Fact-checked by Grok 2 weeks ago

Neurogenesis

Neurogenesis is the by which new neurons are generated from neural and cells within the . This phenomenon occurs extensively during embryonic and early postnatal development, where it establishes the basic architecture of the and through the , , , and integration of neural precursors. In adulthood, neurogenesis continues in a more limited capacity, primarily in two key regions of the mammalian : the subgranular zone (SGZ) of the in the and the subventricular zone (SVZ) lining the . The core stages of neurogenesis mirror those in but adapt to contexts, beginning with the asymmetric division of quiescent neural stem cells (NSCs), often identified as radial glia-like cells expressing (GFAP). These divisions yield transit-amplifying progenitors that undergo rapid , followed by the of neuroblasts into immature neurons, which then migrate—often in chains along pathways like the rostral migratory stream from the SVZ to the —and ultimately integrate into existing neural circuits by forming synapses. This integration is crucial for functionality, with new hippocampal neurons contributing to and circuit refinement over weeks to months. Regulation of neurogenesis involves a complex interplay of intrinsic and extrinsic factors, including signaling pathways such as Wnt, , and Sonic hedgehog (Shh), which promote progenitor maintenance and differentiation, alongside transcription factors like NeuroD1 and TLX that drive neuronal fate. Extrinsic modulators encompass environmental influences like physical exercise and enriched settings, which enhance proliferation via neurotrophic factors such as (BDNF), as well as pharmacological agents including antidepressants that upregulate neurogenesis in the . Aging, , and pathological conditions like ischemia or neurodegeneration typically suppress this process, leading to declines in NSC activity and neuronal output. Functionally, embryonic neurogenesis is essential for forming diverse neuronal populations that underpin sensory, motor, and cognitive systems, while adult neurogenesis supports ongoing brain plasticity, particularly in learning and memory—with hippocampal neurons aiding pattern separation—and olfactory discrimination via SVZ-derived interneurons. Dysregulation is implicated in neurological disorders, including depression, epilepsy, Alzheimer's disease, and stroke, where diminished neurogenesis correlates with cognitive deficits, highlighting its therapeutic potential through strategies aimed at stimulating NSC proliferation and survival. Ongoing research, bolstered by evidence from techniques like bromodeoxyuridine (BrdU) labeling and carbon-14 dating of neuronal DNA, continues to refine our understanding of its extent in humans; as of 2025, genetic studies have confirmed the persistence of adult hippocampal neurogenesis into late adulthood, though debates persist regarding the precise quantity and longevity of adult-born neurons.

Fundamentals

Definition and Process

Neurogenesis is the by which new neurons are generated from neural stem cells (NSCs) or progenitor cells, encompassing the stages of , , , and into existing neural circuits. NSCs are self-renewing, multipotent cells capable of dividing to maintain their population or produce progenitors, while progenitor cells are more restricted intermediates that commit to specific lineages. This process is fundamental to brain development and , occurring prominently during embryogenesis and persisting in select regions throughout adulthood in many species. The core stages begin with the division of NSCs, which can be symmetric—yielding two identical daughter cells, either both stem cells or both —or asymmetric, producing one NSC and one progenitor to balance self-renewal and . then undergo commitment to the neuronal lineage, differentiating into neuroblasts, which are immature, migratory neurons expressing markers like . Neuroblasts subsequently migrate to appropriate locations within the and mature, extending axons and dendrites to form synaptic connections and achieve functional integration. Unlike gliogenesis, which generates non-neuronal glial cells such as and from the same precursor pool, neurogenesis is defined exclusively by the production and maturation of neurons, often regulated by distinct transcriptional programs that favor neuronal over glial fates. Neurogenesis represents an evolutionarily conserved mechanism across metazoans, from invertebrates like to vertebrates including mammals, though it varies in timing, extent, and neurogenic sites—peaking during in most and continuing lifelong in many non-mammalian lineages.

Historical Discovery

For much of the 19th and 20th centuries, the prevailing view in held that the adult mammalian brain does not generate new neurons, a doctrine largely attributed to Santiago Ramón y Cajal's histological studies in the 1890s and early 1900s, which emphasized the fixed nature of neural architecture post-development. This "no new neurons" dogma was reinforced by observations of neuronal stability and was widely accepted, influencing research for decades and suggesting that brain plasticity was limited to synaptic changes rather than cellular addition. The first challenges to this dogma emerged in the 1960s through autoradiographic studies by Joseph Altman and Gopal Das, who injected tritiated thymidine into young adult rodents to label dividing cells and observed labeled neurons in the of the and . Their seminal 1965 paper demonstrated persistent neurogenesis in adult rat brains, providing initial evidence of ongoing neuronal production beyond infancy, though these findings were initially overlooked by the broader scientific community. Further confirmation came in the with the isolation of neural stem cells (NSCs) from the adult mammalian brain. In 1992, Brent Reynolds and Samuel Weiss reported the generation of multipotent progenitor cells from the of adult mice, which could differentiate into neurons and in when stimulated by , establishing the existence of self-renewing NSCs in mature brains. Building on this, Peter Eriksson and colleagues in 1998 provided direct evidence of in humans by analyzing postmortem hippocampal tissue from cancer patients treated with bromodeoxyuridine (BrdU), revealing BrdU-labeled immature neurons in the of individuals up to 72 years old. Despite these advances, controversy persisted regarding human adult neurogenesis, particularly in the hippocampus. A 2018 study by Shawn Sorrells and Arturo Alvarez-Buylla analyzed postmortem tissues across ages and reported no detectable new neurons in the adult human , suggesting neurogenesis ceases by early adulthood and attributing prior evidence to methodological artifacts. This sparked renewed debate, but recent 2025 research using advanced single-nucleus RNA sequencing and on diverse human brain samples has confirmed ongoing hippocampal neurogenesis into late adulthood, resolving the controversy by identifying active neural progenitors and their transcriptional signatures in adults up to 78 years old.

Developmental Neurogenesis

In Vertebrates

In vertebrates, neurogenesis during embryonic and early postnatal development begins with the formation of the during , where the folds and cavitates to create a hollow structure that gives rise to the . This process establishes the foundational architecture, followed by proliferation in germinal zones such as the ventricular zone (VZ), a pseudostratified lining the where neural cells divide to expand the progenitor pool and generate neurons. The (SVZ) emerges later as a secondary proliferative region, particularly in the , producing additional neurons through intermediate progenitors that amplify output. Species-specific variations highlight the diversity of vertebrate neurogenesis. In , embryonic neurogenesis is notably rapid, with primary neurons differentiating within hours post-fertilization to support larval locomotion and sensory functions, featuring an early wave of pioneer neurons that guide axonal in a transparent amenable to live imaging. This process contrasts with more protracted timelines in amniotes but shares conserved mechanisms like signaling for progenitor maintenance. In birds, such as songbirds, embryonic neurogenesis populates key circuits, including the high vocal center (HVC) where neurons projecting to the anterior pathway (HVC→X) are generated during embryogenesis to establish stable song learning substrates. Mammals exemplify complex layering, as in the where radial migration along glial scaffolds positions neurons in an inside-out manner, forming six distinct layers from deep to superficial. Central processes drive neuronal integration and refinement. Proliferation in the VZ involves asymmetric divisions of radial glial progenitors, balancing self-renewal and neurogenic output through spatiotemporal gradients of factors like FGF and . Newly born neurons then undergo radial , guided by radial glia fibers, or tangential for interneurons originating from ganglionic eminences, ensuring precise laminar and areal organization. prunes excess neurons—up to 50% in some regions—via trophic factor competition and activation, sculpting functional circuits by eliminating mismatched or supernumerary cells during peak production. In humans, neurogenesis peaks between embryonic weeks 8 and 20, when the majority of cortical and subcortical neurons are generated, with layer-specific production in the occurring sequentially from deep (layer VI) to superficial (layer II). This phase continues postnatally in select areas, such as the where production from the external granular layer persists until the second postnatal year, and the where generation supports sensory adaptation. Unique to vertebrates, orchestrate anterior-posterior patterning along the , with collinear expression of paralogous groups (e.g., Hox1-4 in hindbrain rhombomeres) specifying segmental identity and neuronal subtypes through of downstream targets like column formation. This genetic framework facilitates the evolution of layered structures, most prominently the mammalian , where expanded SVZ progenitors enable tangential expansion and supragranular layer formation, contrasting with the simpler three-layered in reptiles and birds.

In Invertebrates

Neurogenesis in primarily occurs during embryonic and larval stages, producing a relatively fixed and limited number of neurons organized into modular ganglia rather than a centralized , contrasting with the expansive neural proliferation in vertebrates. In many species, neural progenitors delaminate from the and undergo asymmetric divisions to generate diverse neuronal lineages, often regulated by simpler genetic mechanisms that serve as evolutionary models for more complex systems. For instance, fruit flies () exemplify this process, where approximately 10,000–15,000 neurons are generated, far fewer than the billions in mammalian , highlighting the compact scale of invertebrate nervous systems. In , neurogenesis begins with the of from the ventral during embryogenesis, forming the ventral cord through asymmetric divisions. These self-renew while producing ganglion mother cells (GMCs), which divide once to yield and ; type I generate about 90 per lobe, expressing markers like , while type II produce intermediate neural that amplify output. Proneural genes from the achaete-scute complex, such as lethal of scute, initiate specification in proneural clusters within the ventral cord, with divisions resuming postembryonically during larval and pupal stages to complete the process by pupation. The Delta-Notch signaling pathway mediates here, ensuring precise selection of neural fates in a simpler cascade compared to vertebrates, providing insights into conserved mechanisms of diversification. Nematodes like demonstrate an invariant embryonic neurogenesis, yielding exactly 302 neurons through a series of precisely mapped asymmetric divisions from ectodermal progenitors, without delamination but via internalization during . This fixed , established by early stages, results in a comprising head and tail ganglia connected by a ventral cord, underscoring the deterministic nature of neural development. In annelids, such as leeches (), ganglionic neurogenesis arises from teloblast in the germinal plate, producing metameric ganglia through transverse bands of cells marked by engrailed homologs, with neural precursors spanning segment boundaries to form the ventral nerve cord. These processes, largely confined to embryogenesis with some larval contributions, reflect evolutionary adaptations for segmented, modular architectures in .

Adult Neurogenesis

In Mammals

In mammals, adult neurogenesis primarily occurs in two restricted brain regions: the subgranular zone (SGZ) of the in the and the (SVZ) lining the . In the SGZ, neural stem cells (NSCs) generate immature neurons that differentiate into granule cells, which integrate into the hippocampal circuitry to support functions such as pattern separation, a process that distinguishes similar experiences to aid memory formation. Similarly, in the SVZ, NSCs produce neuroblasts that migrate through the rostral migratory stream to the , where they mature into , contributing to olfactory processing and discrimination. The rate of varies by species and region but is notably robust in , where thousands of new neurons are added daily to the and . In humans, estimates indicate approximately 700 new cells are generated per day in each , representing about 1.75% annual turnover of dentate gyrus neurons, a process confirmed to persist into advanced age, although at a reduced rate due to age-related decline. Recent genetic analyses in 2025 have reinforced these findings, resolving prior debates by demonstrating ongoing hippocampal neurogenesis in adults across the lifespan. Newly generated neurons in mammals integrate functionally into existing neural circuits through synaptic incorporation, forming connections that enhance network . In the , adult-born granule cells establish excitatory synapses with CA3 pyramidal cells, enabling their role in encoding and refinement. In the , SVZ-derived form reciprocal dendrodendritic synapses with mitral and tufted cells, supporting perception, , and short-term . This integration is critical for the adaptive functions of these regions, though the overall scale remains limited compared to developmental neurogenesis.

In Non-Mammals

Adult neurogenesis in non-mammalian vertebrates is characterized by its widespread distribution across multiple brain regions and its persistence throughout the lifespan, often enabling significant regenerative capacities that surpass those observed in mammals. In these species, (NSC) niches are broadly present, including in the telencephalon, optic tectum, and , supporting continuous production for both physiological maintenance and injury repair. For instance, radial glia-like cells serve as primary progenitors in many non-mammals, facilitating tissue regeneration by proliferating and differentiating into and in response to damage. In teleost fish such as , adult neurogenesis occurs extensively in the telencephalon and optic tectum, allowing for full regeneration following . Post-lesion, proliferative zones expand, generating new neurons that integrate into functional circuits to restore lost , a process mediated by NSC activation and minimal . , particularly songbirds like canaries and white-crowned sparrows, exhibit seasonal neurogenesis in song control nuclei such as the high vocal center (HVC), where tens of thousands of new projection neurons—approximately 68,000 in HVC during the breeding season—are added annually to support vocal learning and . Reptiles, including like Podarcis liolepis, show persistent neurogenesis in the striatal regions and medial , with inducing heightened from ventricular progenitors, leading to neuronal without scarring. Amphibians, such as newts and axolotls, demonstrate remarkable regenerative potential, including production after transection, where ependymal cells form a tube-like structure that supports neurogenesis and axonal regrowth. These processes occur at rates far higher than in mammals, with continuous addition enabling lifelong expansion and adaptation. Evolutionarily, this widespread adult neurogenesis in non-mammals promotes sustained neural and recovery from , contrasting with the age-related decline and localization to specific niches in mammalian s. Such capabilities highlight an ancestral trait for environmental adaptability that has been partially conserved across vertebrates.

Regulatory Mechanisms

Molecular and Genetic Factors

Neurogenesis is tightly regulated by a network of signaling pathways and transcription factors that govern the , , and of neural cells (NSCs) across developmental stages and species. The Wnt/β-catenin pathway plays a central role in promoting NSC and neuronal fate specification by stabilizing β-catenin, which translocates to the to activate target genes involved in progression and neurogenesis. In contrast, the / pathway inhibits neuronal by maintaining NSCs in a proliferative state; activation of receptors by ligands leads to the cleavage and nuclear translocation of the Notch intracellular domain, which represses proneural genes and sustains progenitor identity. The BMP/Smad pathway contributes to the gliogenic switch later in development, where BMP ligands bind receptors to phosphorylate Smad1/5/8, promoting astroglial over neurogenesis by antagonizing neuronal-promoting signals. Key transcription factors orchestrate these processes at the genetic level. and are essential for NSC maintenance and self-renewal; sustains progenitor identity by repressing neuronal differentiation genes, while balances and neurogenesis, with its levels critically influencing the timing of neuronal production. For neuronal commitment, basic helix-loop-helix (bHLH) factors such as Neurogenin (Ngn) and NeuroD drive the transition from progenitors to neurons; Ngn promotes neurogenesis while inhibiting gliogenesis through independent regulation of downstream pathways, and NeuroD further specifies neuronal subtypes by binding regulatory elements to activate genes. Genetic models have elucidated the necessity of these factors. In mice, Ascl1 (Mash1) knockouts severely impair neurogenesis, particularly in the dopaminergic system and , leading to reduced neuronal generation and altered progenitor differentiation. Human genome-wide association studies (GWAS) link variants in neurogenesis-related genes to hippocampal volume, with enrichment in pathways involving cell proliferation and neuronal maturation, suggesting genetic influences on adult neurogenic niches. The core molecular machinery exhibits remarkable cross-species conservation, particularly the proneural bHLH family, which includes Ascl1, Ngn, and NeuroD homologs from (e.g., atonal and achaete-scute) to humans, regulating neural competence and diversification across . disrupting this machinery underlie neurodevelopmental disorders; for instance, disruptions in the MCPH1 gene, which encodes microcephalin involved in DNA damage response and centrosome integrity during NSC divisions, cause primary by prolonging G2/M phases and depleting the progenitor pool, resulting in reduced .

Environmental and Epigenetic Influences

Environmental factors significantly influence neurogenesis, particularly in the adult . Physical exercise and have been shown to enhance hippocampal neurogenesis by upregulating (BDNF), which promotes the and of neural cells. In contrast, suppresses neurogenesis through elevated glucocorticoids, which inhibit and induce in newborn neurons via signaling. Nutritional factors also play a role; omega-3 fatty acids promote adult hippocampal neurogenesis by supporting neuronal membrane integrity and modulating inflammatory pathways, though direct links to (PPAR) mechanisms in this context remain under investigation. , often mediated by hypoxia-inducible factor 1α (HIF-1α), can drive neurogenesis in neurogenic niches by activating adaptive responses that enhance and differentiation. Prenatal environmental exposures, such as maternal diet, can alter the fetal epigenome, influencing lifelong neurogenesis potential. High-fat maternal diets induce persistent changes in the offspring's brain, affecting related to neural and potentially reducing neurogenic capacity into hood. Epigenetic modifications provide a key interface between environmental cues and neurogenesis regulation. dynamics, regulated by ten-eleven translocation (TET) enzymes, are crucial for (NSC) identity; TET-mediated demethylation of NSC promoters prevents premature and supports ongoing neurogenesis during . Histone acetylation, conversely, facilitates gene activation in neurogenic processes; inhibition of histone deacetylases (HDACs) enhances acetylation at promoters of neuronal genes, promoting NSC and increasing neurogenesis in both embryonic and contexts. Aging contributes to neurogenesis decline through accumulated epigenetic silencing. Progressive hypermethylation and reduced acetylation lead to repression of neurogenic genes in the , diminishing NSC proliferation and survival over time. A 2025 study shows that regulate GABAergic neurogenesis in the prenatal through IGF1 signaling, promoting progenitor proliferation in the medial during the second and third trimesters and highlighting species-specific mechanisms for production.

Induced Neurogenesis

Pharmacological and Substance Effects

Selective serotonin reuptake inhibitors (SSRIs), such as , enhance neurogenesis in the subgranular zone (SGZ) of the adult by increasing through serotonin signaling pathways. Chronic administration of promotes the survival and differentiation of these progenitors into mature neurons, an effect mediated by activation of 5-HT1A and 5-HT4 receptors. This pro-neurogenic action is observed in models and correlates with efficacy, though human studies show more modest increases in neural progenitors in the of individuals with . Neurotrophic factors and their mimetics also induce neurogenesis, particularly in the (SVZ). (BDNF) supports SVZ progenitor proliferation and neuronal recruitment to the , with BDNF mimetics like small analogs enhancing this process in ischemic conditions. (EPO), acting via its receptor, stimulates SVZ-derived neurogenesis by promoting neural progenitor production and migration along the rostral migratory stream, as demonstrated in both and models of . Cannabinoids exert pro-neurogenic effects through CB1 receptor activation in hippocampal neural stem/ cells (NS/PCs). Endocannabinoids and synthetic agonists increase and survival of new neurons in the SGZ, influencing baseline and activity-dependent neurogenesis stages. In contrast, suppresses hippocampal neurogenesis in a dose-dependent manner, with binge-like exposures reducing , survival, and long-term neuronal integration. Higher doses lead to persistent deficits, potentially via and in the SGZ. Experimental pharmacological agents, including (HDAC) inhibitors like valproic acid, upregulate neurogenesis through epigenetic mechanisms such as increased histone acetylation and in neural progenitors. Recent studies from 2023 to 2025 indicate that psychedelics, such as , boost hippocampal (NSC) activity and promote structural , including enhanced dendritic spine density and , via serotonin 2A receptor agonism. These effects are observed after single or low-dose administrations in preclinical models. However, pharmacological overstimulation of neurogenesis carries risks, including aberrant neuronal integration and potential tumor formation due to dysregulated progenitor proliferation. HDAC inhibitors like valproic acid can perturb postnatal NSC activity, leading to imbalances in differentiation and survival that may contribute to oncogenic pathways in susceptible tissues.

Therapeutic Strategies

Therapeutic strategies for harnessing neurogenesis primarily involve stem cell transplantation and gene therapy approaches to restore neuronal populations in neurodegenerative and neurological disorders. Neural stem cell (NSC) grafts have shown promise in preclinical models of , where transplantation into the promotes integration and improves motor function by enhancing endogenous neurogenesis and reducing inflammation. For instance, human brain-derived NSCs transplanted into rodent models of demonstrated long-term survival and functional recovery, with up to 20% of grafted cells differentiating into tyrosine hydroxylase-positive neurons. targeting the Ascl1 enables in vivo conversion of non-neuronal cells, such as , into functional neurons; in mouse models, Ascl1 overexpression in dorsal led to efficient neuronal reprogramming, with converted cells exhibiting electrophysiological properties and synaptic integration. These strategies aim to replenish lost neurons while modulating the neurogenic niche to support graft survival and host integration. In , of the (SVZ) via electrical or pharmacological means enhances neurogenesis to aid tissue repair and functional restoration. of the SVZ in rat models increased neural by 2-3 fold, leading to improved behavioral outcomes such as enhanced and reduced infarct size. For , therapeutic enhancement of hippocampal neurogenesis through targeted interventions, including techniques like , has been explored to alleviate symptoms by promoting neuron generation. In rodent models of chronic stress-induced , optogenetic of hippocampal progenitors boosted neurogenesis and reversed depressive-like behaviors, with treated animals showing normalized preference and reduced immobility in forced swim tests. Recent developments include a January 2025 Stanford Medicine study showing that elevated glucose levels block new formation in aged brains by impairing activation, suggesting potential interventions to reduce glucose influence and enhance neurogenesis in aging or injured tissue. In 2025, phase II clinical trials for , such as those evaluating the small molecule NA-831, have demonstrated preliminary efficacy in boosting hippocampal neurogenesis; NA-831 treatment in mild Alzheimer's patients improved cognitive scores on the scale by an average of 4.1 points after 24 weeks. These advances highlight the transition from preclinical optimization to human application, with small molecules offering non-invasive options to upregulate neurogenic pathways like BDNF signaling. Despite these progresses, significant challenges persist in therapeutic implementation, including limited integration efficacy of transplanted cells, where only 5-10% of NSCs typically survive and functionally incorporate in host tissue due to immune rejection and vascular deficits. Ethical concerns with induced pluripotent stem cells (iPSCs), such as the of tumorigenicity from incomplete and the need for genetic matching to avoid , have slowed clinical adoption, necessitating rigorous preclinical screening for genetic stability. Delivery methods also pose hurdles; for example, intranasal administration of (BDNF) enhances neurogenesis in models by crossing the blood-brain barrier efficiently, but achieving therapeutic concentrations without nasal irritation or systemic side effects remains inconsistent, with studies showing only transient elevations in hippocampal BDNF levels. Preclinical outcomes in underscore the viability of these strategies across disorders: NSC grafts in Parkinson's models restored levels by 30-50% and ameliorated akinesia, while SVZ stimulation post-stroke promoted alongside neurogenesis, yielding 40% better sensorimotor recovery. In models, hippocampal enhancement via or exercise regimens increased newborn neuron survival by up to 50%, correlating with efficacy. Human phase I/II trials for , such as Neurona Therapeutics' NRTX-1001 using iPSC-derived inhibitory neurons, have reported safety in drug-resistant patients, with approximately 80% showing over 75% seizure reduction after single intracerebral administration. These results indicate scalable potential, though long-term requires further validation in larger cohorts.

Implications and Recent Advances

Role in Brain Function and Disease

Adult hippocampal neurogenesis, primarily occurring in the subgranular zone (SGZ) of the , contributes to formation and retention by enhancing pattern separation and encoding of contextual information. New neurons in this region integrate into existing circuits, supporting long-term spatial learning tasks such as the Morris water maze. Additionally, hippocampal neurogenesis regulates , with reductions linked to depressive states and enhancements promoting emotional through modulation of responses. In the (SVZ), adult-born neurons migrate to the , where they facilitate fine olfactory discrimination by increasing neuronal diversity and in processing. Ablation of these SVZ-derived neurons impairs innate preference and subtle differentiation. In , adult neurogenesis declines early, with amyloid-β oligomers inhibiting neural stem cells (NSCs) in both the SGZ and SVZ, exacerbating cognitive deficits. This inhibition promotes NSC and reduces , contributing to loss. In , impaired SVZ neurogenesis, including reduced and altered neuronal migration, disrupts cortical integration and correlates with psychotic symptoms. In , SGZ neurogenesis is suppressed by , leading to impaired mood regulation, though this suppression is reversible with treatments that restore . Aging leads to a progressive decline in , correlating with cognitive impairments such as reduced and executive function. Recent 2025 studies highlight how senescent in the aged release inflammatory signals, contributing to cognitive decline. This microglial-mediated interference forms an intermediate aging state that drives broader cognitive decline. Newly generated neurons provide protective roles by buffering against , as their enhanced helps maintain circuit homeostasis during . This buffering capacity implies contributions to resilience following trauma, where adult-born neurons support recovery of cognitive functions like learning and emotional processing. Optogenetic studies demonstrate that selective or of newborn dentate neurons impairs learning, including spatial and behavioral flexibility, by disrupting excitatory-inhibitory balance in hippocampal circuits. Such targeted manipulations confirm the necessity of these neurons for acquisition and .

Emerging Research Techniques

Recent advances in intravital imaging have enabled real-time tracking of neurogenesis in living mammalian brains. Intravital two-photon microscopy in mice has been refined to monitor the dynamics of newborn neurons over extended periods, such as 60 days, by labeling cells with retroviral GFP and capturing dendritic growth and integration into neural circuits. These 2025 developments allow for non-invasive, longitudinal observation of adult hippocampal neurogenesis, revealing age-dependent declines in progenitor proliferation and maturation. Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool for dissecting (NSC) heterogeneity and states during neurogenesis. In the forebrain ventricular-subventricular zone, scRNA-seq combined with has identified distinct NSC niches, including dormant and activated states marked by genes like , Veph1, and Ascl1, with injury-induced shifts toward oligodendrogenesis. Cross-analysis of multiple scRNA-seq datasets from 2023–2025 has resolved transcriptional profiles of hippocampal NSCs, highlighting intermediate activation states in quiescent NSCs before full proliferation. Human studies have benefited from refined postmortem techniques and non-invasive imaging to confirm and quantify adult neurogenesis. Carbon-14 dating of genomic DNA from hippocampal tissue, updated in 2025, provides genetic evidence of ongoing neuron formation in adults, estimating a low but persistent rate of new neurons throughout life, thus resolving prior debates on its existence. Genetic tools have advanced the identification of neurogenesis regulators across species. Genome-wide CRISPR-Cas9 screens in aged NSCs have uncovered 654 genes that enhance , including (), whose knockout boosts neurogenesis twofold by altering glucose metabolism. Lineage tracing with Brainbow variants in non-mammalian models, such as , facilitates multicolor labeling of clonally related cells, revealing coordinated and patterns during . Emerging assays have illuminated cellular interactions in neurogenic niches. A 2025 Nature study on human forebrain organoids demonstrated that microglia-NSC interactions via (IGF1) signaling promote progenitor proliferation and production, with microglia concentrating near SOX2+ radial glia. models applied to transcriptomic data have predicted NSC identities and neurogenic potential from genomic profiles, spotting progenitors in adult human brains and supporting the detection of immature neurons. These techniques have profoundly impacted neurogenesis research by confirming adult neuron generation in humans and identifying targets for regeneration. The resolution of the adult neurogenesis debate through C14 and analyses has paved the way for designing therapies that enhance NSC activation in aging and disease.

References

  1. [1]
    Neurogenesis - an overview | ScienceDirect Topics
    Neurogenesis is defined as the process through which neural stem cells generate new neurons, occurring during both embryonic and perinatal stages as well as ...Mechanisms and Stages of... · Functional Roles of...
  2. [2]
    Neurogenesis in the embryonic and adult brain: same regulators ...
    In this review, we will compare and contrast the functions of transcription factors (TFs) and other regulatory molecules in the embryonic brain and in adult ...
  3. [3]
    Adult Neurogenesis in the Mammalian Brain: Significant Answers ...
    Adult neurogenesis, a process of generating functional neurons from adult neural precursors, occurs throughout life in restricted brain regions in mammals.
  4. [4]
    Understanding neurogenesis in the adult human brain - PMC
    Neurogenesis persists throughout life, with new neurons forming in the adult brain, including the dentate gyrus and hippocampus, and is part of the ...
  5. [5]
  6. [6]
  7. [7]
    Factors that influence adult neurogenesis as potential therapy - PMC
    Feb 21, 2018 · Neurogenesis is an endogenous process that involves coordinated proliferation, differentiation, and migration of neural precursor cells [1].
  8. [8]
    The Symmetry of Neural Stem Cell and Progenitor Divisions in the ...
    May 25, 2022 · At the tissue level, NPC division mode progresses from symmetric proliferative to asymmetric and symmetric neurogenic divisions as brain ...
  9. [9]
  10. [10]
    Adult Neurogenesis: An Evolutionary Perspective - PMC
    Adult neurogenesis is found throughout the animal kingdom but varies to a large extent. Mammals might have fewer neurogenic zones than, for example, fish.
  11. [11]
    The end of the central dogma of neurobiology: stem cells ... - PubMed
    We examined how this dogma was broken and who contributed, and the difficulties encountered by the "heretical" researchers who contributed to this goal, ...
  12. [12]
    The dynamics of adult neurogenesis in human hippocampus - LWW
    The adult brain was thought to be hard wired and incapable of generating new neurons. A famous neurobiologist, Santiago Ramon y Cajal in 1913 stated “In the ...Dentate Gyrus In Hippocampus · Neural Stem Cells And... · Cell Apoptosis
  13. [13]
    Are New Neurons Formed in the Brains of Adult Mammals? - Science
    MESSIER, B, CELL PROLIFERATION AND MIGRATION AS REVEALED BY RADIOAUTOGRAPHY AFTER INJECTION OF THYMIDINE-H-3 INTO MALE RATS AND MICE, AMERICAN JOURNAL OF ...
  14. [14]
    the Groundbreaking Research of Joseph Altman and Gopal Das
    One of the earliest lines of evidence gathered came from studies on the production of cerebellar microneurons in the external germinal layer of rodents and ...
  15. [15]
    Generation of Neurons and Astrocytes from Isolated Cells ... - Science
    In this study, cells isolated from the striatum of the adult mouse brain were induced to proliferate in vitro by epidermal growth factor.
  16. [16]
    Neurogenesis in the adult human hippocampus | Nature Medicine
    We demonstrate that new neurons, as defined by these markers, are generated from dividing progenitor cells in the dentate gyrus of adult humans.
  17. [17]
    Formation of the Neural Tube - Developmental Biology - NCBI - NIH
    The neural tube arises from a solid cord of cells that sinks into the embryo and subsequently hollows out (cavitates) to form a hollow tube.
  18. [18]
    Neurogenesis during development of the vertebrate central nervous ...
    Mar 17, 2014 · Here, we discuss the recent advances and insights into regulation of neurogenesis in the developing vertebrate central nervous system.
  19. [19]
    Chapter 20 Neurogenesis in Zebrafish Embryos - ScienceDirect.com
    This chapter reviews the unique features of the zebrafish embryo that make it attractive for the study of early neural development, and examines how ...
  20. [20]
  21. [21]
    Comparative aspects of cortical neurogenesis in vertebrates - PMC
    The mammalian neocortex consists of six layers. By contrast, the reptilian and avian cortices have only three, which are believed to be equivalent to layers I, ...
  22. [22]
    Neuronal migration in the CNS during development and disease
    Jan 9, 2019 · Interneurons initially migrate tangentially in two streams over long distances into the cerebral cortex (Fig. 1A). They then switch to radial ...Neuronal Migration In The... · Neuronal Migration Disorders... · Mouse Models Of Nmds<|separator|>
  23. [23]
    Death of developing neurons: New insights and implications for ...
    Nov 11, 2013 · (A) The apoptotic machinery is not only involved in eliminating cells destined to die, but is also a central player in refining neuronal ...
  24. [24]
    [PDF] Timetables of Neurogenesis in the Human Brain Based on ...
    In the first part of this article, we match developing human and rat brains at 10 different ages (from rat E11/ human week 3.5 to rat E21/human weeks 15-16).
  25. [25]
    Hox genes in development and beyond
    Jan 16, 2023 · Hox genes encode evolutionarily conserved transcription factors that are essential for the proper development of bilaterian organisms.Hox protein structure and... · Regional specificity and... · Continuing roles for Hox...
  26. [26]
  27. [27]
  28. [28]
  29. [29]
  30. [30]
    Paradox of Pattern Separation and Adult Neurogenesis: A Dual Role ...
    Hippocampal adult neurogenesis is thought to subserve pattern separation, the process by which similar patterns of neuronal inputs are transformed into distinct ...Pattern Separation By The... · New Neurons Are Pattern... · New Neurons Maintain...
  31. [31]
    Adult Neurogenesis and the Olfactory System - PMC - PubMed Central
    Neuroblasts from the subventricular zone (SVZ) migrate along the rostral migratory stream (RMS) into the olfactory bulb, where they differentiate into ...
  32. [32]
    Adult neural stem cells in the mammalian central nervous system
    May 12, 2009 · In the adult brain, NSCs are primarily located in the SVZ of the lateral ventricle and the SGZ of the hippocampal dentate gyrus (Figure 1A). In ...<|control11|><|separator|>
  33. [33]
    Dynamics of Hippocampal Neurogenesis in Adult Humans
    Jun 6, 2013 · In adult humans, 700 new neurons are added in each hippocampus per day, corresponding to an annual turnover of 1.75% of the neurons within the renewing ...
  34. [34]
    Genetic evidence that our brains make new neurons in adulthood ...
    Jul 3, 2025 · His team's earlier work suggested roughly 700 new neurons are formed each day, which is less than 0.03% of the neurons in an adult hippocampus.
  35. [35]
    Adult neurogenesis in the dentate gyrus - Neurology.org
    Sep 27, 2013 · INCORPORATION OF ADULT-BORN DG GRANULE CELLS INTO THE HIPPOCAMPAL CIRCUITRY ... Pattern separation in the human hippocampal CA3 and dentate gyrus.Neural Precursors In The Dg · Neurogenesis In Human... · Clinical Correlations
  36. [36]
    The functional significance of newly born neurons integrated into ...
    Two decades of huge investigation in adult neurogenesis revealed the biological importance of integration of new neurons into the olfactory circuits. In this ...
  37. [37]
    Conserved and Divergent Features of Adult Neurogenesis in Zebrafish
    Adult neurogenesis, ie. the generation of neurons from neural stem cells (NSCs) in the adult brain, contributes to brain plasticity in all vertebrates.Abstract · Neural Stem Cells: a Variety of... · Physiological and Pathological...
  38. [38]
    Neural stem cells and neurogenesis in the adult zebrafish brain
    Lifelong neurogenesis in vertebrates relies on stem cells producing proliferation zones that contain neuronal precursors with distinct fates.
  39. [39]
    Regenerative neurogenesis: the integration of developmental ...
    May 3, 2022 · Research in zebrafish has revealed several endogenous signals that activate the regeneration of new neurons. We first describe regeneration ...
  40. [40]
    Adult neurogenesis and brain regeneration in zebrafish - PubMed
    Zebrafish can produce new neurons throughout life and have extensive regenerative capacity, producing new neurons to replenish lost ones after injuries.
  41. [41]
    Adult neurogenesis in the telencephalon of the lizard Podarcis liolepis
    Feb 22, 2023 · Adult neurogenesis is the process by which neurons are generated from neural stem cells in the adult brain, either to add or to replace neurons ...
  42. [42]
    Neurogenesis in the Adult Avian Song-Control System - PMC - NIH
    New neurons are added throughout the forebrain of adult birds, especially in the song-control system, and are linked to the death of mature neurons.
  43. [43]
    Seasonal changes in neuronal turnover in a forebrain nucleus in ...
    In the song control nucleus HVC of adult male Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelli) nearly 68,000 neurons are added each breeding ...
  44. [44]
    Neurogenesis during caudal spinal cord regeneration in adult newts
    Transection induces a proliferation response in cells lining the ependymal canal, giving rise to an ependymal tube in which neurogenesis occurs.
  45. [45]
    Neurogenesis and growth factors expression after complete spinal ...
    It is noteworthy that urodele amphibians are the only tetrapod vertebrates that can regenerate all regions of their spinal cord as adults (Chernoff, 1996).Material And Methods · Nestin Expression In... · Fgf-2 And Fgfr2 Mrna In...
  46. [46]
    Neurogenesis and neuronal regeneration in the adult reptilian brain
    Adult neurogenesis and neuronal regeneration take advantage of the same mechanisms that are present during embryonic neurogenesis. New neurons are born in the ...
  47. [47]
    Broadening the functional and evolutionary understanding of ...
    Aug 11, 2020 · This Review will begin by describing the processes of adult neurogenesis in reptiles and identifying the similarities and differences in these ...
  48. [48]
    Wnt/β-catenin signalling: function, biological mechanisms ... - Nature
    Jan 3, 2022 · The Wnt/β-catenin pathway comprises a family of proteins that play critical roles in embryonic development and adult tissue homeostasis.
  49. [49]
    The Level of the Transcription Factor Pax6 Is Essential for ...
    The transcription factor Pax6 is essential for neural stem cell proliferation, multipotency, and neurogenesis in many regions of the central nervous system.
  50. [50]
    NeuroD1 reprograms chromatin and transcription factor landscapes ...
    Oct 29, 2015 · NeuroD1 directly binds regulatory elements of neuronal genes that are developmentally silenced by epigenetic mechanisms.
  51. [51]
    Identification of ASCL1 as a determinant for human iPSC-derived ...
    Nov 15, 2021 · In ASCL1 knockout mice, midbrain dopaminergic neuron differentiation ... KO causes severe defects in midbrain dopaminergic neurogenesis and ...
  52. [52]
    Genome-wide association analysis of hippocampal volume ... - Nature
    Oct 10, 2019 · Our results suggest that neurogenesis-related pathways may be enriched for hippocampal volume and that hippocampal volume may serve as a potential phenotype.
  53. [53]
    All in the family: proneural bHLH genes and neuronal diversity - NIH
    Proneural basic Helix-Loop-Helix (bHLH) proteins are required for neuronal determination and the differentiation of most neural precursor cells.
  54. [54]
    MCPH1: a window into brain development and evolution - PMC
    Two missense mutations in the primary autosomal recessive microcephaly gene MCPH1 disrupt the function of the highly conserved N-terminal BRCT domain of ...
  55. [55]
    Exercise-Mediated Neurogenesis in the Hippocampus via BDNF
    The present review synthesizes the extant literature detailing the relationship between exercise and hippocampal neurogenesis, and identifies a key molecule ...Missing: seminal | Show results with:seminal
  56. [56]
    Stress, glucocorticoid receptors, and adult neurogenesis: a balance ...
    Here, we review the complex interplay between stress and adult neurogenesis. In particular, we review the role of the glucocorticoid receptor, the main ...
  57. [57]
    Omega-3 fatty acids upregulate adult neurogenesis - PMC
    Therefore, omega-3 fatty acids may alter the rate of neurogenesis via their contributions to the dynamic structure and function of neuronal membranes. A second ...Missing: PPAR | Show results with:PPAR
  58. [58]
    Functional hypoxia drives neuroplasticity and neurogenesis via ...
    Mar 9, 2020 · In the kidney, it is hypoxia and hypoxia-inducible factors (Hif), which are well known to induce EPO expression. We therefore hypothesized that ...
  59. [59]
    Maternal diet induces persistent DNA methylation changes in the ...
    Jan 28, 2023 · Maternal nutrition during pregnancy can induce epigenetic alterations in the fetal genome, such as changes in DNA methylation.Missing: neurogenesis lifelong
  60. [60]
    Developmental DNA demethylation is a determinant of neural stem ...
    Aug 28, 2024 · We demonstrate that developmental DNA demethylation, driven by ten-eleven translocation 1/2/3 (TET1/2/3) enzymes, is essential for establishment of neural stem ...
  61. [61]
    Histone deacetylases 1 and 2 control the progression of neural ...
    May 12, 2009 · The specific role of HDACs in neuronal differentiation is of particular interest given recent reports that HDAC inhibitors enhance learning and ...
  62. [62]
    Epigenetic mechanisms during ageing and neurogenesis as novel ...
    Jun 29, 2017 · Among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and ...
  63. [63]
    Microglia regulate GABAergic neurogenesis in prenatal human ...
    Aug 6, 2025 · It has been shown that microglia regulate PV+ interneuron development and positioning and lead to PV+ interneuron deficits in setting of ...
  64. [64]
    Fluoxetine targets early progenitor cells in the adult brain - PNAS
    Chronic treatment with antidepressants increases neurogenesis in the adult hippocampus. This increase in the production of new neurons may be required for ...
  65. [65]
    The role of serotonin in adult hippocampal neurogenesis
    Jan 15, 2015 · Chronic, but not acute, treatment with fluoxetine (trade name 'Prozac') also leads to increased hippocampal neurogenesis, e.g. increased cell ...Missing: seminal paper
  66. [66]
    Antidepressants increase neural progenitor cells in the human ...
    We determined whether SSRIs or TCAs increase neural progenitor (NPCs) and dividing cells in the human DG in major depressive disorder (MDD).Missing: seminal paper
  67. [67]
    BDNF control of adult SVZ neurogenesis - PMC - PubMed Central
    A role for BDNF in the control of SVZ neurogenesis was initially identified by Goldman and colleagues in the mid 1990's. They found that BDNF administered to ...Missing: erythropoietin | Show results with:erythropoietin
  68. [68]
    Erythropoietin Regulates the In Vitro and In Vivo Production of ...
    Recent studies have shown that neurogenesis is enhanced after hypoxia and that erythropoietin (EPO) ... SVZ to the OB along the RMS, as well as the implantation ...
  69. [69]
    Cannabinoids promote embryonic and adult hippocampus ...
    We show that both embryonic and adult rat hippocampal NS/PCs are immunoreactive for CB1 cannabinoid receptors, indicating that cannabinoids could act on CB1 ...
  70. [70]
    Alcohol and adult hippocampal neurogenesis - PubMed Central - NIH
    NPC/neuroblast survival is generally decreased in alcohol exposure models, but again, this effect is heavily dose-dependent, i.e., higher doses of alcohol ...
  71. [71]
    Long-lasting reduction in hippocampal neurogenesis by alcohol ...
    Studies in rodent models have suggested that alcohol reduces proliferation and neurogenesis in the adolescent and adult hippocampus through increased cell death ...
  72. [72]
    Valproic acid, a histone deacetylase inhibitor, regulates cell ...
    Aug 4, 2014 · The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain. ... Valproic acid promotes neuronal differentiation by ...<|separator|>
  73. [73]
    Effects of psychedelics on neurogenesis and broader neuroplasticity
    Dec 19, 2024 · This review presents an extensive study into how different psychedelics may affect the birth of new neurons and other brain-related processes.
  74. [74]
    Towards an understanding of psychedelic-induced neuroplasticity
    Sep 19, 2022 · At what dose do psychedelics enhance neuroplasticity? Several studies have investigated how different doses of psychedelic drugs affect ...
  75. [75]
    HDAC inhibitors dysregulate neural stem cell activity in the postnatal ...
    Collectively, these data show that clinically used HDAC inhibitors like VPA and TSA can perturb postnatal neurogenesis; and their use should be carefully ...
  76. [76]
    A role for adult neurogenesis in spatial long-term memory - PubMed
    Adult hippocampal neurogenesis has been linked to learning but details of the relationship between neuronal production and memory formation remain unknown.
  77. [77]
    A Functional Role for Adult Hippocampal Neurogenesis in Spatial ...
    The dentate gyrus (DG) is thought to contribute to spatial or episodic memory by functioning as a pattern separator (1-3). Pattern separation is the formation ...
  78. [78]
    Hippocampal Neurogenesis: Regulation by Stress and ...
    Accumulating evidence implicates hippocampal neurogenesis in the pathophysiology of depression. Psychosocial stress reduces neurogenesis in rodents, ...
  79. [79]
    Continuous neurogenesis in the adult forebrain is required for innate ...
    Neurons born in the SVZ migrate into the olfactory bulb, whereas neurons born in the SGZ migrate into the hippocampal dentate gyrus. The functional significance ...
  80. [80]
    SVZ-derived newly generated neurons populate several olfactory ...
    Gheusi [19] and others have shown that newly generated neurons in the olfactory bulb are important for olfactory discrimination learning [19–21]. Moreover, ...
  81. [81]
    Impaired adult neurogenesis is an early event in Alzheimer's ...
    Oct 7, 2019 · Our results demonstrate that SVZ neurogenesis is impaired already at a presymptomatic stage of AD and is caused by endogenously generated intracellular AβOs in ...
  82. [82]
    Alzheimer's Amyloid-β Accelerates Cell Senescence and ...
    Feb 4, 2024 · In summary, our study revealed that the AD-associated pathogenic protein Aβ accelerated cellular senescence in human NSCs via SIRT1 inhibition, ...
  83. [83]
    The role of adult neurogenesis in psychiatric and cognitive disorders
    Jan 15, 2017 · Several reports have suggested that increased adult neurogenesis in the V–SVZ may alleviate symptoms of schizophrenia by targeting dopamine ...
  84. [84]
  85. [85]
    The intricate interplay between microglia and adult neurogenesis in ...
    Modulating microglial function and phenotype represents a promising approach to enhance adult neurogenesis and potentially alleviate cognitive deficits in AD. ...
  86. [86]
    Microglia aging in the hippocampus advances through intermediate ...
    Apr 29, 2025 · Microglia advancement through intermediate aging states drives transcriptional inflammatory activation and hippocampal-dependent cognitive decline.
  87. [87]
    Senescent Microglia Mediate Neuroinflammation‐Induced Cognitive ...
    Jul 7, 2025 · Microglia-mediated neuroinflammation has been shown to exert an important effect on the progression of a growing number of neurodegenerative ...
  88. [88]
    Increasing Adult Hippocampal Neurogenesis Promotes Resilience ...
    Taken together, our data suggest that increasing AHN promotes stress resilience on some depressive-like symptoms but also in cognitive symptoms, which are often ...
  89. [89]
    Early life adversity shapes neural circuit function during sensitive ...
    Aug 1, 2022 · These high levels of excitability enable new neurons to synapse onto other neurons more readily, and to out-compete older connections that have ...
  90. [90]
    Silencing dentate newborn neurons alters excitatory/inhibitory ...
    Jan 10, 2024 · Silencing dentate newborn neurons alters excitatory/inhibitory balance and impairs behavioral inhibition and flexibility.
  91. [91]
    Genetic Ablation of Neural Progenitor Cells Impairs Acquisition of ...
    Sep 16, 2019 · Indeed, there are some studies that have found that reducing the number of newborn neurons impairs memory acquisition on different associative ...
  92. [92]
    Review Advances in intravital imaging of adult neurogenesis in mice
    Sep 9, 2025 · With two-photon microscopy, they imaged retrovirus-labeled GFP-expressing newborn neurons over a 60-day period to monitor dendritic growth ...
  93. [93]
    Advances in intravital imaging of adult neurogenesis in mice - PubMed
    Sep 9, 2025 · Here, we review recent advances in the field of adult neurogenesis achieved by using in vivo imaging approaches in mice and discuss future ...Missing: two- photon
  94. [94]
  95. [95]
    Cross‐Analysis of Single‐Cell Transcriptomic Datasets Reveals ...
    Jun 4, 2025 · Here, we reanalyze single-cell RNA sequencing datasets demonstrating hippocampal adult neural stem cell (NSC) heterogeneity to resolve ...
  96. [96]
    Neural Progenitor Cells Tracked Non-invasively in Humans
    Nov 9, 2024 · Researchers have developed a non-invasive spectroscopic imaging method that detects the density of neural progenitor and stem cells in living ...
  97. [97]
    CRISPR–Cas9 screens reveal regulators of ageing in neural stem ...
    Oct 2, 2024 · Here we develop in vitro and in vivo high-throughput CRISPR–Cas9 screening platforms to systematically uncover gene knockouts that boost NSC activation in old ...
  98. [98]
    Multicolor lineage tracing using in vivo time-lapse imaging reveals ...
    Sep 15, 2019 · We have developed an approach using Brainbow in the developing zebrafish to visualize and follow multiple clones of related cells in vivo over time.
  99. [99]
    Machine learning spots neural progenitors in adult human brains
    Jul 3, 2025 · Neural progenitor cells exist in the adult human hippocampus all the way into old age, a new transcriptomics study published today in Science suggests.Missing: genomic | Show results with:genomic