What is needed is a more detailed understanding about the link between neural activation and blood flow. That suggests a relationship between cell populations, from brain cells to smooth muscle cells. (After all, it is the vasodilation or vasoconstriction of these encircling muscle cells that ultimately controls localized changes in blood flow, and thus the BOLD signal). That means understanding the mechanisms that can coax more energy out of the system . . . perhaps in reaction to some “depleting signal,” such as a loss of localized oxygen concentration, or a level below some critical threshold, or blood vessel involvement.
Happily, our understanding of this relationship is becoming clearer. It is now evident that there exists an array of switching mechanisms that can promote brain energy supply—some that use localized oxygen levels as their guide. Though the story is somewhat complicated, it is well worth the journey.
Figures 1 and 2 assist in understanding this biochemical mechanism. These data give just one view of the complex relationship between blood flow and neural activity and show both the enthusiasms—and the cautions—that one must deploy when interpreting fMRI signals.
Of astrocytes, glycolysis, and blood flow
Much of our story involves metabolic processes that occur in astrocytes. Astrocytes are an important member of the glial cell population, a community made up of about 90% of all cells in the brain.
For many years, glial cells were thought to play only a supporting structural role in brain biology (indeed, the word glial means “glue”). We don’t think that anymore, and the signal processing discussed below is a good example of why we’ve had to change our minds. Neurons need oxygen and glucose to function, and their delivery is regulated by glial cells. Astrocytes provide key metabolic support for busy neurons by increasing the availability of glucose and trafficking the energy supply through a vast network of connecting cells.
Our story begins by examining what happens to energy processing and vascular behavior under conditions when oxygen levels are low. Energy is derived from this activity via glycolysis (ie, the Embden-Meyerhof pathway).
Many important metabolic events are stimulated if localized oxygen levels drop below a certain threshold. Excess extracellular lactate levels rise, as do intracellular concentrations of adenosine(Drug information on adenosine). (This is because there is insufficient energy to make adenosine triphosphate [ATP], resulting in the accumulation of precursors).
It has recently been shown that what cells do with this surplus of lactate and adenosine assists in regulating blood flow to the area in which the surplus occurs. Indeed, these metabolic by-products have direct effects on the behavior of blood vessels. To help understand that relationship, we also need to review a few molecular facts about vasodilation and vasoconstriction.
Blood flow is obviously controlled by either relaxing or constricting local arterioles in the brain, which means interacting with the brain’s smooth muscle cells. One way to induce constriction in these cells is to increase calcium influx, which occurs via the muscle’s voltage-gated channels. If this entry is inhibited, the constriction does not occur. Predicting whether relaxation or dilation occurs depends in part on understanding the signals that regulate calcium entry into smooth muscle cells (Figure 1).
Prostaglandin is involved in these processes. Prostaglandin is made from arachidonic acid, itself generated from membrane lipids inside astrocytes. Prostaglandins are classic vasodilators and exert such power that their local concentrations have to be tightly regulated. This control is activated via transporter proteins embedded in cell membranes. Acting like finicky gatekeepers, these proteins can either allow prostaglandins entrance, which reduces their extracellular concentration, or keep them out, which elevates extracellular concentrations. Interestingly, these fin-icky gatekeepers need to be “bribed” (stimulated) to get them to work. This bribing occurs via a series of controlled molecular exchanges and plays an important part in our blood-flow controlling story.
Arachidonic acid by-products don’t always display vasodilating activity. If arachidonic acid does not convert to prostaglandin, you can get it to work like a vasoconstrictor. It has to hang around long enough to diffuse into the encircling smooth muscle cells. If it does, the acid becomes transformed into a derivative called 20-HETE, which has powerful vasoconstricting properties. The system thus works in a straightforward manner. Whether blood flow is increased or decreased depends on what the originating cell decides to do with arachidonic acid.
A critical question emerges: what causes arachidonic acid to be made from membrane lipids in the first place? The answer is: active neurons. It turns out that excitable neurons control their energy supplies by incessantly sending regulatory signals to their local supporting astrocyte network. These signals are carried via the neurotransmitter glutamate, which, when released from activated neurons, raises internal glial calcium ion concentrations. This rise in calcium stimulates astrocytes to synthesize arachidonic acid from their cell membranes. This role forms a critical molecular link between neural activation and blood flow.