The role(s) of astrocytes and astrocyte activity in neurometabolism, neurovascular coupling, and the production of functional neuroimaging signals

Abstract

Data acquired with functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) are often interpreted in terms of the underlying neuronal activity, despite mounting evidence that these signals do not always correlate with electrophysiological recordings. Therefore, considering the increasing popularity of functional neuroimaging, it is clear that a more comprehensive theory is needed to reconcile these apparent disparities and more accurately explain the mechanisms through which various PET and fMRI signals arise. In the present article, we have turned our attention to astrocytes, which vastly outnumber neurons and are known to serve a number of functions throughout the central nervous system (CNS). For example, astrocytes are known to be critically involved in neurotransmitter uptake and recycling, and empirical data suggests that brain activation increases both oxidative and glycolytic astrocyte metabolism. Furthermore, a number of recent studies imply that astrocytes are likely to play a key role in regulating cerebral blood delivery. Therefore, we propose that, by mediating neurometabolic and neurovascular processes throughout the CNS, astrocytes could provide a common physiological basis for fMRI and PET signals. Such a theory has significant implications for the interpretation of functional neuroimaging signals, because astrocytic changes reflect subthreshold neuronal activity, simultaneous excitatory/inhibitory synaptic inputs, and other transient metabolic demands that may not elicit electrophysiological changes. It also suggests that fMRI and PET signals may have inherently less sensitivity to decreases in synaptic input (i.e. 'negative activity') and/or inhibitory (GABAergic) neurotransmission.

Lactate Transport and Metabolism in the Human Brain: Implications for the Astrocyte-Neuron Lactate Shuttle Hypothesis: Figure 1.

“…Notwithstanding that, the prediction that plasma lactate could supply up to 60% of the brain's oxidative fuel, combined with reports that lactate administration is sufficient to support brain function during hypoglycemia (Boumez- Figley and Stroman, 2011). Therefore, despite a higher nominal affinity for lactate uptake into astrocytes (Gandhi et al, 2009), empirical data suggest that large amounts of lactate are transported into neurons, and that this is not likely to represent a rate-limiting step for the ANLSH.…”

“…Although it is now mostly agreed that activity-dependent lactate increases occur, and that these are important for cerebrovascular coupling and the production of functional neuroimaging signals (Figley and Stroman, 2011), both the cellular origin and the ultimate fate of lactate remain to be definitively confirmed.…”

Original article Transcription factor Pax6 is expressed by astroglia after transient brain ischemia in the rat model

“…This allows them to maintain regulatory functions in conditions in which neurons are unable to sustain the balance of energetic metabolism, because of a lower level of anaerobic glycolysis, higher susceptibility to excitotoxicity and lesser concentration of antioxidants. In pathological conditions, astrocytes support neurons with antioxidants and energetic metabolites, like lactate and ATP [3,15].…”

“…It has been proved that various brain regions are characterized by differentiated density of capillary vessels [10], which results in unequal levels of CBF reduction, adjusted to the metabolic demands. In pathological circumstances, it may explain different susceptibility of these regions to cerebral ischemia [15]. Another explanation may be concerned with different susceptibility of protoplasmic and fibrous astrocytes to ischemic conditions.…”

Astrocytes Grown in Alvetex® Three Dimensional Scaffolds Retain a Non-reactive Phenotype

“…Astrocytes are important cells of the central nervous system (CNS) with a wide range of properties [1][2][3]. Functions ascribed to astrocytes include supplying neurons with lactate, uptake and conversion of L-glutamate to glutamine [4][5][6][7], and secretion of glutathione in response to the generation of reactive oxygen species [8].…”