This page deals primarily with those molecules produced from exercise which effect the brain. Many studies have suggested that the parts of the brain that control thinking and memory (the prefrontal cortex and medial temporal cortex) have greater volume in people who exercise versus people who don’t.
BDNF --brain-derived neurotrophic factor
BDNF is an endogenous neuropeptide that activates the TrkB(Tropomyosin receptor kinase B) receptor. The neurotrophins that activate TrkB are: BDNF (Brain Derived Neurotrophic Factor), neurotrophin-4 (NT-4, also known as NT-4/5), and neurotrophin-3 (NT-3). The activation of Trk receptors by neurotrophin binding may lead to activation of signal cascades resulting in promoting survival and other functional regulation of cells. Below is a molecular model (style-cartoon) showing the two subunits of neurotropin-4 bound to the fifth subdomain of TrkB (see Reference 13 below).
CRYSTAL STRUCTURE OF TRKB-D5 BOUND TO NEUROTROPHIN-4/5
BDNF is also active in the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses. In the brain, it is active in the hippocampus, cortex, and basal forebrain. BDNF plays a significant role in neurogenesis. BDNF can promote protective pathways and inhibit damaging pathways in the NSCs and NPCS that contribute to the brain’s neurogenic response by enhancing cell survival.
"...Findings from both rodent and human studies suggest brain-derived neurotrophic factor (BDNF) as a potential mechanism of the effect of acute exercise on memory. significant associations have been observed between acute exercise-induced changes in pBDNF concentration and cognitive performance in studies assessing memory, and non-significant associations have been found in studies assessing non-memory cognitive domains..." (Reference 9)
Endorphins - β-Endorphin
"Most studies have demonstrated that serum concentrations of endogenous opioids, in particular beta-endorphin and beta-lipotrophin, increase in response to both acute exercise and training programs. Elevated serum beta-endorphin concentrations induced by exercise have been linked to several psychological and physiological changes, including mood state changes and 'exercise-induced euphoria', altered pain perception, menstrual disturbances in female athletes, and the stress responses of numerous hormones (growth hormone, ACTH, prolactin, catecholamines and cortisol). Many reports have described a role for the endorphin response as seen during exercise and have used the opioid receptor antagonist, naloxone, to investigate and verify the degree of involvement of the opioids." (Reference 7)
β-Lipotropin is a 90-amino acid polypeptide that is the carboxy-terminal fragment of POMC. β-Lipotropin stimulates melanocytes to produce melanin, and can also be cleaved into smaller peptides. In humans, γ-lipotropin, β-MSH, and β-endorphin, are all possible fragments of β-lipotropin. Evidence shows that β-Lipotropin is metabolized into endorphins that can greatly affect mood and behavior and is thus regarded as a prohormone.
Ketones -Runners’ brains contain high levels of ketones, which are a byproduct of the breakdown of fat. During strenuous exercise, the body relies in part on fat for fuel and winds up creating ketones, some of which are tiny enough to cross the blood-brain barrier. The brain uses these ketones for fuel when blood sugar levels grow low. But it appears that ketones also cause the molecules that hinder the BDNF gene to become more active. In a paper by Moses Chao (Reference 1) evidence is provided that an endogenous molecule, DBHB (D-β-hydroxybutyrate), that crosses the blood brain barrier, is increased by physical exercise. They provide a mechanism demonstrating that exercise induces the accumulation of the ketone body DBHB in the hippocampus, where it serves both as an energy source and an inhibitor of class I histone deacetylases (HDACs) to specifically induce BDNF expression. (Reference 1).
Irisin--FNDC5 (and the irisin created from it) was responsible for exercise-induced benefits to the brain—in particular, increased levels of a crucial protein called brain-derived neurotrophic factor (BDNF), which is essential for maintaining healthy neurons and creating new ones. (Reference 4). Although there was a debate on the work in Reference 4 a follow-up studied appears to have demonstrated the existance of the irisin (See Reference 10)
Dopamine (DA), noradrenaline (NE), and serotonin (5-HT) are the three major monoamine neurotransmitters that are known to be modulated by exercise. All three share common activation mechanism mediated through G protein-coupled receptors (GPCRs). It is important to note that DA, NE and 5-HT receive reciprocal regulation from each other. For instance, 5-HT enhances DA release through the 5-HT4 receptors. The stimulation of the monoamine system is dependent on exercise intensity. Treadmill exercise and voluntary wheel running are the two most common forms of exercise used in rodent models with different exercise intensities. Treadmill exercise is more effective in enhancing the muscle aerobic capacity and in increasing the serum corticosterone level than that of wheel-running exercise. See Reference 11 for extensive review.
Dopamine--Endocannabinoids and opioids can indirectly activate dopamine cells of the ventral tegmental area (the VTA, a key portion of the pleasure circuit). We know that exercise can be addictive and that other substances and behaviors that are addictive have increased dopamine release in VTA target regions as a common property. In rats, sustained wheel-running can cause dopamine release in the nucleus accumbens and other VTA target regions. Rats also show some signs of exercise addiction . (See Reference 12). See the Dopamine Molecule
Norepinephrine -- In addition to stress resistance, NE also participates in commanding the consolidation and retrieval of memory, especially emotional memory. See the Norepinephrine Molecule
Serotonin--Several lines of research suggest that exercise increases brain serotonin function in the human brain. In addition to antidepressant and anxiolytic properties, 5-HT system has also been linked to cognitive function. See the Serotonin Molecule
It has been shown that aerobic exercise causes an increase in plasma anandamide levels, where the magnitude of this increase is highest at moderate exercise intensity ( i.e., exercising at ~70–80% maximum heart rate). Increases in plasma anandamide levels are associated with psychoactive effects because anandamide is able to cross the blood–brain barrier and act within the central nervous system. (14) Thus, because anandamide is a euphoriant and aerobic exercise is associated with euphoric effects, it has been proposed that anandamide partly mediates the short-term mood-lifting effects of exercise (e.g., the euphoria of a runner's high) via exercise-induced increases in its synthesis (14).
Readings and References
14-Tantimonaco M, Ceci R, Sabatini S, Catani MV, Rossi A, Gasperi V, Maccarrone M (2014). "Physical activity and the endocannabinoid system: an overview". Cell. Mol. Life Sci. 71(14): 2681–2698.