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Corporation; and Research Fellowships for Young Scientists from the Japan Society for the Promotion of Science.
Introduction Modeling human diseases with pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced PSCs (iPSCs), has remarkable potential to generate new insights into understanding disease pathogenesis and to open up new avenues for effective therapies. In particular, modeling neurological diseases is of great interest given that it is difficult to obtain patient-derived neural cells or tissues because of the limited accessibility to the brain. Indeed, ESCs and iPSCs derived from patients have been used to study several neurological diseases, including amyotrophic lateral sclerosis (ALS; Dimos et al., 2008; Egawa et al., 2012), Alzheimer’s disease (AD; Israel et al., 2012; Kondo et al., 2013; Yagi et al., 2011), Parkinson’s disease (Devine et al., 2011; Imaizumi et al., 2012; Nguyen et al., 2011), schizophrenia (Brennand et al., 2011; Bundo et al., 2014; Hook et al., 2014), epilepsy (Higurashi et al., 2013; Jiao et al., 2013; Liu et al., 2013), and Rett syndrome (Andoh-Noda et al., 2015; Marchetto et al., 2010). Because most neurological diseases affect one or more specific lesion area(s), PSCs were differentiated into corresponding neuronal subtypes in such studies (Imaizumi and Okano, 2014; Marchetto and Gage, 2012; Mattis and Svendsen, 2011; Okano and Yamanaka, 2014). However, these approaches cannot procure the mechanism of subtype specificity of disease phenotypes; that is, why some neuronal subtypes are selectively damaged whereas others evade pathogenesis.