Adult Neurogenesis and Mood Regulation | René Hen & Alain Prochiantz

Ketamine, traditionally known as an anesthetic and party drug, has emerged as a revolutionary treatment for treatment-resistant depression because it works differently from conventional antidepressants by promoting rapid synaptic regrowth and neural repair, producing significant mood improvement within hours to days compared to the weeks or months required by traditional antidepressants, with response rates of 50-80% versus 10-20% for standard medications.

Depression involves extensive astrocyte pathology affecting all four critical steps of glutamate trafficking: release, receptor expression, receptor trafficking, and glial-neuronal communication. Excess glutamate activates microglia, triggering pro-inflammatory cytokine production (IL-6, TNF-alpha, IL-1beta) that destroys synaptogenesis and neuronal plasticity. This explains why traditional antidepressants with 1% improvement rates have failed since the 1950s. Ketamine works paradoxically as an NMDA antagonist that paradoxically increases glutamate release, triggering AMPA receptor activation, BDNF elevation, mTOR activation, PSD-95 activation, and GSK-3 inhibition. Single infusions achieve response rates comparable to eight weeks of traditional antidepressants within 2-4 hours. Meta-analyses confirm statistically significant reductions in suicidal ideation, representing a paradigm shift toward viewing depression as a disorder of synaptogenesis and neuroplasticity rather than primarily a monoamine deficiency disorder.

Modern research suggests depression involves inflammatory processes: systemic inflammation activates cytokines that cross the blood-brain barrier, microglia activation occurs, tryptophan metabolism shifts toward kynurenine pathway reducing serotonin, and glutamate dysregulation causes excitotoxicity. Advanced treatments include anti-TNF monoclonal antibodies, transcranial magnetic stimulation, vagus nerve stimulation, deep brain stimulation, ketamine therapy, and psychedelic research.

The discovery of ketamine's antidepressant effects emerged from challenges to the monoamine hypothesis. Research showed that serotonin and catecholamine depletion alone do not induce depression in healthy individuals, suggesting pathology resides in higher brain centers like the cortex and limbic system. Since glutamate is the primary excitatory neurotransmitter in these regions, researchers investigated glutamatergic systems as alternative targets, ultimately leading to ketamine's discovery as a rapid-acting antidepressant.

The cytokine or inflammatory hypothesis proposes that depression is linked to systemic inflammation rather than purely brain chemistry imbalances. This theory is better supported by medical evidence than the traditional monoamine hypothesis. From an evolutionary perspective, inflammation would have prompted rest, isolation, and healing—symptoms aligning with depression. Modern chronic low-grade inflammation creates ongoing depressive symptoms because our bodies remain in a perpetual stress response. Physical conditions like Hashimoto's thyroiditis can present with bipolar-like symptoms (mania during hyperthyroid states, depression during hypothyroid states), demonstrating how physical imbalances masquerade as mental illness and can be resolved through proper diagnosis and treatment.

Several lifestyle factors significantly impact hippocampal neurogenesis: chronic stress decreases neurogenesis and contributes to depression-like behaviors; aging naturally reduces neurogenesis rates; however, these effects can be mitigated through healthy lifestyle choices including exercise, proper sleep, and balanced nutrition.

Multiple evidence-based strategies enhance neurogenesis: (1) Exercise increases both new neuron production and survival, counteracting age-related decline; (2) Positive environments with social stimulation and sensory experiences promote neurogenesis; (3) Stress and depression reduce new neuron production and survival; (4) Diet matters—zinc, resveratrol, omega-3s, flavonoids, and curcumin increase neurogenesis while alcohol, sugar, and deficiencies decrease it; (5) Learning new things, adequate sleep, and social interaction all support neurogenesis. New neurons activate 4-8 weeks after creation, suggesting starting learning activities weeks before exams optimizes retention.

The adult brain can generate new neurons in the hippocampus, a region critical for learning, memory, and emotional regulation; this neurogenesis can be enhanced through learning, exercise, calorie restriction, intermittent fasting, flavonoid-rich foods, and omega-3 fatty acids, while being reduced by stress, sleep deprivation, saturated fats, and alcohol, with implications for memory improvement, mood regulation, and prevention of age-related cognitive decline.

Research has established significant links between neurogenesis and neurological conditions. Alzheimer's disease is associated with reduced newborn neuron production in the hippocampus, potentially contributing to memory impairment. Similarly, depression correlates strongly with decreased neurogenesis, while sleep deprivation impairs the survival of newborn neurons. Aging naturally reduces both neural stem cell populations and neurogenesis rates. However, lifestyle interventions offer promising ways to enhance neurogenesis: engaging in continuous learning challenges the brain and stimulates new neuron production; regular exercise activates neural stem cells and increases neuronal generation; exploring novel environments further promotes neurogenesis. Combining exercise with learning maximizes benefits, as learning enhances the survival of newborn neurons.

Adult neurogenesis occurs in specific brain regions including the dentate gyrus of the hippocampus and the lateral ventricle lining. Stem cells continuously produce new cells that migrate to the olfactory bulb or remain in the dentate gyrus. This phenomenon was controversial in humans, with 2018 research suggesting it only occurs until age 13, but later refuted by 2019 studies showing neurogenesis persists up to age 73. Neurogenesis exists across many vertebrate species including primates and humans. The laboratory developed methods for whole-brain 3D imaging using optical clearing with organic solvents, producing permanent samples maintaining fluorescence for at least three months. This revealed unexpected patterns of dividing cell distribution including distinct bands suggesting new migration pathways. Image registration is a mathematical process that aligns multiple 3D brain samples by warping different parts of images to match each other, enabling comparison of samples from different animals or time points. By overlaying registered samples from different time points, researchers create pseudo-4D images showing dynamic processes like cell migration. Analysis revealed migration pathways are heterogeneous, with the posterior two-thirds showing both proliferation and migration while the anterior one-third shows only migration without proliferation. In developing brains, neurogenesis differs from adult neurogenesis: migration takes longer (10 days), the entire rostral migratory stream is proliferative, and cells migrate from the external germinal layer to the cerebellum. Whole-brain imaging revealed that cerebellar folia form through discrete patches that appear only genetically (detected by zebrin protein) and not morphologically. Counting cells in whole-brain 3D images is challenging due to overlapping cells and varying fluorescence. The laboratory developed an algorithm called 'Corgi' using multiple filtering steps for automated cell counting, validated to be more accurate than manual counting or other automated methods. The methods can be applied to study gene expression patterns in the whole brain after inducing behavioral models. Segmentation divides 3D brain images into anatomical structures by registering samples to reference brain atlases like the Allen Brain Atlas. The hippocampus has distinct subregions (dorsal, ventral, intermediate) with different functions. Molecular topography uses gene expression patterns to define these boundaries, as morphological atlases cannot precisely define these regions. Memantine, used for Alzheimer's treatment, induces neurogenesis in the dentate gyrus, demonstrating that pharmacological agents can modulate adult neurogenesis.

Confirming adult neurogenesis in humans required overcoming significant technical and conceptual challenges. Steve Goldman's 1990s work demonstrated that cultured temporal lobe tissue could generate neurons in vitro. Frank Gage's landmark study used post-mortem brains from BrdU-treated patients, identifying cells expressing both neuronal markers (NeuN) and BrdU, proving new neuron formation in the adult hippocampus. Building on this, researchers obtained surgical specimens from the human sub-ventricular zone and discovered that purified astrocytes from this region form neurospheres capable of differentiating into neurons, oligodendrocytes, and astrocytes. Critically, single SVZ astrocytes could generate neurons without exogenous growth factors, while cortical and striatal astrocytes failed to do so. This demonstrated unique properties of SVZ astrocytes and established the existence of functional neural stem cells in the adult human brain.

Neural stem cells maintain a homeostatic equilibrium between quiescent and activated states, residing in neurogenic niches such as the subventricular zone and subgranular zone of the hippocampus, where they undergo symmetric and asymmetric division to generate neural progenitors that migrate and differentiate into neurons, astrocytes, and oligodendrocytes; while adult neurogenesis in humans was historically controversial, evidence now confirms its existence but demonstrates significant age-related decline and pathological reduction in Alzheimer's disease, with neurogenesis markers progressively decreasing from age 40 and being nearly absent in advanced Alzheimer's patients.

The scientific community once believed adult humans couldn't generate new brain cells, leading to warnings about brain injury prevention. However, research since 1998 revealed that the adult hippocampus does produce new neurons. A landmark study in Nature Medicine confirmed this neurogenesis continues into late adulthood, finding thousands of young neurons even in 87-year-old brains. Researchers detected these new cells using doublecortin (DCX), a protein expressed during neuronal development. Previous studies underestimated neurogenesis partly because older brain specimens degraded over time in storage, making detection difficult. This discovery challenges fundamental assumptions about brain plasticity and opens possibilities for treating neurological conditions like Alzheimer's.