The human body is an efficient model to explore the popular theory of supply and demand. When you physically exert yourself, your bioenergetic “supply” is down, so you feel hungrier as your system “demands” more food. In much the same way, the neurons in your brain are busy firing action potentials, and their bioenergetic fuel quickly gets used up. So, how do these neurons signal that they need more energy?
Neurons display their “low fuel” signal by releasing vasoactive compounds, which are molecules that alter the activity of blood vessels. Some neurotransmitters like glutamate stimulate the production of vasodilators, molecules that dilate or widen blood vessels to increase blood flow. Together, these vasoactive and vasodilating compounds boost blood supply to active neurons, providing them with oxygen and glucose via the blood-brain barrier. This elegant system of refueling the brain’s tank by modulating cerebral blood flow per neuronal demand has been known since mid-1900s. In fact, this concept forms the crux of brain mapping by functional magnetic resonance imaging (fMRI)! Considering that neurons are surrounded by numerous cell types, including astrocytes, endothelial cells and pericytes, it has been difficult to ascertain which particular cell type governs this “supply and demand” control of neuronal energy.
A recent research study published in Nature may have the answer. By investigating the molecular mechanisms underlying dilation of capillaries, Hall et al. report that the pericytes, in particular, may be actively involved in the brain’s refueling mode of action. Pericytes are contractile cells that surround the capillaries (peri: surround; cyte: cell). This research team showed that pericytes relax their grip on capillaries in response to excitatory neurotransmitters. It’s almost as if a clamp on a hose is slowly released, allowing more fluid to flow through. As pericytes loosen their grip on capillaries, vasodilation occurs, allowing more blood, oxygen and glucose to flow to the site of high neuronal activity.
The researchers further explored the role of pericytes on the event of a stroke, wherein a blood clot obstructs the blood supply to the brain. Treatments for stroke have involved dissolving the clot to restore blood supply to the brain, but this strategy does not have much therapeutic benefit if the reopening of the blood vessel is delayed. In the current study, the research team identified pericytes as one of the culprits in the no-reflow phenomenon after a stroke. In conditions of stroke in mice, pericytes constrict the capillaries (the clamp on the hose is further tightened) and then die in rigor mortis. This stiffness of dead pericytes upon stroke keeps the blood vessels strangulated even after the clot is removed, thus preventing any resupply of blood to the injured regions of the brain.
Two important findings stem from this fascinating research: (1) pericytes decode the brain’s “low fuel” signals and help with bioenergetic refueling, and (2) their death after stroke keep the blood vessels strangulated, aggravating brain injury. The study has sparked a great deal of interest in targeting these unassuming yet interesting cells – pericytes – as a potential candidate for stroke therapy.
Hall C.N., Reynell C., Gesslein B., Hamilton N.B., Mishra A., Sutherland B.A., O’Farrell F.M., Buchan A.M., Lauritzen M. & Attwell D. & (2014). Capillary pericytes regulate cerebral blood flow in health and disease, Nature, 508 (7494) 55-60. DOI: 10.1038/nature13165
Images made by Anita Ramanathan.