Unraveling the brain's response to hypoglycemia: Neurovascular coupling

Abstract

Functional magnetic resonance imaging has suggested the possibility that hypoglycemia could interfere with neurovascular coupling. Here we discuss the implications of a study by Nippert and colleagues showing that hypoglycemia does not impair neurovascular coupling.

The brain is highly dependent on a consistent and adequate supply of glucose and oxygen by cerebral blood flow (CBF). Neurovascular coupling, that is, the increase in CBF in response to increased neuronal activity, is considered to be a key element of regulation. Contrary to earlier assumptions, the function of neurovascular coupling does not seem to meet the increased consumption of oxygen and glucose. ¹ While its actual function is still unclear, disturbance of neurovascular coupling is often associated with cerebrovascular or neurodegenerative diseases. Therefore, it is interesting that acute hypoglycemia has been reported to reduce blood-oxygen-level-dependent (BOLD) responses to sensory stimulation in functional magnetic resonance imaging (fMRI) experiments. ² Such observations have suggested that the neurovascular coupling might be decreased during hypoglycemia, which could have detrimental effects on brain function. However, as alternative explanation neuronal activity could be reduced by hypoglycemia. The field has hitherto lacked a study that specifically related neuronal activity with local vasodilation at low plasma glucose concentrations.

Nippert et al. have now addressed the relationship between blood glucose levels and neurovascular coupling. ³ The original and novel approach of this study was the simultaneous measurement of neuronal activity (Ca²⁺ transients) and vascular dilation (vessel diameter) in the cortex of awake mice during hypoglycemia. For that, the authors took advantage of a transgenic mouse line expressing the genetically encoded fluorescent Ca²⁺ sensor GCaMP6s in excitatory neurons, and injected a fluorescent dextran molecule that is largely confined to the vascular compartment. Although it is expected that variations in vessel diameter lead to equivalent changes in local brain perfusion, the authors have not measured activity-dependent changes in CBF.

In this study, the authors have confirmed that the basal diameter of arterioles and capillaries increases during insulin-induced hypoglycemia in mice. ⁴ Most importantly, the authors show that changes in the magnitude of neuronal activity parallel the responses of the vascular compartments. These results indicate that the neurovascular coupling is not altered during hypoglycemia in awake mice. Previously, the same group has also reported that hypoglycemia-associated arteriole dilation is paralleled by increases in Ca²⁺ activity within astrocyte end-feet and processes, through a mechanism that involves signaling by eicosanoids. ⁵ In another study, Hariharan et al. demonstrated that low glucose activates K_ATP channels to hyperpolarize pericytes, which could result in signal transmission upstream in the vessel network leading to an increase in local CBF. ⁶ Altogether, we can conclude that current evidence points to astrocytes and pericytes as active cells in the cerebrovascular responses to hypoglycemia, including the global increase in vessel dilation and the preservation of the neurovascular coupling at low blood glucose.

Further research should be encouraged to validate these findings and elucidate why hypoglycemia reduces BOLD-fMRI responses to somatosensory stimuli despite an adequate supply of glucose and oxygen to fuel neurons.

Unraveling brain responses to hypoglycemia is of particular interest for diabetes research. Hypoglycemia can be a severe complication of insulin treatment in diabetes, and impacts brain function, possibly leading to cognitive impairment, mood alterations and, in severe cases, coma. Moreover, repeated hypoglycemia episodes lead to the development of a dampened counter-regulatory response through mechanisms that include signaling by neuromodulators and peripheral hormones, as well as metabolic adaptations such as increased glucose transport, utilization of alternative fuels, and availability of glycogen within brain cells.^7,8 It has indeed been suggested that diabetes impairs the neurovascular coupling. ⁹ Decreased nitric oxide bioavailability and signaling has been reported to participate in the mechanism of reduced neurovascular coupling in diabetes, ¹⁰ but further research on diabetes models is needed for illuminating the whole picture. Surely the various cells of the neurovascular unit, and many signaling mechanisms will be pinpointed as contributors to the diabetes-induced neurovascular impairment.