Immature Neurons in the Postnatal Brain: Markers, Modulation, and Involvement in Normal and Aberrant Plasticity

Adult neural stem cell pools in homeostasis and pathogenesis.

Adult neural stem cells (NSCs) persist throughout life in discrete neurogenic niches of the mammalian brain, most prominently the subventricular zone (SVZ), the subgranular zone (SGZ) of the hippocampal dentate gyrus, and the hypothalamic ventricular zone (HVZ). These niches harbor regionally specialized NSC populations that support neural plasticity, cognitive and emotional regulation, and, in the hypothalamus, systemic metabolic and neuroendocrine homeostasis. While adult neurogenesis in the SGZ and SVZ has been extensively characterized, the HVZ has emerged as a functional adult NSC niche linking stem cell regulation to whole-body physiology. Here, we review recent advances across the SGZ, SVZ, and HVZ to define shared organizational principles and region-specific regulatory mechanisms governing adult NSC identity, homeostasis, and lineage output. We also highlight how intrinsic transcriptional programs, metabolic states, and niche-derived signals shape NSC behavior in each region, and how aging, inflammation, and metabolic stress differentially disrupt these processes. By integrating insights from both classical and hypothalamic neurogenic niches, this review provides a unified framework for understanding adult NSC diversity and disease susceptibility, and discusses strategies to modulate endogenous stem cell niches to preserve homeostasis and minimize disease risk.

Role of hippocampal dentate granule cells in memory: neuronal birth timing matters.

Single-nucleus analysis of the adult human olfactory epithelium uncovers shared neurogenesis programs with the brain

Neurogenesis, a critical process implicated in diverse brain disorders, is greatly diminished in the adult human brain, complicating direct investigations into its mechanistic role in disease. In the olfactory epithelium (OE), olfactory sensory neurons (OSNs) maintain homeostasis via continual neurogenesis throughout life, providing a niche to investigate neurogenesis in vivo. However, the molecular mechanisms underlying this process and its similarities to brain neurogenesis remain largely unknown. Here, we performed single-nucleus RNA-seq on specimens of human OE from 6 living adult donors, yielding high-quality transcriptomes representing 145,720 cells. Integrating with two independent OE single-cell transcriptomics datasets, different developmental stages of OSNs were identified, including neural precursor cells (globose basal cells, GBCs), as well as immature and mature OSNs. We inferred trajectories and assessed the transcriptional and regulatory dynamics of OSN development. Genes and transcription factors (TFs) involved in regulating neuronal differentiation and neurogenesis were highly expressed in GBCs and early immature OSNs, but were downregulated in mature neurons. OSNs and cortical excitatory neurons exhibited convergence during early developmental stages, including dynamically expressed genes, TFs, biological processes, and polygenic enrichment for psychiatric disorders. In addition, expression trajectory alignment between OSNs and cortical excitatory neurons (CENs) revealed that OSNs could partially track the expression dynamics of autism spectrum disorder (ASD) risk genes in CENs. Overall, cells in the neuronal lineage of the OE represent a potential proxy to study gene programs involved in neurogenesis in the human brain, providing an accessible model for investigating neurodevelopmental dysfunction in psychiatric disorders. Adult human brain neurogenesis is difficult to investigate directly. Here, authors show that the adult olfactory epithelium recapitulates key transcriptional and regulatory programs of cortical neurogenesis, providing an accessible model for studying psychiatric disease-associated neurodevelopment.

Epigenetic control of hippocampal stem cells: modulation by hyperactivation, glucocorticoids and aging

Morphological maturation and circuit integration of adult-born neurons are key to functional recovery after traumatic brain injury.

Successful repair after brain injury requires a chain of events, including the generation, migration, and successful integration of adult-born neurons into preexisting circuits. In mammals, the capacity for neuronal regeneration is extremely limited and further declines with age, constraining recovery. Regeneration-competent vertebrates offer a unique opportunity to uncover mechanistic principles of seamless brain repair. We here introduce the African turquoise killifish, a naturally short-lived vertebrate in which tissue repair occurs at young but not old age. We established an integrative approach combining i) an optimized retroviral vector application to birthdate GFP-labeled dividing neural stem cells and their progeny, ii) targeted electrophysiology to quantify synaptic and intrinsic maturation of such neurons, and iii) a conditioned avoidance assay to track recovery of learned behavior in adult killifish. We applied this workflow to the dorsomedial telencephalon, a region homologous to the mammalian amygdala. We reveal that injury-induced adult-born neurons survive, mature, and integrate synaptically into preexisting circuits, and that this coincides with the recovery of learned avoidance behavior by two months postinjury. Only when newborn neurons display mature morpho-electric properties, including complex dendritic arborization and abundant dendritic spines, recovery of behavior is accomplished. That full functional recovery takes around 50 d, substantially longer than previously inferred from histological analyses alone, is a striking finding given the killifish's short lifespan. These findings establish the killifish as a powerful vertebrate model and introduce a scalable platform for experimentally manipulating neuronal maturation and integration in vivo, particularly in the context of aging and age-related regenerative decline.

Glia orchestrate neural circuit development.

Over the past ∼25 years, our understanding of neural circuit development in the central nervous system has shifted. Once considered passive supporters, glial cells, namely, astrocytes, oligodendrocyte lineage cells, and microglia, are increasingly recognized as active regulators of developmental circuit formation and maturation. In this review, we synthesize evidence for the multifaceted functions by which glial cells instruct neuronal circuit establishment and maturation across developmental stages and in both vertebrate and invertebrate nervous systems. We describe the programs deployed to guide successive phases of synapse formation, refinement, plasticity, and stabilization in a circuit- and experience-dependent manner. We also highlight how an extensive glia-glia communication repertoire provides another critical layer of control over development. In summary, glia cooperatively shape circuit development by instructing, stabilizing, or eliminating specific wiring programs. Disruption of this coordinated logic, beyond dysfunction of any single glial or neuronal process, underlies vulnerability to neurodevelopmental and neuropsychiatric disease.