To systematize current data on neurogenesis and its role in the pathogenesis of neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease, with a focus on molecular mechanisms of regulation, the nature of disorders in neurodegeneration, and the evaluation of therapeutic approaches aimed at stimulating neurogenesis. Research papers published in scientific databases, mainly Scopus, PubMed, and Google Scholar, over the past 5 years were used for this review. Special attention was paid to studies on neurogenesis and its role in the pathogenesis of neurodegenerative diseases. The review included studies that met the following criteria: publications from the past five years reporting current neurogenesis data, using clearly identified experimental and clinical techniques, published in peer-reviewed international journals with a high impact factor, and providing reliable statistics to support the results. Modern research has significantly expanded the understanding of neurogenesis and its role in neurodegenerative diseases. Neurogenesis has been confirmed to occur in specific areas of the adult brain, including the hippocampus, where it is involved in cognitive processes such as learning, memory consolidation, spatial adaptation, cognitive flexibility, and regulation of affective behavior. However, the extent and functional significance of neurogenesis in different brain regions remain a matter of debate. The effect of neurodegenerative diseases on neurogenesis varies: in Alzheimer's disease, studies in animal models demonstrate its impairment; however, data on humans are inconsistent: a decrease in neurogenesis is observed in the early stages of the disease, but in some cases, its increase is reported, likely as a compensatory mechanism. Factors influencing neurogenesis in Alzheimer's disease include β-amyloid and tau protein accumulation, neuroinflammation, mitochondrial dysfunction, and oxidative stress. Parkinson's disease is associated with a decrease in neurogenesis in the subventricular zone and hippocampus due to the degeneration of dopaminergic neurons and the accumulation of α-synuclein; however, deep brain stimulation is able to enhance neuronal proliferation. Therapeutic strategies include pharmacological approaches aimed at stimulating neurogenesis, such as the use of neurotrophic factors, acetylcholinesterase inhibitors, selective serotonin reuptake inhibitors, Wnt and EGFR signaling pathway modulators, uric acid, and MFG-E8, as well as non-pharmacological methods, including physical activity, enriched environment, cognitive training, electrical stimulation, and music therapy. Neurodegenerative diseases are a significant problem in modern healthcare, requiring an in-depth study of the mechanisms of neurogenesis and its role in pathogenesis. Despite conflicting evidence on neurogenesis in adult humans, animal model studies and cellular technologies demonstrate prospects for its therapeutic stimulation. Pharmacological and non-pharmacological methods, including the use of neurotrophic factors, electrical stimulation, and cognitive training, as well as cellular and gene therapy, are the basis of new intervention strategies. However, the issues of controlling the differentiation and integration of new neurons, as well as the ethical aspects associated with the use of stem cells, remain unresolved. Further interdisciplinary research aimed at studying the regulatory mechanisms of neurogenesis and its therapeutic potential may lead to the development of effective treatment strategies that can slow or even reverse the progression of neurodegenerative diseases. It highlights the need to integrate advanced technologies and approaches in modern neuroscience and clinical practice.

ABSTRACTContinued integration of new neurons persists in only a few areas of the adult mouse brain. In the olfactory bulb (OB), immature adult‐born neurons respond differently to olfactory stimuli compared to their more mature counterparts and have heightened levels of activity‐dependent plasticity. These distinct functional features are thought to bestow unique properties onto existing circuitry. OB interneurons, including those generated through adult neurogenesis, consist of a set of highly distinct subtypes. However, we do not currently know the different cell‐type‐specific mechanisms underlying their functional development and plastic potential. Here, we specifically characterised electrophysiological maturation and experience‐dependent plasticity in a single, defined subtype of adult‐born OB neuron: dopaminergic cells. We selectively live‐labelled both adult‐born and ‘resident’ dopaminergic cells, and targeted them for whole‐cell patch‐clamp recordings in acute mouse OB slices. Surprisingly, we found that from the time—at ~1 month of cell age—that live adult‐born dopaminergic neurons could first be reliably identified, they already possessed almost fully mature intrinsic firing properties. We saw significant maturation only in increased spontaneous activity and decreased medium afterhyperpolarisation amplitude. Nor were adult‐born dopaminergic cells especially plastic. In response to brief sensory deprivation via unilateral naris occlusion we observed no maturation‐specific plastic alterations in intrinsic properties, although we did see deprivation‐associated increases in spike speed and amplitude across all adult‐born and resident neurons. Our results not only show that adult‐born OB dopaminergic cells rapidly functionally resemble their pre‐existing counterparts, but also underscore the importance of subtype identity when describing neuronal maturation and plasticity.

Rhythmic light flicker alleviates cognitive impairments in various animal models of neurological diseases. However, its long‐term effects and underlying mechanisms remain unclear. Here, a cohort of adult mice is subjected to long‐term exposure to 40 Hz light flicker (1 hour daily for 30 days) and observed significant enhancements in hippocampal neurogenesis and spatial learning without any adverse behavioral effects. Specific ablation of hippocampal newborn neurons using DCXDTR mice abolished these effects. Furthermore, the inactivation or elimination of GABAergic parvalbumin (PV) interneurons not only impaired 40 Hz light flicker entrainment but also reduce neurogenesis in the dentate gyrus (DG). Long‐term flicker exposure increases excitatory input to DG PV interneurons, which enhances PV interneuron excitability, elevated GABA levels, and strengthened inhibitory transmission to newborn neurons, thereby promoting better integration of new neurons into the DG. Blocking GABAA receptors reverse the light flicker‐induced increase in neurogenesis and spatial learning. Prolonged flicker exposure do not affect DG regional cerebral blood flow or the activity of excitatory cholinergic, vasoactive intestinal peptide (VIP), or cholecystokinin (CCK) interneurons. These findings suggest that long‐term light flicker enhances spatial learning through PV‐dependent neurogenesis, with elevated GABAergic activity supporting the development and integration of immature neurons in the adult DG.

Adult neurogenesis in the hippocampus, involving the generation and integration of new neurons, is essential for behavioral pattern separation, which supports accurate memory recall and cognitive plasticity. Here, we explore the role of the DNA repair protein NEIL3 in adult hippocampal neurogenesis and behavioral pattern separation. NEIL3 is required for efficient proliferation and neuronal differentiation of neonatal NSPCs and adult-born NPCs in the hippocampus following a behavioral pattern separation task. NEIL3-depleted mice exhibited a reduced preference for the novel object location, indicating a deficit in pattern separation. NEIL3-deficient adult-born neurons exhibited a significant reduction in mature-like membrane properties, indicating impaired functional maturation. Interestingly, these impairments were not associated with the decreased genomic integrity but with the altered transcriptional regulation of the Wnt signaling pathway. Given the importance of adult neurogenesis in cognitive function, targeting NEIL3 could offer therapeutic potential for addressing age-related hippocampal dysfunction and cognitive decline.

JOURNAL/rmrep/04.03/02273995-202503000-00002/figure1/v/2025-03-10T115452Z/r/image-tiff Epilepsy is often seen to present with perturbations to adult hippocampal neurogenesis, a process intrinsically linked with neuro-regeneration and plasticity in the brain. As adult-born neurons are exceptionally rare within the nervous system, adult hippocampal neurogenesis is an attractive target for regenerative medicine. The increased neuronal activity in the epileptic brain leads to increased production of newborn cells and altered integration of new neurons within the hippocampus. Glial cells are important contributors to the neurogenic niche and astrocytes also exhibit a specific pathological response in the hippocampus of temporal lobe epilepsy patients. Here, we set out to investigate the increased number of astrocytes following status epilepticus and their association with adult hippocampal neurogenesis. Initial investigations employed immunolabeling of brain sections from the mouse intra-amygdala kainic acid model of epilepsy and were corroborated with publicly available single-cell RNA sequencing datasets of human tissue to assess newborn cells in the dentate gyrus. We found an increased number of immature neurons and reactive astrocytes in the epileptic mouse hippocampus. Additionally, we identified a cell population that expressed both neurogenesis (doublecortin) and astrocyte (glial fibrillary acidic protein) markers in the epileptic brain of both mice and humans. We further evaluated the expression profile of this cell population. Immunolabeling of mouse tissue showed that cells expressing both, doublecortin and glial fibrillary acidic protein, also expressed mature astrocyte markers aquaporin 4 and glutamate transporter-1. Human single-cell RNA sequencing data highlighted the expression of neurogenesis and astrocyte markers in the doublecortin/glial fibrillary acidic protein-expressing cells. These findings suggest chronic epilepsy may drive early neuroblasts to fate-switch to an astrocyte lineage. Further studies may reveal the mechanisms that promote neuroblast fate-switching and whether this can or should be prevented, thereby providing new targets for regenerative medicine in epilepsy and perhaps other neurologic diseases.

The hippocampus in mammalian brain is one of the first regions experimentally demonstrated for adult neurogenesis, which is the evidence overturned Cajals hypothesis. Adult hippocampal neurogenesis (AHN) involves the incorporation of newly generated neurons into the innermost granule cell layer (GCL) of the dentate gyrus, and the integration of new neurons into the existing hippocampal circuitry is associated with increased resilience to stress. However, chronic stress, as an upstream factor that can be controlled by neurogenesis, also have counterproductive effects on adult hippocampal neurogenesis. Considering the current trend of increasing social chronic stressors and soaring incidence of major depressive disorder (MDD), analyzing the complex interactions between chronic stress and AHN is particularly important.

Adult hippocampal neurogenesis (AHN) is closely related to hippocampal plasticity, learning, memory and post-injury repair of the brain. In patients with neurodegenerative diseases, the ability of neural stem cells to proliferate and generate new neurons is sharply decreased, and AHN level is significantly weakened, which is not conducive to the repair of brain function. As immune cells in the nervous system, microglia play an important role in the generation and integration of new neurons. There is evidence that microglia are critical to the regulation of adult hippocampal neurogenesis, and different groups of microglia can perform different functions. Therefore, the link between microglia and adult hippocampal neurogenesis provides a new target for intervention in neurodegenerative diseases. This paper summarizes the modulating effect of microglia on adult hippocampal nerve and provides new ideas for solving the problems related to neurodegenerative diseases.

The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene is a critical tumor suppressor that plays an essential role in the development and functionality of the central nervous system. Located on chromosome 10 in humans and chromosome 19 in mice, PTEN encodes a protein that regulates cellular processes such as division, proliferation, growth, and survival by antagonizing the PI3K‑Akt‑mTOR signaling pathway. In neurons, PTEN dephosphorylates phosphatidylinositol‑3,4,5‑trisphosphate (PIP3) to PIP2, thereby modulating key signaling cascades involved in neurogenesis, neuronal migration, and synaptic plasticity. PTEN is crucial for embryonic neurogenesis, controlling the proliferation of neural progenitor cells and guiding the migration and proper lamination of neurons in cortical and hippocampal structures. It also regulates dendritic growth and axon guidance, ensuring correct neuronal connectivity. In postnatal neurogenesis, PTEN maintains the balance of stem cell proliferation and integration of new neurons into existing circuits, particularly in the hippocampal dentate gyrus. Animal models with PTEN deletion or mutation exhibit significant structural and functional neuronal abnormalities, including enlarged soma and dendritic hypertrophy, increased synaptic density, and altered synaptic plasticity mechanisms such as long‑term potentiation and long‑term depression. These changes lead to deficits in learning and memory tasks, as well as impairments in social behaviors. PTEN mutations are associated with neurodevelopmental disorders like intellectual disability, epilepsy, and autism spectrum disorders accompanied by macrocephaly. Understanding PTEN's mechanisms offers valuable insights into its contributions to neurodevelopmental disorders and presents potential therapeutic targets for cognitive impairments and neurodegenerative diseases. Future research should focus on elucidating PTEN's functions in mature neurons and its influence on established neuronal networks, which may have significant implications for memory enhancement and behavioral modifications.

Abstract Continued integration of new neurons persists in only a few areas of the adult mouse brain. In the olfactory bulb (OB), immature adult-born neurons respond differently to olfactory stimuli compared to their more mature counterparts, and have heightened levels of activity-dependent plasticity. These distinct functional features are thought to bestow unique properties onto existing circuitry. OB interneurons, including those generated through adult neurogenesis, consist of a set of highly distinct subtypes. However, we do not currently know the different cell-type-specific mechanisms underlying their functional development and plastic potential. Here, we specifically characterised electrophysiological maturation and experience-dependent plasticity in a single, defined subtype of adult-born OB neuron: dopaminergic cells. We selectively live-labelled both adult-born and ‘resident’ dopaminergic cells, and targeted them for whole-cell patch-clamp recordings in acute mouse OB slices. Surprisingly, we found that from the time – at ∼1 month of cell age – that live adult-born dopaminergic neurons could first be reliably identified, they already possessed almost fully mature intrinsic firing properties. We saw significant maturation only in increased spontaneous activity and decreased medium afterhyperpolarisation amplitude. Nor were adult-born dopaminergic cells especially plastic. In response to brief sensory deprivation via unilateral naris occlusion we observed no maturation-specific plastic alterations in intrinsic properties, although we did see deprivation-associated increases in spike speed and amplitude across all adult-born and resident neurons. Our results not only show that adult-born OB dopaminergic cells rapidly functionally resemble their pre-existing counterparts, but also underscore the importance of subtype identity when describing neuronal maturation and plasticity.

Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons

This study evaluates the sustained antidepressant-like effects and neurogenic potential of a 3-day intranasal co-administration regimen of galanin receptor 2 (GALR2) agonist M1145 and neuropeptide Y Y1 receptor (NPY1R) agonist [Leu31, Pro34]NPY in the ventral hippocampus of adult rats, with outcomes analyzed 3 weeks post-treatment. Utilizing the forced swimming test (FST), we found that this co-administration significantly enhances antidepressant-like behaviors, an effect neutralized by the GALR2 antagonist M871, highlighting the synergistic potential of these neuropeptides in modulating mood-related behaviors. Insitu proximity ligation assay (PLA) indicated a significant increase in GALR2/NPYY1R heteroreceptor complexes in the ventral hippocampal dentate gyrus, suggesting a molecular basis for the behavioral outcomes observed. Moreover, proliferating cell nuclear antigen (PCNA) immunolabeling revealed increased cell proliferation in the subgranular zone of the dentate gyrus, specifically in neuroblasts as evidenced by co-labeling with doublecortin (DCX), without affecting quiescent neural progenitors or astrocytes. The study also noted a significant uptick in the number of DCX-positive cells and alterations in dendritic morphology in the ventral hippocampus, indicative of enhanced neuronal differentiation and maturation. These morphological changes highlight the potential of these agonists to facilitate the functional integration of new neurons into existing neural circuits. By demonstrating the long-lasting effects of a brief, 3-day intranasal administration of GALR2 and NPY1R agonists, our findings contribute significantly to the understanding of neuropeptide-mediated neuroplasticity and herald novel therapeutic strategies for the treatment of depression and related mood disorders, emphasizing the therapeutic promise of targeting neurogenesis and neuronal maturation processes.

Adult hippocampal neurogenesis (AHN) enhances brain plasticity and contributes to the cognitive reserve during aging. AHN is impaired in neurological disorders, yet the molecular mechanisms regulating the maturation and synaptic integration of new neurons have not been fully elucidated. In this regard, gamma-aminobutyric acid (GABA) is a master regulator of adult and developmental neurogenesis. Here we used a novel retrovirus encoding the fusion protein Gephyrin:GFP to longitudinally study the formation and maturation of inhibitory synapses during AHN in vivo.

Adult hippocampal neurogenesis enhances brain plasticity and contributes to the cognitive reserve during aging. Adult hippocampal neurogenesis is impaired in neurological disorders, yet the molecular mechanisms regulating the maturation and synaptic integration of new neurons have not been fully elucidated. GABA is a master regulator of adult and developmental neurogenesis. Here we engineered a novel retrovirus encoding the fusion protein Gephyrin:GFP to longitudinally study the formation and maturation of inhibitory synapses during adult hippocampal neurogenesis in vivo. Our data reveal the early assembly of inhibitory postsynaptic densities at 1 week of cell age. Glycogen synthase kinase 3 Beta (GSK-3β) emerges as a key regulator of inhibitory synapse formation and maturation during adult hippocampal neurogenesis. GSK-3β-overexpressing newborn neurons show an increased number and altered size of Gephyrin+ postsynaptic clusters, enhanced miniature inhibitory postsynaptic currents, shorter and distanced axon initial segments, reduced synaptic output at the CA3 and CA2 hippocampal regions, and impaired pattern separation. Moreover, GSK-3β overexpression triggers a depletion of Parvalbumin+ interneuron perineuronal nets. These alterations might be relevant in the context of neurological diseases in which the activity of GSK-3β is dysregulated.

Neurogenesis persists in the mammalian subventricular zone after birth, producing various populations of olfactory bulb (OB) interneurons, including GABAergic and mixed dopaminergic/GABAergic (DA) neurons for the glomerular layer. While olfactory sensory activity is a major factor controlling the integration of new neurons, its impact on specific subtypes is not well understood. In this study we used genetic labeling of defined neuron subsets, in combination with reversible unilateral sensory deprivation and longitudinal in vivo imaging, to examine the behavior of postnatally born glomerular neurons. We find that a small fraction of GABAergic and of DA neurons die after 4 weeks of sensory deprivation while surviving DA-neurons exhibit a substantial decrease in tyrosine hydroxylase (TH) expression levels. Importantly, after reopening of the naris, cell death is arrested and TH levels go back to normal levels, indicating a specific adaptation to the level of sensory activity. We conclude that sensory deprivation induces adjustments in the population of glomerular neurons, involving both, cell death and adaptation of neurotransmitter use in specific neuron types. Our study highlights the dynamic nature of glomerular neurons in response to sensory deprivation and provide valuable insights into the plasticity and adaptability of the olfactory system.

Adult hippocampal neurogenesis is important for preserving learning and memory-related cognitive functions. Physical exercise, especially voluntary running, is one of the strongest stimuli to promote neurogenesis and has beneficial effects on cognitive functions. Voluntary running promotes exit of neural stem cells (NSCs) from the quiescent stage, proliferation of NSCs and progenitors, survival of newborn cells, morphological development of immature neuron, and integration of new neurons into the hippocampal circuitry. However, the detailed mechanisms driving these changes remain unclear. In this review, we will summarize current knowledge with respect to molecular mechanisms underlying voluntary running-induced neurogenesis, highlighting recent genome-wide gene expression analyses. In addition, we will discuss new approaches and future directions for dissecting the complex cellular mechanisms driving change in adult-born new neurons in response to physical exercise.

Adult hippocampal neurogenesis in Alzheimer's disease: A roadmap to clinical relevance.

The birth, maturation, and integration of new neurons in the adult hippocampus regulates specific learning and memory processes, responses to stress, and antidepressant treatment efficacy. This process of adult hippocampal neurogenesis is sensitive to environmental stimuli, including peripheral signals from certain cytokines, hormones, and metabolites, which can promote or hinder the production and survival of new hippocampal neurons. The trillions of microorganisms resident to the gastrointestinal tract, collectively known as the gut microbiota, also demonstrate the ability to modulate adult hippocampal neurogenesis. In doing so, the microbiota-gut-brain axis can influence brain functions regulated by adult hippocampal neurogenesis. Unlike the hippocampus, the gut microbiota is highly accessible to direct interventions, such as prebiotics, probiotics, and antibiotics, and can be manipulated by lifestyle choices including diet. Therefore, understanding the pathways by which the gut microbiota shapes hippocampal neurogenesis may reveal novel targets for non-invasive therapeutics to treat disorders in which alterations in hippocampal neurogenesis have been implicated. This review first outlines the factors which influence both the gut microbiome and adult hippocampal neurogenesis, with cognizance that these effects might happen either independently or due to microbiota-driven mechanisms. We then highlight approaches for investigating the regulation of adult hippocampal neurogenesis by the microbiota-gut-brain axis. Finally, we summarize the current evidence demonstrating the gut microbiota's ability to influence adult hippocampal neurogenesis, including mechanisms driven through immune pathways, microbial metabolites, endocrine signalling, and the nervous system, and postulate implications for these effects in disease onset and treatment.

Traumatic spinal cord injury (SCI) is a leading cause of permanent neurologic disabilities in young adults. Functional impairments after SCI are substantially attributed to the progressive neurodegeneration. However, regeneration of spinal-specific neurons and circuit re-assembly remain challenging in the dysregulated milieu of SCI because of impaired neurogenesis and neuronal maturation by neural precursor cells (NPCs) spontaneously or in cell-based strategies. The extrinsic mechanisms that regulate neuronal differentiation and synaptogenesis in SCI are poorly understood. Here, we perform extensive in vitro and in vivo studies to unravel that SCI-induced upregulation of matrix chondroitin sulfate proteoglycans (CSPGs) impedes neurogenesis of NPCs through co-activation of two receptor protein tyrosine phosphatases, LAR and PTPσ. In adult female rats with SCI, systemic co-inhibition of LAR and PTPσ promotes regeneration of motoneurons and spinal interneurons by engrafted human directly reprogramed caudalized NPCs (drNPC-O2) and fosters their morphologic maturity and synaptic connectivity within the host neural network that culminate in improved recovery of locomotion and sensorimotor integration. Our transcriptomic analysis of engrafted human NPCs in the injured spinal cord confirmed that inhibition of CSPG receptors activates a comprehensive program of gene expression in NPCs that can support neuronal differentiation, maturation, morphologic complexity, signal transmission, synaptic plasticity, and behavioral improvement after SCI. We uncovered that CSPG/LAR/PTPσ axis suppresses neuronal differentiation in part by blocking Wnt/β-Catenin pathway. Taken together, we provide the first evidence that CSPGs/LAR/PTPσ axis restricts neurogenesis and synaptic integration of new neurons in NPC cellular therapies for SCI. We propose targeting LAR and PTPσ receptors offers a promising clinically-feasible adjunct treatment to optimize the efficacy and neurologic benefits of ongoing NPC-based clinical trials for SCI.SIGNIFICANCE STATEMENT Transplantation of neural precursor cells (NPCs) is a promising approach for replacing damaged neurons after spinal cord injury (SCI). However, survival, neuronal differentiation, and synaptic connectivity of transplanted NPCs within remain challenging in SCI. Here, we unravel that activation of chondroitin sulfate proteoglycan (CSPG)/LAR/PTPσ axis after SCI impedes the capacity of transplanted human NPCs for replacing functionally integrated neurons. Co-blockade of LAR and PTPσ is sufficient to promote re-generation of motoneurons and spinal V1 and V3 interneurons by engrafted human caudalized directly reprogramed NPCs (drNPC-O2) and facilitate their synaptic integration within the injured spinal cord. CSPG/LAR/PTPσ axis appears to suppress neuronal differentiation of NPCs by inhibiting Wnt/β-Catenin pathway. These findings identify targeting CSPG/LAR/PTPσ axis as a promising strategy for optimizing neuronal replacement, synaptic re-connectivity, and neurologic recovery in NPC-based strategies.

Abstract Introduction/Objective Dentate gyrus (DG), a neurogenic niche, is a metabolically dense subregion of the hippocampus. Continuous production and integration of new neurons in the existing circuit and harmonious relationship between excitatory and inhibitory neurons accompanied by neuron-glia coupling is essential to maintain hippocampal homeostasis throughout adulthood. Imbalance in the neuronal activity generates seizures and can result in mesial temporal lobe epilepsy (MTLE). MTLE affects 50 million people across the globe and impairs the overall hippocampal network and its associated functions such as memory and cognition. Although altered lipid metabolism has been associated with status epilepticus, the role of lipid droplets (LDs), the minuscule metabolically active organelle known to provide a substrate for cellular energy, has not been explored in DG during seizure. LDs are composed of neutral lipids and surrounded by phospholipid monolayer, which is studded with a structural Perilipin family of proteins 1-5, reported to be involved in lipid metabolism. Methods/Case Report To study LDs in the brain, we used a novel approach by injecting Bodipy, a lipid dye in the tail vein of mice, and successfully labeled LDs in the DG. We used the pilocarpine-induced seizure model. After Bodipy injection followed by seizure induction, mice were sacrificed at four time-points 0.5, 1-, 3- and 18 hours. Results (if a Case Study enter NA) We found a significant increase in Bodipy signal and Perilipin 4, LDs specific marker expression at four time-points post-seizure than in the control cohort. To elucidate the role of neuron-glia metabolic coupling in DG, we measured LDs in microglia and astrocytes and found a significant increase in LDs in seizure mice than control groups suggesting the role of glia in lipid regulation in DG. Conclusion Overall, this novel study will highlight the undiscovered role of LDs in dentate gyrus during seizure and, in the future, can be used as a therapeutic target to alleviate the MTLE phenotype.

Studies on brain plasticity have undertaken different roads, tackling a wide range of biological processes: from small synaptic changes affecting the contacts among neurons at the very tip of their processes, to birth, differentiation, and integration of new neurons (adult neurogenesis). Stem cell-driven adult neurogenesis is an exception in the substantially static mammalian brain, yet, it has dominated the research in neurodevelopmental biology during the last thirty years. Studies of comparative neuroplasticity have revealed that neurogenic processes are reduced in large-brained mammals, including humans. On the other hand, large-brained mammals, with respect to rodents, host large populations of special “immature” neurons that are generated prenatally but express immature markers in adulthood. The history of these “immature” neurons started from studies on adhesion molecules carried out at the beginning of the nineties. The identity of these neurons as “stand by” cells “frozen” in a state of immaturity remained un-detected for long time, because of their ill-defined features and because clouded by research ef-forts focused on adult neurogenesis. In this review article, the history of these cells will be reconstructed, and a series of nuances and confounding factors that have hindered the distinction between newly generated and “immature” neurons will be addressed.