While raising internal calcium concentrations will certainly give astrocytes lots of arachidonic acid, it hardly answers the question about control. What coaxes the arachidonic acid to take either the pathway toward relaxation or constriction? To answer, I need to return to the 2 molecules whose extracellular concentration rises in response to low oxygen levels, adenosine and the tightly regulated prostaglandin (Figure 2).
Adenosine levels rise in brain cells bathed in a low-oxygen environment (they can’t generate ATP). What neurons and astrocytes do with this excess adenosine is to treat it like any toxic waste: they transport it outside their cytosols. This transport to the extracellular compartment immediately exposes the adenosine to arteriole smooth muscle cells. The exposure has a remarkable effect. Excess adenosine prevents calcium from entering smooth muscle cells through their voltage-gated channels. The prevention of calcium into smooth muscle is interpreted by those cells as a “do not constrict” signal. The muscle obeys, and stays open for business. This naturally creates a change in blood flow.
But that’s not all that happens. Low oxygen concentrations create an increased presence of lactate and prostaglandins can be transported in and out of cells by finicky membrane-bound transporter proteins. I used the word “bribe” to describe an interesting exchange between lactate and prostaglandin. If there is a small amount of extracellular lactate, the cell is glad to exchange it for pros-taglandin, vacuuming up extracellular prostaglandins and forcing the vasodilator to reside in the cytosol. But it is a finicky gatekeeper. If there is too much extracellular lactate (as always exists in an oxygen-poor environment because of increased energy generation by glycolysis), the transporter refuses to keep up the exchange. As a result, prostaglandin is forced to stay outside.
And what does prostaglandin do in the extracellular space? Prostaglandin, the archetypal vasodilator, coaxes the arterioles to open up.
This is an extraordinary finding. Low concentrations of oxygen inhibit vasoconstriction (via excess extracellular adenosine) and simultaneously stimulate vasodilation (via excess extracellular prostaglandin). The link between energy use and arteriole diameter has an explanation at the molecular level.
Although these data support the notion that blood flow and neural activity are positively correlated, many questions about fMRI remain. Could the low levels of oxygen concentration that accompany neural activity perturb the astrocyte network with sufficient speed to generate the hemo-dynamic changes seen when using fMRI? The answer awaits further research. We know that there is a substantial delay (about 5 seconds) between neural activity and observed changes in blood flow.
Another question is more fundamental. How do we integrate this detailed blood-flow promoting system with some of the other data mentioned earlier—such as activity also capable of promoting vasoconstriction? And what about inhibition? Because of space limitations, I did not discuss other systems that can regulate blood flow and are also involved in glutamate metabolism (such as nitric oxide, a molecule also released by active neurons and possessing powerful blood-flow regulating capac-ities). The bottom line is that there appear to be many switching mechanisms. We are just beginning to characterize a few of them. A complete picture will have to involve a description of how all these switches interact.
This lack of data forms the core of why we must be cautious when interpreting fMRI. It is not as simple as saying increased blood supply means increased neural activity. Although many studies suggest a positive correlation, there is no full explanation of the relationship, which suggests a need for prudence.
I will have much more to say about being cautious when viewing fMRI data in the final installment on this topic. Noninvasive imaging, such as fMRI, is a great and powerful technology, but it provides no easy answers in our quest to understand how the brain processes information.