Research Blog

Serotonin is necessary for Exercise-Induced Cerebral Neurogenesis

the molecular structure of serotonin or 5-hydroxytryptamine


A recent study demonstrates that the neurotransmitter serotonin (structure on the right) is necessary for exercise-induced neurogenesis.  Interestingly, serotonin had no affect on baseline neurogenesis.






Before we dive into the importance of serotonin for exercise-induced cerebral neurogenesis, lets get some background information on the subject.

In 1999, Henriette van Praag and her colleagues at the Salk Institute (San Diego, CA, USA) showed that running induces cerebral neurogenesis in mice (Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus, 1999.  van Praag, et al.). Cerebral neurogenesis is the growth of new neurons in the brain, a process that was discovered only recently. The paper sparked a flurry of research into the mechanisms of cerebral neurogenesis. Since the paper was published, exercise-induced cerebral neurogenesis has been shown to require VEGF, a growth factor that produces new vasculature in the skeletal muscle in response to aerobic exercise. Earlier this year, an ingenious study published in the journal Cell demonstrated human cerebral neurogenesis by looking at carbon isotope density in post-mortem human hippocampus samples (Dynamics of Hippocampal Neurogenesis in Adult Humans, 2013.  Spalding, et al.). Nuclear bomb testing in the middle to the 20th century altered atmospheric Carbon-14 levels in a time-dependent manner. The authors exploited the changes in atmospheric Carbon-14 to measure the development of new neurons in the hippocampus during adulthood. A graphical abstract of the human neurogenesis study is shown below.

human hippocampal neurogenesis using radioactive carbon labeling from nuclear testing

A recent study published in the Journal of Neuroscience demonstrated that serotonin (also known as 5-hydroxytryptamine) is necessary for exercise-induced cerebral neurogenesis (Serotonin Is Required for Exercise-Induced Adult Hippocampal Neurogenesis, 2013. Klempin, et al.). Serotonin is a monoamine neurotransmitter that has been linked to depression. Many anti-depressant medications work by fixing serotonin imbalances within the brain. It is believed by some researchers that serotonin’s role in regulating neurogenesis may be the link between exercise and depression. Exercise is often used as a substitute for anti-depression medication. While the aforementioned study successfully showed that serotonin is a necessary link between exercise and cerebral neurogenesis in mice, the full role that serotonin plays in mediating exercise’s anti-depressant effects is unknown.

To show serotonin is necessary for exercise-induced cerebral neurogenesis, tryptophan hydroxylase 2 (Tph2) was knocked out in the experimental group of mice. Tph2 is an enzyme required for serotonin synthesis. Therefore, it is not surprising that mice genetically engineered to be deficient in Tph2 (Tph2-/-) lack serotonin in the brain. To generate a running response, the mice ran voluntarily on running wheels for six days. Three different ages of mice were used: 42 days of age (P42), 80 days of age (P80) and one year of age. The figure below demonstrates the differences in neuronal proliferation using BrdU labeling. Surprisingly, no significant difference in neurogenesis was measured between wild-type (WT) and Tph2 deficient mice. However, running increased neural proliferation in the wild-type mice, but not the Tph2 deficient mice.

Lack of serotonin prevents the neurogenesis proliferation effect of running.

The authors also eluted a mechanism. It was found that at baseline, before running, the Tph2-/- mice had increased density of GFAP-/Sox2+ cells, a neural stem cell. However, this measurement was reversed after running.  Furthermore, microglia activity was increased in the Tph2-/- mice. Microglia are cerebral scavengers, removing dead cells. This suggests that the mice lacking serotonin had increased apoptosis (cell death) of their neural stem cells. By producing more stem cells, the serotonin-deficient mice could compensate for the increase in stem cell apoptosis to maintain wild-type levels of cerebral neurogenesis at baseline. However, this strategy was insufficient for compensating for the increased neurogenesis that occurs with exercise in wild-type mice.

This study is the first to demonstrate that serotonin is necessary for exercise-induced cerebral neurogenesis. More research will be needed to determine what other agents link exercise, neurogenesis and depression. In the future, alternative treatments may be available for patients suffering from depression or neurodegenerative diseases.

Physical and Mental Activity Together Best Protect the Aging Brain


Physical activity exerts its greatest anti-aging effects on the brain when performed in conjunction with a cognitive activity (such as sightseeing, as these cyclists are doing on the right).








 

Numerous studies have shown exercise reduces age-related brain degeneration.  Many of these studies have been discussed on Exercisemed, including the effects of physical activity on Alzheimer's and our telomeres. Furthermore, physical activity has been found in mouse models to enhance cognitive ability and memory. However, new research is finding that other factors can confound the cerebral effects of exercise. One of the problems with good scientific experiments is that every outside variable is fully controlled. By controlling these outside variables, researchers are able to isolate changes to the single, experimental variable. In exercise physiology research this means that physical activity is performed under strict supervision on a mundane treadmill. This is true for both human and animal studies.  

Yet in the natural world, animals (humans are the one exception) never find themselves exercising on a treadmill. Physical activity is performed in conjunction with cognitive tasks, such as scouring for food or exploring unknown territory. A recent review appearing in the Journal of Sleep Medicine highlights importance of "getting out and about" on maintaining neuroplasticity (Exercise benefits for the aging brain depend on the accompanying cognitive load: insights from sleep electroencephalogram, 2013.  Jim Horne).

Sleep Electroencephalogram 

sleep EEG

Researchers can use sleep electroencephalogram (EEG) to measure various markers of neuroplasticity in subjects while they sleep. Neuroplasticity is a measure of how malleable the brain is. For example, new synaptic connections are made to generate memories in the hippocampus. As we age, neuroplasticity decreases, which is one potential explanation for why the elderly have impaired memory capabilities. The research presented in the aforementioned paper suggests that physical activity performed with cognitive tasks that require curiosity and analysis can have a greater effect on the aging brain than physical activity or cognitive challenges by themselves.

In a world where physical activity is increasingly being pursued in static environments (i.e. on a treadmill or cycling machine), it may be advisable to move our exercise habits in the opposite direction. There are many ways for achieving a simultaneous physical and mental workout. Instead of sightseeing from the car, explore a new place while on your bike. Go trail running, kayaking, hiking, even window shopping. Please share how you like to challenge yourself physically and mentally in the comments section to the left.

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