Editors' ChoiceNEUROLOGICAL DISORDERS

The brain’s matchmakers

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Science Translational Medicine  08 Mar 2017:
Vol. 9, Issue 380, eaam9863
DOI: 10.1126/scitranslmed.aam9863

Abstract

Pericytes match capillary blood flow to local neural activity, thus ensuring proper oxygenation of the brain.

Ample blood flow and oxygenation are vital to a properly functioning nervous system. The neurovascular unit consists of vascular cells, glial cells, and neurons. Among this cast of characters, pericytes, positioned in the basement membrane of brain capillaries, serve a number of important functions, including regulation of blood-brain barrier permeability, angiogenesis, and clearance of toxins. However, their contributions to neurovascular coupling—defined as the relationship between local neural activity and subsequent changes in cerebral blood flow—have been more challenging to pin down. Kisler and colleagues have now discovered that pericytes are essential for maintaining capillary responses to neuronal activity and neurovascular coupling, thereby ensuring proper oxygenation of the brain. Because delivery of oxygen and nutrients is critical for brain function, the findings in this study have far-reaching implications for nervous system diseases. Indeed, pericyte deterioration is a common feature of neurodegenerative diseases associated with neurovascular dysfunction, including Alzheimer’s disease and amyotrophic lateral sclerosis.

As a first step to test if pericytes influence neurovascular coupling, the authors took advantage of mice with reduced and mosaic pericyte coverage along the brain’s capillary walls [platelet-derived growth factor receptor β (Pdgfrb+/–) mice]. Next, using intrinsic optical signal (IOS) imaging in somatosensory cortex of these mice, they observed decreased dilation and hemodynamic responses in capillaries devoid of pericytes. Two-photon laser scanning microscopy was used to observe areas with lower oxygen partial pressure, and microdialysis of interstitial fluid recovered higher amounts of lactate, an alternative fuel source commonly favored by neurons during hypoxia, in Pdgfrb+/– mice than in controls. Local field potential recordings, arteriolar response and endothelium-dependent vasodilation experiments, and immunostaining analyses confirmed that these effects were not due to abnormal neuronal excitability or changes in endothelial-, smooth muscle–, or astrocyte-dependent mechanisms regulating cerebral blood flow. Last, the authors show that the global cerebral blood flow impairments observed in the Pdgfrb+/– mice progress with age and are accompanied by neuropathological changes, including altered neuronal morphology and cell death. Collectively, these findings highlight the pericyte as a key element of the neurovascular unit that may prove to be a useful therapeutic target for age-associated neurodegenerative diseases, as well as for ischemic stroke and conditions of chronic hypoperfusion or hypoxia, in which metabolic stress may accelerate tissue damage.

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