When having the nerve is helped by having the muscle

Suppose just now you had picked up this journal, flipped it open and started to read this article. When this started to happen we might assume that there would be some physiological changes in the brain to support this extra brain work and indeed neuroscientists can now put together a rather plausible description of what they might be. On the basis of evidence from the study of the brain, not only in vitro, but also in vivo, with tools like positron emission tomography and magnetic resonance spectroscopy, the story goes something like this. The arousal associated with reading and making sense of the words would have activated various areas of your brain and the fuel metabolism of neurons (and almost immediately of astrocytes also) would have increased to support the increased nervous activity. Release and re-uptake of neurotransmitters, and pumping of ions across cell membranes and between sub-cellular compartments is energetically expensive. Accordingly, soon after an activating stimulus it is possible to detect markedly increased glycolytic lactate production, probably occurring almost exclusively in astroglia in response to glutamate stimulation, followed by a rise in accumulation of extracellular lactate, then a fall as it is taken up and oxidised completely in neurons. The initial burst of glycolysis probably takes place at the expense of blood glucose transported rapidly through the blood-brain barrier, but there is a substantial back-up of astroglial glycogen which can be used if the demand exceeds the supply of glucose for a variety of reasons (or if there is hypoxia when glycolysis is the only energy-producing process).

Now, normally, it is very difficult to detect any of these metabolic events by observing inflows to and outflows from the brain via the blood. Most physiology textbooks until recently taught that brain blood flow did not change under any but extreme circumstances – and then only in one direction – down. In fact there can be large local changes in blood flow and oxygen consumption, but the local metabolic disturbances are buffered, as it were, by the large unperturbed quiescent mass of the brain, and they do not show up as, for example, arterio-venous (A-V) O₂ differences.

A paper by Ide et al. published in this issue of The Journal of Physiology provides a fascinating example of alterations of brain metabolism which probably involve major modifications to the general processes described above. The aim of the study carried out by the authors was twofold. First, to re-examine the extent of glucose and oxygen uptake by the brain, to confirm or deny earlier inconclusive reports, and second, in the light of both our new understanding of the importance of lactate as a neuronal fuel and the known marked increase in availability in blood of lactate effluxing from working muscles, to determine whether the brain used this lactate during strenuous exercise, as the authors hypothesised it would.

To test their hypothesis they persuaded six young men to cycle in a semi-recumbent position with cannulae for sampling placed in an artery and also in the jugular vein. The subjects cycled at a progressively increasing rate to exhaustion, which occurred after about 10 min.

The results demonstrated conclusively that the A-V concentration difference of glucose was not changed, but that lactate A-V difference increased dramatically; the A-V oxygen difference rose by about 16% but this failed to reach significance. After exercise, lactate uptake continued to be high for 30 min afterwards. Immediately after exercise, oxygen consumption actually increased to a value significantly above the resting value before gradually returning to normal. The A-V difference in glucose suddenly increased immediately after exercise and then declined.

One of the difficulties of interpreting these data is the lack of information on jugular vein blood flow, which is needed to make a true metabolite mass uptake calculation. However, it is possible to minimise the interpretative problem by relating the metabolite concentration differences to oxygen content – the so-called oxygen quotient method. When Ide et al. did this it was apparent that the amount of oxygen used per six carbon atoms (i.e. per mole of glucose equivalents) fell during exercise and fell further afterwards. The authors interpret this as evidence of activation by exercise of brain metabolism of exogenous lactate, probably oxidatively, and then, during recovery, stimulation of glucose uptake to replenish stores of glycogen presumably depleted during exercise. This of course is also an energy-requiring process, possibly explaining the continued high metabolic rate. If the astroglial glycogen stores were depleted by exercise, then the amount of lactate taken up and oxidised may be an underestimate.

The cerebral circulation is very reactive to blood carbon dioxide concentration, which increases during mild exercise and falls during strenuous exercise. Ide et al. suggested that in their study cerebral blood flow might have fallen, given the changes in carbon dioxide, but it may be that they are being too cautious. There is now substantial evidence that the control of cerebral blood flow by carbon dioxide may be overridden during strenuous exercise, which if true would make it easier to accept an oxidative fate for the lactate taken up during and possibly after exercise.

What drives this substantial increase in lactate utilisation? Ide et al. believe that brain activation of lactate uptake requires brain activation, since they could not obtain increased uptake of lactate by rat brain simply by increasing availability. However, this may not be a robust conclusion, since uptake of lactate in response to increased availability has been observed in a number of different circumstances, in both human and animal brains. (By the way, it causes panic attacks in some individuals, possibly explaining the reaction of some sensitive souls to school PE.) Nevertheless the lack of any post-exercise washout of lactate does suggest its complete disposal, and while it may have been used to help replete glycogen post exercise this fate is unlikely during exercise-induced activation. The authors themselves point out that brain activation is a controversial topic, without much persuasive evidence. Unfortunately, at the time of review neither they, nor this editor knew that a paper, providing this evidence rather convincingly, had been published in this very journal (Williamson et al. 1997). This group used magnetic resonance imaging and single photon emission computed tomography to demonstrate activation of regional blood flow to the left insular cortex during volitional (as opposed to passive) cycling. So it all fits: your brain turns on your muscles, which fuel your brain. Clever.