Adult hippocampal neurogenesis represents one of the most remarkable examples of neural plasticity in the mammalian brain. Unlike most regions of the adult central nervous system, the dentate gyrus of the hippocampus maintains the capacity to generate new neurons throughout lifedisouky2026 2026, disouky2026. This process, termed adult hippocampal neurogenesis (AHN), involves the proliferation of neural stem cells (NSCs), differentiation into neural progenitor cells (NPCs), migration of neuroblasts, and finally integration of mature granule neurons into existing hippocampal circuitsdisouky , disouky.
A landmark study published in Nature (March 2026) used single-nucleus RNA-Seq and ATAC-Seq to analyze hippocampal neurogenesis across the lifespankempermann2024 2024, kempermann2024. The research compared neural stem cells and immature neurons in people with Alzheimer's disease, healthy older adults, and "superagers"—individuals 80+ with memory matching people decades younger. The findings reveal nearly opposite epigenetic profiles between AD and superagerskempermann2024 2024, kempermann2024.
The concept of adult neurogenesis was first proposed in the 1960s by Joseph Altman, who used tritiated thymidine labeling to identify newly divided cells in the dentate gyrus of adult ratssorrells2018 2018, sorrells2018. However, due to technical limitations and skepticism from the scientific community, it wasn't until the 1990s that robust evidence emerged confirming AHN in adult mammalsgage2024 2024, gage2024.
Whether adult hippocampal neurogenesis occurs in humans has been debated for decades. Early studies using carbon-14 dating suggested that approximately 700 new neurons are added daily to the human hippocampusaimone2024 2024, aimone2024. Subsequent studies using various markers including BrdU labeling, DCX expression, and nestin positivity have provided converging evidence for AHN in humanseriksson1998 1998, eriksson1998sorrells2018a 2018, sorrells2018a.
The Nature 2026 study definitively confirms AHN exists in humans and reveals dramatic differences between:
In adult mammals, including humans, two primary neurogenic niches exist: the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampusboldrini2018 2018, boldrini2018. The SGZ is the primary source of new hippocampal neurons.
The neurogenic niche comprises multiple cell types:
The extracellular matrix (ECM) within the niche plays crucial roles in regulating neurogenesis. Proteoglycans, tenascin-C, and laminin create a permissive environment for neuronal progenitor survival and differentiationables2010 2010, ables2010.
The Notch signaling pathway plays a critical role in maintaining NSC quiescence and regulating the balance between self-renewal and differentiationsu2025 2025, su2025. Notch activation in NSCs:
Notch1 and Notch2 receptors, along with ligands Jagged1, Jagged2, and Delta-like1, are expressed in the SGZyang2025 2025, yang2025. Conditional deletion of Notch1 in adult mice leads to premature NSC activation and exhaustionliu2025 2025, liu2025.
Wnt/β-catenin signaling is essential for neuronal differentiation in the dentate gyruschen2024 2024, chen2024. Wnt3, produced by hilar mossy cells and astrocytes, promotes neuroblast differentiationjohnson2026 2026, johnson2026. Disruption of Wnt signaling leads to impaired hippocampal neurogenesis and cognitive deficitssaieva2025 2025, saieva2025.
Bone morphogenetic proteins (BMPs) regulate multiple aspects of AHN. BMP7 promotes NSC proliferation and neuronal differentiation, while BMP4 tends to promote astrogliogenesispeng2025 2025, peng2025. The balance between BMP and Noggin (a BMP antagonist) critically determines neuronal versus glial fate decisionstrem2025 2025, trem2025.
Sonic hedgehog (Shh) signaling from the choroid plexus regulates NSC proliferation in the dentate gyruswang2025 2025, wang2025. Shh knockout mice show significantly reduced neurogenesis, while Shh overexpression enhances progenitor cell proliferationpaolillo2025 2025, paolillo2025.
BDNF is a key component of resilience signature in superagerskempermann2024 2024, kempermann2024. BDNF mediates many of the effects of environment and experience on hippocampal neurogenesisyuan2025 2025, yuan2025. The TrkB receptor mediates BDNF's effects on:
FGF2 is a potent mitogen for NSCs in the dentate gyrusdietert2026 2026, dietert2026. FGF2 expression declines with age, and exogenous FGF2 can restore neurogenesis in aged miceli2026 2026, li2026. FGF18 also contributes to AHN, with distinct temporal expression patternssurya2025 2025, surya2025.
EGF receptor signaling promotes NSC proliferation in the SGZwalter2025a 2025, walter2025a. However, EGF tends to bias differentiation toward glial lineages, necessitating careful regulationguo2026 2026, guo2026.
IGF-1 enhances neurogenesis, with systemic IGF-1 administration increasing NSC proliferationma2025 2025, Hippocampal Neurogenesis in Alzheimer. The age-related decline in IGF-1 signaling contributes to reduced AHNencinas2011 2011, encinas2011.
The 2026 Nature study revealed that diagnosis-related differences are more prominent in chromatin accessibility than gene expressionkempermann2024 2024, kempermann2024. Key epigenetic regulators include:
Physical exercise, particularly aerobic exercise, is the most robust environmental enhancer of AHNyang2024 2024, yang2024. Voluntary wheel running increases:
Exercise-induced neurogenesis is mediated by multiple factors including BDNF, IGF-1, and VEGFzhao2006 2006, zhao2006. The beneficial effects of exercise on cognition are partially mediated by enhanced hippocampal neurogenesisgage2024a 2024, gage2024a.
Housing in enriched environments with complex sensory, motor, and social stimulation enhances AHNyassa2011 2011, yassa2011. Enrichment effects are cumulative and depend on:
Caloric restriction (CR) extends lifespan and enhances neurogenesis in multiple speciesrolls2024 2024, rolls2024. CR effects are mediated through:
The ketogenic diet, used to treat epilepsy, enhances AHN through mechanisms including:
Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) promote neurogenesiskempermann2018 2018, kempermann2018. DHA deficiency is associated with impaired AHN and cognitive deficits.
Hippocampal-dependent learning and memory tasks enhance the survival of new neurons born during or shortly before learningmalberg2000 2000, malberg2000. This experience-dependent survival is thought to contribute to hippocampal plasticity and memory function.
Chronic stress and elevated glucocorticoid levels suppress AHNrevest2009 2009, revest2009. The stress hormone cortisol in humans and corticosterone in rodents:
Sleep deprivation reduces neurogenesis, while adequate sleep promotes AHNkempermann2012 2012, Adult neurogenesis: an evolutionary perspective. The effects are mediated through:
New granule neurons undergo a prolonged maturation process (weeks to months) before becoming fully functionalcameron2001 2001, cameron2001. This process involves:
New neurons exhibit distinct electrophysiological characteristics during maturationribic2019 2019, ribic2019:
The functional significance of AHN remains an active area of investigation. Evidence supports roles in:
The Nature 2026 study reveals that in AD, NSCs were abundant, but neuroblasts and immature neurons were scarce—the process "gets stuck"kempermann2024 2024, kempermann2024. This reflects:
AD and superaging profiles were nearly "polar opposites" in terms of chromatin accessibilitykempermann2024 2024, kempermann2024.
Amyloid-beta (Aβ) and tau pathology directly affect AHNkuhn2016 2016, kuhn2016:
The findings suggest treatments must help neurons complete the full process:
Earlier intervention before severe dementia is more effective than reversalkempermann2024 2024, kempermann2024.
Neurogenesis is also affected in PD, though less extensively studied than in ADming2011 2011, ming2011. Factors include:
AHN is reduced in major depressive disorder, and many antidepressants work partly by enhancing neurogenesispolygenic2024 2024, polygenic2024. This includes:
Seizures alter AHN, often paradoxically increasing proliferation while impairing differentiation and integrationkempermann1997 1997, kempermann1997. This contributes to hippocampal hyperexcitability.
AHN declines dramatically with age in both rodents and humansvaynman2004 2004, vaynman2004. Contributing factors include:
Superagers—individuals 80+ with memory matching people decades younger—show approximately 2× more immature neurons than other groupskempermann2024 2024, kempermann2024. Their profile represents "a response to aging, rather than a delay of aging"kempermann2024 2024, kempermann2024. Key features include:
"New neurons might indeed create a buffer to compensate for age- or disease-related losses in the hippocampus." — Gerd Kempermannkempermann2024 2024, kempermann2024
Adult hippocampal neurogenesis represents a remarkable form of neural plasticity with significant implications for understanding brain health, cognitive function, and neurodegenerative diseases. The 2026 Nature study revealing opposite epigenetic profiles between Alzheimer's disease and superagers provides crucial insights into therapeutic strategies. Key findings include:
Future therapeutic approaches must focus on helping new neurons complete the entire neurogenic process—growth, maturation, survival, and proper circuit integration. The concept of a "neurogenic reserve" suggests that maintaining AHN may provide a buffer against age- and disease-related cognitive decline.