Neurogenesis Explained: How the Brain Grows New Neurons

The Discovery of Adult Neurogenesis

For most of the twentieth century, neuroscience operated under the dogma that the adult brain could not produce new neurons. Santiago Ramon y Cajal, the founder of modern neuroscience, declared that in the adult brain, nerve paths are fixed and immutable, a view that persisted largely unchallenged for decades. The first evidence against this dogma came from Joseph Altman in the 1960s, who used radioactive thymidine labeling to show new neuron production in the rat hippocampus, but his findings were largely ignored by the scientific community because they contradicted the prevailing paradigm.

The modern era of adult neurogenesis research began in the 1990s when Fernando Nottebohm demonstrated seasonal neurogenesis in songbirds, showing that new neurons were functionally integrated into circuits controlling song learning. Shortly after, Elizabeth Gould demonstrated adult neurogenesis in the primate hippocampus, and Fred Gage's laboratory showed that new neurons are born in the human hippocampus throughout life, using bromodeoxyuridine (BrdU) labeling in cancer patients who had received the compound as part of their treatment. A landmark study by Kirsty Spalding used carbon-14 dating from atmospheric nuclear testing to confirm that approximately 700 new neurons are added to the adult human hippocampus each day, a rate that declines with age but persists into old age.

Where Neurogenesis Occurs

In the adult mammalian brain, neurogenesis has been conclusively demonstrated in two regions. The subgranular zone of the hippocampal dentate gyrus produces new granule cells that migrate a short distance into the granule cell layer and integrate into hippocampal circuitry. The subventricular zone lining the lateral ventricles produces neural progenitor cells that migrate along the rostral migratory stream to the olfactory bulb, where they differentiate into interneurons involved in odor processing. In rodents, the olfactory neurogenesis is robust and well-characterized, though its extent in the adult human brain remains debated.

Whether neurogenesis occurs in other adult brain regions remains a topic of active investigation and controversy. Some studies have reported evidence of new neuron production in the neocortex, striatum, and amygdala, but these findings have been difficult to replicate consistently, and the extent and functional significance of any non-canonical neurogenesis remain uncertain. The question of whether human adult hippocampal neurogenesis itself persists at meaningful levels has also been debated, with a high-profile 2018 study by Sorrells and colleagues finding little evidence of new neurons in adult human hippocampal tissue, while subsequent studies by other groups using different methods confirmed ongoing neurogenesis. Methodological differences in tissue preparation, antibody selection, and detection sensitivity likely account for much of the discrepancy between studies.

The Biology of New Neuron Development

Adult neurogenesis recapitulates many aspects of embryonic neuron development within the mature brain environment. Neural stem cells in the subgranular zone divide asymmetrically to produce one daughter cell that remains a stem cell and one that becomes a transit-amplifying progenitor. These progenitors undergo several additional divisions before differentiating into immature neurons, or neuroblasts, that extend dendrites into the molecular layer and an axon along the mossy fiber pathway to the CA3 region of the hippocampus. The maturation process takes approximately four to eight weeks, during which the new neurons progressively develop adult electrophysiological properties and synaptic connections.

Not all newly born neurons survive to maturity. Approximately 50 to 80 percent of new neurons die through programmed cell death within the first few weeks of their existence, a selection process that is influenced by neural activity and behavioral experience. Neurons that receive synaptic input and are activated during learning are more likely to survive, while those that fail to integrate into functional circuits are eliminated. This activity-dependent selection ensures that new neurons are incorporated into circuits that are actively processing behaviorally relevant information, making the survival of new neurons contingent on their functional utility.

What Regulates Neurogenesis

Numerous factors modulate the rate of adult hippocampal neurogenesis. Physical exercise, particularly aerobic activity such as running, is one of the most potent positive regulators, increasing neurogenesis by two to three fold in rodent studies through mechanisms involving increased blood flow, elevated brain-derived neurotrophic factor (BDNF) production, and enhanced growth factor signaling. Environmental enrichment, which provides novel objects, social interaction, and opportunities for exploration, also promotes neurogenesis and the survival of new neurons, suggesting that cognitive stimulation and novelty support the production and integration of new cells.

Chronic stress and elevated glucocorticoid levels are among the most powerful negative regulators of neurogenesis, reducing both the proliferation of neural progenitors and the survival of new neurons. This relationship has implications for depression, as reduced hippocampal neurogenesis has been proposed as one mechanism contributing to the cognitive and emotional symptoms of major depressive disorder. Sleep deprivation also suppresses neurogenesis, while adequate sleep supports it. Aging produces a gradual decline in neurogenesis rate, though the process continues at reduced levels even in old age. Diet influences neurogenesis as well, with caloric restriction and diets rich in flavonoids and omega-3 fatty acids associated with enhanced new neuron production, while high-fat diets and excessive alcohol consumption reduce it.

Functions of New Neurons

New hippocampal neurons contribute to specific aspects of learning and memory. Because they have enhanced synaptic plasticity during their maturation period, approximately two to six weeks after birth, new neurons are particularly suited for encoding new memories and distinguishing between similar experiences, a computational function called pattern separation. Studies in which adult neurogenesis is selectively eliminated show impairments in tasks requiring the discrimination of similar contexts or locations, while tasks requiring simpler forms of spatial memory remain intact, suggesting that new neurons add a specific computational capability rather than simply supplementing existing circuits.

New neurons also play a role in forgetting, paradoxically promoting the clearance of old memories as they integrate into established circuits. The integration of new neurons into existing hippocampal networks disrupts previously stored synaptic patterns, weakening older memory traces and potentially making room for new learning. This neurogenesis-mediated forgetting may explain why infantile amnesia, the inability to remember events from early childhood, coincides with the period of highest hippocampal neurogenesis. The dual role of new neurons in both forming new memories and weakening old ones suggests that neurogenesis serves to keep the hippocampus optimized for new learning rather than simply accumulating information indefinitely.

Neurogenesis and Mental Health

The relationship between neurogenesis and depression has been an active area of research since the observation that many effective antidepressant treatments increase hippocampal neurogenesis. Selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed antidepressants, require several weeks to produce therapeutic effects, a timeline that coincides with the maturation period of new hippocampal neurons. Blocking neurogenesis in animal models attenuates some behavioral effects of antidepressants, suggesting that new neuron production contributes to their therapeutic mechanism, though it is likely not the only mechanism involved.

Stress-related reductions in neurogenesis may contribute to the hippocampal volume reductions observed in patients with major depression and post-traumatic stress disorder. Exercise, which robustly increases neurogenesis, also has well-documented antidepressant effects that are comparable to medication for mild to moderate depression. While the neurogenesis hypothesis of depression remains debated and is certainly an oversimplification of a complex disorder involving multiple brain systems, the connection between new neuron production, stress resilience, and mood regulation represents one of the most important translational implications of adult neurogenesis research. Future research aims to develop pharmacological approaches that can safely enhance neurogenesis in humans, potentially providing new treatments for depression, age-related cognitive decline, and neurodegenerative disorders in which hippocampal function is compromised.