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Deciphering cerebral blood flow to change the course of disease
Brain imaging techniques allow us to see the brain in action and, particularly, to visualize the changes in the activity of specific populations of neurons in an individual performing tasks such as looking at a picture, listening to music, smelling odors, reading, counting or sleeping. Literally, brain imaging sees the “brain at work” and identifies the exact regions involved in the execution of any given task. Brain imaging techniques are also widely used to look at the sick brain in pathologies such as Parkinson’s disease, Alzheimer’s disease, epilepsy, or stroke in order to get insight into the areas that are malfunctioning. There is convincing evidence showing that in action, but also at rest, a sick brain does not behave like a healthy brain.
In a broadly used approach to map changes in brain activity, scientists use brain imaging to look at the increased blood supply to activated areas as a surrogate marker of increased neuronal activity. This method is based on the fact that activated neurons require more nutrients from the blood stream, particularly glucose and oxygen, while performing a task as compared to neighboring neurons that are not ‘working’ and remain quiet. However, quite surprisingly, despite the universal use of vascular signals to map changes in brain activity under physiological and pathological conditions, the understanding of how changes in neuronal activity translate into changes in perfusion is still in its infancy.
Slightly more than five years ago, the idea that astrocytes (an abundant cell type in the brain that ensheaths synapses and blood vessels) could act as a relay to translate neuronal signals into vascular responses gained much attention. It is now thought that neurotransmitters released from activated neurons induce calcium signaling in astrocytes, which causes the astrocytes to synthesize and release vasoactive messengers from their perivascular endfeet directly onto blood vessels, thus triggering the increase in blood flow.
In my laboratory, we investigate at the cellular and molecular levels the mechanisms by which the main neurotransmitter systems control cerebral blood flow. More specifically, we investigate whether astrocytes can translate signals from excitatory and inhibitory neurons, which are both activated by any given stimulus. We use physiological stimulation paradigms to activate specific neuronal populations in combination with pharmacological approaches to block the synthesizing cells and chemical messengers under investigation, and directly observe the effects on cerebral blood flow. We also routinely isolate blood vessels in the brain to assess their function independent of the influence of neurons and astrocytes. Knowing the cellular basis of the perfusion signals is crucial to deciphering the alterations in cerebral blood flow seen in different disease states, as this may reflect changes in the health of the neurons, astrocytes or blood vessels themselves.
In Alzheimer’s disease, for instance, vascular pathology and chronic cerebral hypoperfusion develop early. Recent studies in mouse models of Alzheimer’s disease, including those from my laboratory, have shown that it is possible to rescue these deficits even at a very advanced stage of the disease. Although restoring blood supply to the brain does not repair the damaged blood vessels or neurons, it is undeniable that it allows for better functioning, which could improve patient outcomes and retard disease progression. The real challenge now is to identify the molecules that exert beneficial effects at all levels, namely on the neurons, astrocytes, and blood vessels, that are targeted by the pathology so we can hopefully counter disease progression and limit its debilitating effects.
