Neurovascular coupling in a central nervous system white matter tract

by Alejandro Restrepo Arango
Doctoral thesis
Date of Examination:2022-06-20
Date of issue:2022-08-08
Advisor:Prof. Dr. Klaus-Armin Nave
Referee:Prof. Dr. Klaus-Armin Nave
Referee:Prof. Dr. Susann Boretius
Referee:Dr. Nuno Raimundo
Persistent Address: http://dx.doi.org/10.53846/goediss-9398

 

 

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Abstract

English

Neurovascular coupling is the process by which blood vessels dilate upon increased neuronal activity. It has been extensively studied in the murine grey matter and there are several models explaining possible molecular and cellular pathways that communicate neuronal needs to the vascular system. However, neurovascular coupling in the white matter, which represents half of the human brain, has been constantly overlooked. I used the optic nerve as a model system to study neurovascular coupling in white matter. In the optic nerve, spiking axons release glutamate into the periaxonal space. Glutamate activates NMDA receptors located in the myelin membrane, and oligodendrocytes increase their glycolytic metabolism to support the ATP production of the underlying axon. This process of neurometabolic coupling requires that the vascular system matches the axonal activity and increases the availability of glucose and oxygen. How this is done in the white matter remains elusive. My experiments show that axonal activity induces a small vessel dilation which is both prolonged and sustained for more than 20 min after the end of the stimulation. Pharmacological inhibition suggests that the electrically-evoked dilation is mediated by the prostaglandin E2 receptor EP4 and can be modulated by oxygen concentration. These experiments demonstrate that some of the principles that govern the response of the grey matter are also in place for the white matter. By using neurogenetics, I show that the vessel dilation is partially mediated by oligodendroglial NMDA receptors, supporting the published white matter neurometabolic model. A preliminary study using task-based fMRI immediately followed by a long resting-state fMRI shows a positive and strong BOLD signal in the corpus callosum during the resting state only when the task was performed. These data suggest that white matter neurovascular coupling is a process that mainly happens after the neuronal activation has finished, hinting that neurovascular coupling in white matter is necessary to replenish the energy stores that have been used, and not to support the axonal activity.
Keywords: Neurovascular coupling; White matter; Axo-glia communication; Optic nerve