Weixiang Guo’s research while affiliated with State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences and other places

Adult neurogenesis is a unique cellular process of the ongoing generation of new neurons throughout life, which primarily occurs in the subgranular zone (SGZ) of the dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricle. In the adult DG, newly generated granule cells from neural stem cells (NSCs) integrate into existing neural circuits, significantly contributing to cognitive functions, particularly learning and memory. Recently, more and more studies have shown that rather than being a homogeneous population of identical cells, adult NSCs are composed of multiple subpopulations that differ in their morphology and function. In this study, we provide an overview of the origin, regional characteristics, prototypical morphology, and molecular factors that contribute to NSC heterogeneity. In particular, we discuss the molecular mechanisms underlying the balance between activation and quiescence of NSCs. In summary, this review highlights that deciphering NSC heterogeneity in the adult brain is a challenging but critical step in advancing our understanding of tissue-specific stem cells and the process of neurogenesis in the adult brain.

The Cre-lox site-specific recombinase system is one of the most powerful and versatile technology platforms for studying neural stem cells (NSCs) in adult brain, which is now challenged due to the complex and dynamic nature of in vivo gene expression. In this study, we develop an inducible dual recombinase-mediated intersectional genetics by combining Dre-rox and Cre-lox recombination technologies to specifically target two subpopulations of NSCs (α- and β-NSCs). By visiting their cell lineage and functionality, we find that α- and β-NSCs display distinct self-renewal and differentiation potential, as well as differential responses to external stimuli. Notably, in contrast to α-NSCs, the number of β-NSCs is not affected in aged mice and an APP/PS1 mouse model of Alzeimer’s disease. Single cell transcriptome analysis reveals divergent molecular signatures between type α- and β-NSCs and identifies PRMT1 as an important regulatory element to differentially regulate the neurogenic potential of α- and β-NSCs. Inhibition of PRMT1 specifically enhances the neurogenic capacity of β-NSCs and promotes the cognition functions in aged mice. Importantly, PRMT1 inhibition combined with increased BDNF levels pharmacologically ameliorates the cognitive impairments in APP/PS1 mice. Together, our study suggests that understanding the functional heterogeneity of NSCs might pave the way for harnessing the specific subpopulation of NSCs to treat brain disorders.

Despite seizure control by early high-dose pyridoxine (vitamin B6) treatment, at least 75% of pyridoxine-dependent epilepsy (PDE) patients with ALDH7A1 mutation still suffer from intellectual disability. It points to a need for additional therapeutic interventions for PDE beyond pyridoxine treatment, which provokes us to investigate the mechanisms underlying the impairment of brain hemostasis by ALDH7A1 deficiency. In this study, we show that ALDH7A1-deficient mice with seizure control exhibit altered adult hippocampal neurogenesis and impaired cognitive functions. Mechanistically, ALDH7A1 deficiency leads to the accumulation of toxic lysine catabolism intermediates, α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate, which in turn impair de novo pyrimidine biosynthesis and inhibit NSC proliferation and differentiation. Notably, supplementation of pyrimidines rescues abnormal neurogenesis and cognitive impairment in ALDH7A1-deficient adult mice. Therefore, our findings not only define the important role of ALDH7A1 in the regulation of adult hippocampal neurogenesis but also provide a potential therapeutic intervention to ameliorate the defective mental capacities in PDE patients with seizure control.

The circadian clock throughout the day organizes the activity of neural stem cells (NSCs) in the dentate gyrus (DG) of adult hippocampus temporally. However, it is still unclear whether and how circadian signals from the niches contribute to daily rhythmic variation of NSC activation. Here, we show that norepinephrinergic (NEergic) projections from the locus coeruleus (LC), a brain arousal system, innervate into adult DG, where daily rhythmic release of norepinephrine (NE) from the LC NEergic neurons controlled circadian variation of NSC activation through β3-adrenoceptors. Disrupted circadian rhythmicity by acute sleep deprivation leads to transient NSC overactivation and NSC pool exhaustion over time, which is effectively ameliorated by the inhibition of the LC NEergic neuronal activity or β3-adrenoceptors-mediated signaling. Finally, we demonstrate that NE/β3-adrenoceptors-mediated signaling regulates NSC activation through molecular clock BMAL1. Therefore, our study unravels that adult NSCs precisely coordinate circadian neural circuit and intrinsic molecular circadian clock to adapt their cellular behavior across the day.

Neural stem cells (NSCs) are a type of multipotent stem cell that generate functional newborn neurons through a process called neurogenesis. Neurogenesis in adult brain is tightly regulated and plays a pivotal role in the maintenance of brain function. Disruption of adult neurogenesis impairs cognitive function and is correlated with numerous neurologic disorders. Deciphering the mechanism underlying adult neurogenesis not only advances our understanding of how brain functions, but also offers new insight of neurologic diseases and potentially contributes to the development of effective treatments. The field of adult neurogenesis is experiencing significant growth in China. Chinese researchers have demonstrated a multitude of factors governing adult neurogenesis and revealed the correlation and underlying mechanisms between adult neurogenesis and neurologic disorders. Here, we provide an overview of recent advancements conducted by Chinese scientists in the field of adult neurogenesis. This article is protected by copyright. All rights reserved.

Neural stem cells (NSCs) in the adult hippocampus are composed of multiple subpopulations. However, their origin and functional heterogeneity are still unclear. Here, we found that the contribution of murine Wnt-responsive (Axin2+) and Hedgehog-responsive (Gli1+) embryonic neural progenitors to adult NSCs started from early and late postnatal stages, respectively. Axin2+ adult NSCs were intended to actively proliferate, whereas Gli1+ adult NSCs were relatively quiescent and responsive to external stimuli. Moreover, Gli1+ NSC-derived adult-born neurons exhibited more complex dendritic arborization and connectivity than Axin2+ NSC-derived ones. Importantly, genetic cell ablation analysis identified that Axin2+ and Gli1+ adult NSCs were involved in hippocampus-dependent learning, but only Axin2+ adult NSCs were engaged in buffering stress responses and depressive behavior. Together, our study not only defined the heterogeneous multiple origins of adult NSCs but also advanced the concept that different subpopulations of adult NSCs may function differently.