Exercise makes your brain bigger: skeletal muscle VEGF and hippocampal neurogenesis

The hippocampus plays an important role in learning and memory. Unlike most brain cells (whose numbers are fixed before birth), thousands of new hippocampal granule cells continue to be generated every day throughout adult life. Performance in behavioural tasks is positively correlated with neurogenesis in the dentate gyrus, whereas inhibition of neurogenesis impairs learning tasks, which supports the concept that hippocampal neurogenesis contributes to learning and memory (Cameron & Glover, 2015).

The newly formed hippocampal neurons face several possible fates: some die within a few weeks, but others go on to form synaptic connections and integrate into existing hippocampal circuits. Both the rate of neurogenesis and the probability of cell survival are strongly regulated by environmental factors and experience. Hippocampal volume decreases 1–2% per year in older adults, which is thought to contribute to age‐related decreases in neural function. On the other hand, performance of learning tasks can prevent the death of new hippocampal neurons. Recently, much attention has been focused on the role of exercise as a stimulus for hippocampal neurogenesis. Regular aerobic exercise improves neurocognitive functions such as attention, memory, information processing speed and cognitive flexibility in normal adults, and lowers the risk or slows the progression of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Hippocampal volume is increased by exercise: training increases the numbers of neuronal precursor cells and promotes their commitment to a neuronal‐specific lineage. It is proposed that the increased levels of hippocampal angiogenesis and neurogenesis induced by exercise may underlie the beneficial effects of physical activity on neural function.

The mechanism by which exercise promotes hippocampal neurogenesis remains unclear. Exercise increases the hippocampal levels of several growth factors, including brain‐derived neurotrophic factor (BDNF), insulin‐like growth factor 1 (IGF‐1) and vascular endothelial growth factor (VEGF): IGF‐1 and VEGF are thought to mediate hippocampal neurogenesis and angiogenesis. Yet, the link between the exercising muscle and the hippocampus has not been clearly established.

The dentate gyrus of the hippocampus is a highly vascularised environment, and both IGF‐1 and VEGF can cross the blood–brain barrier. IGF‐1 and VEGF are increased in the periphery during exercise: peripherally added VEGF stimulated hippocampal neurogenesis, whereas peripheral block of VEGF inhibited exercise‐induced hippocampal neurogenesis (Fabel et al. 2003), leading to the suggestion that hippocampal neurogenesis may be stimulated by growth factors of peripheral origin. In their study in the current issue of The Journal of Physiology, Rich et al. (2017) investigated whether VEGF released by skeletal myofibres contributed to exercise‐induced hippocampal proliferation: the group compared the effects of exercise training between adult conditional skeletal‐myofibre‐specific VEGF gene‐ablated mice (VEGF^HSA−/−) and non‐ablated (VEGF^f/f) littermates.

VEGF gene ablation reduced skeletal muscle VEGF content, in agreement with previous reports suggesting that myofibres contribute most of the VEGF content of muscle, and it also prevented the increase in muscle VEGF induced by exercise training in normal mice.

Myofibre‐specific VEGF knockout has previously been shown to reduce muscle capillarity in developing animals, and to inhibit both the increase in muscle oxidative capacity and the angiogenic response to exercise training in adult animals, although pre‐training capillarity was maintained in the adults (Delavar et al. 2014). In agreement with this, Rich et al. (2017) also found that the VEGF gene‐ablated mice were unable to improve their exercise performance, despite performing a similar voluntary training regime to their normal littermates.

Importantly, in their current study, Rich et al. found that the number of neuronal precursor cells in the dentate gyrus, defined as those cells expressing both the proliferation marker bromo‐deoxyuridine and the neuronal precursor cell marker nestin, was increased by exercise training in VEGF^f/f mice, but not in VEGF^HSA−/−, suggesting that skeletal myofibre‐derived VEGF plays an important role in stimulating hippocampal neurogenesis. However, it was not possible to determine whether myofibre‐derived VEGF entered the hippocampus: resting hippocampal VEGF was similar between the groups, and myofibre VEGF‐null mice could not sustain a sufficiently high exercise intensity to elevate hippocampal VEGF. Previous studies investigating whether VEGF expression within the hippocampus was enhanced by exercise training have produced contradictory findings (Fabel et al. 2003; Tang et al. 2009). Hippocampal blood flow was substantially lower in the myofibre VEGF‐null mice (Rich et al. 2017), although this did not appear to result from decreased angiogenesis in the dentate gyrus, since the number of new endothelial cells (defined as CD31+/BrdU+ cells) was similar in the two groups. However, it may indicate that adequate hippocampal blood flow is a necessary prerequisite for neurogenesis.

The exact role of the myofibre‐derived VEGF in stimulating hippocampal proliferation therefore remains unclear, and a number of explanations are plausible: (1) VEGF released from exercising myofibres may enter the brain and directly stimulate neurogenesis; (2) myofibre VEGF may stimulate the release or activation of other regulatory factors or metabolites that travel to the hippocampus to stimulate neurogenesis; (3) myofibre VEGF (or another factor regulated by myofibre VEGF) may stimulate skeletal muscle afferent nerve activity, which may play a role in stimulating cerebral neurogenesis; or (4) neurogenesis may be regulated by hippocampal blood flow, which is in turn regulated directly or indirectly by myofibre‐derived VEGF through any of the above‐mentioned mechanisms. It is therefore of crucial importance to determine whether or not the myofibre‐derived VEGF enters the hippocampus, in order to advance our understanding of its role.