Background: How is the brain supplied with food for thoughts?
And what goes wrong when we age, or suffer from a neurodegenerative disorder?
Normal brain function depends on preserved supply of glucose and oxygen and even minor deficits in control of the cerebral circulation lead to loss of brain function. The robust coupling between brain activity and cerebral blood flow (CBF), the so-called neurovascular coupling regulates the minor local CBF alterations that take place all the time. In the past, the dynamics of CBF control was based on an understanding of brain arterioles and on capillaries for exchange of substances between blood and brain. This notion has undergone an important change in recent years because it has been discovered that both arterioles and capillaries take part in 1) substance exchange and 2) cerebrovascular resistance.
Specifically, it was recently discovered that contractile cells called pericytes, which are attached to the capillaries, can regulate CBF at the capillary level. Understanding how microvascular blood flow and permeability is controlled will enable us to define and target mechanisms at the level of the smallest blood vessels, brain capillaries, which supply nerve cells with oxygen and glucose, i.e. brain energy. Failure of this energy supply causes neural tissue to degenerate, independently of the primary disease aetiology. The energy supply thus forms an attractive point of intervention for the development of disease modifying therapies for neurodegenerative diseases.
Drug transport across the brain endothelium forming the blood-brain barrier is another research challenge because of the low intrinsic permeability of the barrier to most solutes and the presence of active efflux transporters. However, it is of great importance to understand the mechanisms that control the access of active compounds across the BBB and to be able to study BBB permeability characteristics quantitatively and repeatedly is the same animal.
We use a combination of techniques to study neuroenergetics, cerebral blood flow and the signaling between cells of the neurovascular unit: electrophysiological techniques to record spike activity from single cells and local field potentials, electro-chemically recorded oxygen consumption, assessment of local blood flow with double-wavelength laser-Doppler flowmetry and laser speckle, opthogenetics and multi-photon microscopy for in vivo measurements in mice. We study both normal physiology, healthy aging and disease states such as stroke, cortical spreading depression and hypertension.
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