Serotonin Is Required for Exercise-Induced Adult Hippocampal Neurogenesis

Abstract

Voluntary wheel running has long been known to induce precursor cell proliferation in adult hippocampal neurogenesis in rodents. However, mechanisms that couple activity with the promitotic effect are not yet fully understood. Using tryptophan hydroxylase (TPH) 2 deficient (Tph2-deficient) mice that lack brain serotonin, we explored the relationship between serotonin signaling and exercise-induced neurogenesis. Surprisingly, Tph2-deficient mice exhibit normal baseline hippocampal neurogenesis but impaired activity-induced proliferation. Our data demonstrate that the proproliferative effect of running requires the release of central serotonin in young-adult and aged mice. Lack of brain serotonin further results in alterations at the stage of Sox2-positive precursor cells, suggesting physiological adaptations to changes in serotonin supply to maintain homeostasis in the neurogenic niche. We conclude that serotonin plays a direct and acute regulatory role in activity-dependent hippocampal neurogenesis. The understanding of exercise-induced neurogenesis might offer preventive but also therapeutic opportunities in depression and age-related cognitive decline.

The role of serotonin in adult hippocampal neurogenesis

“…The mechanism of compensation could have significant clinical relevance for restoring serotonin homeostasis in models of disease. For Tph2 -/-mice, although no change in overall proliferation was detected, there is a deficiency in the transition from type-1 stem cells to type-2 progenitors with an altered balance of precursor cell proliferation and cell death rate, accompanied by changes in the number of Sox2-expressing cells (Klempin et al, 2013). We suggested population changes on the cellular level in the absence of serotonin as potential compensatory mechanism that maintains the progenitor cell pool and thus homeostasis in Tph2 -/-mice.…”

“…It is important to define serotonin's essential roles in brain function and behavior, as it is equally important to 3 discover the regulators and interactive pathways by which serotonin mediates brain function. In this regard, we have recently tested serotonin action in a loss-of-function model in which the availability of brain-derived serotonin is selectively depleted (Alenina et al, 2009, Klempin et al, 2013. These data together with others from genetically modified mouse models shed a distinct light on the mechanisms proposed in earlier studies to be reviewed here.…”

“…Elucidation of adult hippocampal neurogenesis revealed no measurable changes in baseline proliferation of precursor cells in mice that are almost devoid of brain serotonin (Tph2 -/-, VMAT2 SERT-Cre ) or with a drastic reduction in serotonin levels (Tph2KI, Pet1 -/-) (Diaz et al, 2013, Klempin et al, 2013, Sachs et al, 2013. Considering the results reviewed above on pharmacological depletion of serotonin signaling that leads to a decrease in neurogenesis, it is surprising that sustained neurogenesis can occur in the absence of serotonin.…”

Neural Mechanisms of Exercise: Effects on Gut Miccrobiota and Depression

“…Physical exercise has been recognized as one important approach to fight against mood disorders. The underlying mechanisms include adult hippocampal neurogenesis, alterations of brain blood perfusion, modulation of neuroinflammation, increased expression of neurotrophic factors in the brain, modulation of synaptic transmission and regulation of neurotransmitters such as serotonin [14][15][16][17][18][19][20][21][22]. Interestingly, a series of studies have shown the effects of physical exercise on gut microbiota dynamics, suggesting that gut microbiota regulation might act as one mediator for the effects of exercise on the brain.…”

“…Therefore the exercise-induced brain benefits might as well be modulated through gut microbiota changes. For instance, serotonin is required for running induced benefits on neurogenesis [16,17], while gut the major source of serotonin production in the body [37]; GF mice exhibited altered serotonin signaling as well as relevant behaviors [9,14,38], suggesting that GF mice might lack the benefits of exercise on neurogenesis. Future studies are required to systemically examine such possibilities.…”