Adult neurogenesis — the generation of new neurons in the mature brain — represents one of the most remarkable discoveries in modern neuroscience. Once believed to be impossible, it is now established that specific brain regions in mammals, including humans, retain the capacity to produce new neurons throughout life. This process holds profound implications for understanding brain plasticity, memory formation, and potentially treating neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). [1]
This comprehensive page explores the biology of adult neurogenesis, its modulation in neurodegenerative conditions, the ongoing scientific debate regarding its extent in humans, and emerging therapeutic strategies that harness neurogenesis for brain repair. [2]
The adult mammalian brain contains discrete regions where neural stem cells (NSCs) continue to proliferate and generate new neurons. These specialized microenvironments are termed neurogenic niches and provide the molecular signals necessary to maintain stem cell pools and guide neuronal differentiation. [3]
The largest neurogenic niche in the adult brain resides in the subventricular zone (SVZ), located along the lateral walls of the lateral ventricles. The SVZ contains several cell types essential for continuous neurogenesis: [4]
New neurons generated in the SVZ migrate via the rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into various interneurons that participate in odor processing and discrimination. [5]
The second major neurogenic niche is the subgranular zone (SGZ) of the hippocampal dentate gyrus. The SGZ produces neurons that integrate into the granule cell layer and contribute to hippocampal-dependent learning and memory. The SGZ contains: [6]
Unlike SVZ-derived neurons that migrate long distances, SGZ-born neurons undergo local migration and extend axons to CA3 pyramidal neurons within weeks of their birth. [7]
Adult neurogenesis exhibits a striking age-dependent decline across mammalian species. In mice, neurogenesis in the SGZ decreases approximately 10-fold between youth and old age. Similar patterns are observed in humans, though the extent and significance remain debated. [8]
Factors contributing to age-related neurogenesis decline include: [9]
Neurogenesis is significantly altered in Alzheimer's disease, though the relationship remains complex. Studies in human postmortem tissue and animal models reveal: [10]
In Parkinson's disease, neurogenesis alterations are observed in both the SVZ and SGZ: [11]
One of the most contentious debates in contemporary neuroscience concerns the extent and functional significance of adult neurogenesis in the human hippocampus. [12]
In 2018, Sorrells et al. published a influential study examining adult neurogenesis in human hippocampus across the lifespan. Using postmortem tissue and stereological methods, they concluded that: [13]
In contrast, Moreno-Jimenez et al. (2019) reported robust adult hippocampal neurogenesis in humans. Their findings: [14]
Subsequent studies using improved methodologies suggest that: [15]
Several growth factors critically regulate adult neurogenesis:
Brain-Derived Neurotrophic Factor (BDNF)
BDNF is essential for neuronal survival, differentiation, and synaptic plasticity. Exercise increases BDNF expression in the hippocampus, mediating some cognitive benefits. BDNF signaling through TrkB receptors promotes neurogenesis in both SVZ and SGZ.
Nerve Growth Factor (NGF)
NGF supports cholinergic neuron survival and influences neurogenesis in specific brain regions.
Vascular Endothelial Growth Factor (VEGF)
VEGF promotes angiogenesis and directly stimulates neurogenesis through VEGF receptor 2 (Flk-1) signaling.
Insulin-like Growth Factor-1 (IGF-1)
IGF-1 from peripheral circulation and local production enhances neurogenesis.
Wnt/β-catenin Signaling
Wnt proteins, particularly Wnt3a in the hippocampus, promote neural stem cell proliferation and neuronal differentiation. Wnt signaling declines with age.
Notch Signaling
Notch receptors regulate neural stem cell maintenance and fate decisions. Notch activation maintains stemness, while Notch inhibition promotes neuronal differentiation.
Sonic Hedgehog (Shh) Signaling
Shh from the choroid plexus and local sources promotes neurogenesis. Shh signaling declines in aging.
BMP Signaling
Bone morphogenetic proteins have complex, context-dependent effects on neurogenesis. BMP signaling generally promotes astrogliogenesis while inhibiting neurogenesis.
Physical exercise, particularly aerobic exercise (running, swimming, cycling), is the most robust environmental enhancer of adult neurogenesis:
Complex environments with sensory, motor, and social stimulation promote neurogenesis:
Several dietary factors influence neurogenesis:
Several drugs and compounds modulate neurogenesis:
Enhancing endogenous neurogenesis represents a promising therapeutic strategy:
Alzheimer's Disease
Parkinson's Disease
Several clinical trials target neurogenesis:
Translating neurogenesis enhancement to human therapies faces significant challenges:
Huntington's disease provides unique insights into neurogenesis dysfunction. Studies demonstrate: [16]
Neurogenesis alterations in ALS include: [17]
MSA shows distinct neurogenesis patterns: [@sloan2021]
Neurogenesis in DLB: [18]
Neurogenesis is controlled by epigenetic mechanisms: [@yahata2012]
DNA Methylation
Histone Modifications
** chromatin Remodeling**
Metabolic state critically affects neurogenesis: [19]
Mitochondrial Function
mTOR Signaling
AMPK Activation
Calcium flux controls neurogenesis: [20]
New neurons contribute to memory processes: [21]
Pattern Separation
Contextual Memory
Neurogenesis affects mood and emotion: [22]
Mouse models reveal neurogenesis mechanisms: [23]
Key markers identify neurogenesis stages: [24]
| Cell Type | Markers |
|---|---|
| Neural Stem Cells | Nestin, Sox2, Pax6, GFAP |
| Proliferating Cells | Ki67, PCNA, BrdU |
| Neuroblasts | DCX, Tuj1 (βIII-tubulin) |
| Mature Neurons | NeuN, Calbindin, Prox1 |
Modern techniques visualize neurogenesis: [@ponts2013]
Pharmacological enhancement strategies: [25]
FDA-Approved Drugs
Experimental Compounds
Cell-based and factor-based therapies: [26]
Non-pharmacological stimulation: [27]
Evidence-based lifestyle modifications: [28]
Several trials investigate neurogenesis: [29]
Neurogenesis biomarkers under development: [30]
Major hurdles remain: [31]
FDA perspectives on neurogenesis therapies: [@carlsson2010]
Patient-derived iPSCs offer new approaches: [32]
CRISPR-based strategies: [33]
3D culture and tissue engineering: [34]
Sorrells et al. Human hippocampal neurogenesis drops sharply in children (2018). 2018. ↩︎
Moreno-Jimenez et al. Robust hippocampal neurogenesis in adult humans (2019). 2019. ↩︎
Eriksson et al. Neurogenesis in the adult human hippocampus (1998). 1998. ↩︎
Kempermann et al. Functional significance of adult hippocampal neurogenesis (2018). 2018. ↩︎
Boldrini et al. Hippocampal neurogenesis in humans (2018). 2018. ↩︎
Lieberwirth et al. Hippocampal adult neurogenesis (2016). 2016. ↩︎
Bond et al. Adult hippocampal neurogenesis in aging and AD (2015). 2015. ↩︎
Perez-Lopez et al. Physical exercise and adult neurogenesis (2022). 2022. ↩︎
Choi et al. Neurogenesis in neurodegenerative disease (2018). 2018. ↩︎
Mobley et al. BDNF and Alzheimer's disease (2019). 2019. ↩︎
Winkler et al. VEGF and neurogenesis (2020). 2020. ↩︎
Suh et al. Wnt signaling in adult neurogenesis (2020). 2020. ↩︎
Zhang et al. Notch signaling in adult neurogenesis (2019). 2019. ↩︎
Petrik & Lagace, Neurogenesis and Parkinson's disease (2022). 2022. ↩︎
Zhao et al. Exercise enhances neurogenesis (2021). 2021. ↩︎
Izzo et al. Neurogenesis in neurodegenerative disease (2020). 2020. ↩︎
Bard et al. Neural stem cells and neurodegenerative disease (2019). 2019. ↩︎
Forster et al. Neurogenesis in Lewy body disease (2019). 2019. ↩︎
Lange et al. Metabolic regulation of neural stem cells (2016). 2016. ↩︎
Lange et al. Calcium signaling in neurogenesis (2016). 2016. ↩︎
Sahay et al. Adult hippocampal neurogenesis and memory (2011). 2011. ↩︎
Wehbe et al. Neurogenesis and emotional regulation (2019). 2019. ↩︎
Lagace et al. Dynamic changes in adult neurogenesis (2010). 2010. ↩︎
Kempermann et al. Principles of neurogenesis (2015). 2015. ↩︎
Silachev et al. Neurogenic compounds for brain repair (2019). 2019. ↩︎
Gould et al. Neurotrophic factors and neurogenesis (2019). 2019. ↩︎
Arisi et al. Physical stimulation and neurogenesis (2016). 2016. ↩︎
Perez et al. Lifestyle factors and neurogenesis (2019). 2019. ↩︎
Kumar et al. Clinical trials targeting neurogenesis (2019). 2019. ↩︎
Boldrini et al. Biomarkers of human neurogenesis (2019). 2019. ↩︎
Hur et al. Challenges in neurogenesis translation (2019). 2019. ↩︎
Takahashi et al. Induced pluripotent stem cells (2007). 2007. ↩︎
Kong et al. CRISPR applications in neurogenesis (2018). 2018. ↩︎
Lancaster et al. Brain organoids for disease modeling (2017). 2017. ↩︎