What Is Neurogenesis?

Neurogenesis is the process by which new neurons are generated from neural stem cells and progenitor cells. It occurs extensively during embryonic and fetal development, when the vast majority of the central nervous system is constructed, and continues in restricted regions of the adult mammalian brain throughout life. The discovery of adult neurogenesis, confirmed in the 1990s through the work of Fred Gage at the Salk Institute using bromodeoxyuridine labeling in rodent hippocampus, challenged the long-held view that the brain is a fixed structure incapable of producing new neurons after early development. Neurogenesis research sits within developmental neuroscience, cell biology, and regenerative medicine, and has implications for understanding learning, memory, depression, and recovery from injury.

The field distinguishes between embryonic neurogenesis, which builds the brain's initial architecture through a coordinated sequence of proliferation, migration, differentiation, and programmed cell death, and adult neurogenesis, which operates in a more restricted manner in specific neurogenic niches.

Embryonic Neurogenesis

During embryonic development, the neuroepithelium lining the neural tube contains radial glia, a class of progenitor cell that divides to produce neurons and later glial cells through a series of symmetric and asymmetric cell divisions. Neurons born in the ventricular and subventricular zones of the cortex migrate along radial glial scaffolds to their final positions, assembling the six-layered cortical structure in an inside-out sequence: deeper layers form first, and later-born neurons migrate past them to populate more superficial layers. Dysregulation of this sequence through genetic mutations, environmental teratogens, or viral infection produces cortical malformations associated with epilepsy, intellectual disability, and autism spectrum disorder.

Adult Neurogenesis in the Hippocampus

In adult mammals, neurogenesis has been documented most thoroughly in the subgranular zone (SGZ) of the hippocampal dentate gyrus and in the subventricular zone (SVZ) adjacent to the lateral ventricles, where neurons migrate to the olfactory bulb. In the dentate gyrus, radial glia-like type 1 stem cells give rise to transiently amplifying progenitors, which differentiate into granule neurons over two to four weeks in rodents. New granule cells integrate into hippocampal circuits during a sensitive window in their early maturation and show enhanced synaptic plasticity compared to older neurons, which has led to proposals that they support pattern separation and the encoding of new episodic memories. The processes governing this progression are reviewed in a comprehensive survey of adult neurogenesis published in Cell, which covers the cellular stages from quiescent stem cell to mature neuron.

Regulation of Neurogenesis

Rates of adult neurogenesis are sensitive to a wide range of physiological and environmental variables. Physical exercise, environmental enrichment, and learning tasks increase hippocampal neurogenesis in rodents, while chronic stress, glucocorticoids, and aging decrease it. The Wnt signaling pathway, BDNF (brain-derived neurotrophic factor), and numerous transcription factors regulate the proliferation and survival of newborn neurons. Questions about the extent and functional significance of adult hippocampal neurogenesis in humans remain active areas of investigation; studies using postmortem tissue have produced conflicting findings about whether neurogenic activity persists substantially into adulthood in the human dentate gyrus. Research from PMC on adult neurogenesis and the promise of adult neural stem cells and recent work on hippocampal neurogenesis as a target for therapeutic intervention address these ongoing debates.

Applications

Neurogenesis has applications in a range of fields, including:

• Depression treatment research, where antidepressants including SSRIs increase hippocampal neurogenesis in rodents and may act partly through this mechanism
• Traumatic brain injury and stroke recovery, exploring whether endogenous neurogenesis can be augmented to repair damaged circuits
• Alzheimer's disease and dementia research, investigating whether impaired neurogenesis contributes to memory decline
• Cell therapy and regenerative medicine, using induced pluripotent stem cells to produce neurons for transplantation
• Oncology, studying how glioblastoma cells co-opt neurogenic signaling pathways for proliferation