Metabolic coupling during activation: A cellular view

A tight coupling exists between neuronal activity and energy metabolism. Over a century ago Roy and Sherrington postulated that “the brain possesses intrinsic mechanisms by which its vascular supply can be varied locally in correspondence with local variations of functional activity” (1). The modern functional imaging techniques such as Positron Emission Tomography (PET) with 15O-labelled water and the optical imaging approaches discussed in this book, have provided extensive documentation of such coupling, as well as valuable research and clinical tools. With remarkable insight Roy and Sherrington also proposed that “chemical products of cerebral metabolism” produced in the course of neuronal activation could provide the mechanism to couple activity with increased blood flow (1). We know now that potassium ions or neurotransmitters such as adenosine, noradrenaline, acetylcholine and Vasoactive Intestinal Peptide which, among others, are released by active neurons can increase local blood flow (2). Recently nitric oxide has also been proposed as a coupling agent between neuronal activity and blood flow (3). Evidence for a role of lactate and H+ have also been provided (2). While all the aforementioned agents may indeed play a role, it is fair to say that the precise mechanism(s) of neurovascular coupling are still debated. Regardless of the identity of the neurovascular coupling agent, the activity-linked increase in blood flow results in the delivery per unit time of more substrates, namely glucose and oxygen, necessary to meet the additional energy demands of the activated region. Indeed, increased local glucose utilization can be detected upon physiological activation, using PET for 18F-labelled 2-deoxyglucose (4). In contrast, mounting evidence indicates that oxygen consumption does not increase commensurately to glucose utilization during activation (5,6). This observation has led to the unexpected realization that during functional activation the brain resorts to the locally-restricted and transient glycolytic processing of the additional glucose taken up from the circulation (5,6).