Arousal-induced cortical activity triggers lactate release from astrocytes

Abstract

It has been suggested that, in states of arousal, release of noradrenaline and -adrenergic signalling affect long-term memory formation by stimulating astrocytic lactate production from glycogen. However, the temporal relationship between cortical activity and cellular lactate fluctuations upon changes in arousal remains to be fully established. Also, the role of -adrenergic signalling and brain glycogen metabolism on neural lactate dynamics in vivo is still unknown. Here, we show that an arousalinduced increase in cortical activity triggers lactate release into the extracellular space, and this correlates with a fast and prominent lactate dip in astrocytes. The immediate drop in astrocytic lactate concentration and the parallel increase in extracellular lactate levels underline an activity-dependent lactate release from astrocytes. Moreover, when -adrenergic signalling is blocked or the brain is depleted of glycogen, the arousal-evoked cellular lactate surges are significantly reduced. We provide in vivo evidence that cortical activation upon arousal triggers lactate release from astrocytes, a rise in intracellular lactate levels mediated by -adrenergic signalling and the mobilization of lactate from glycogen stores.

A Dual Nanosensor Approach to Determine the Cytosolic Concentration of ATP in Astrocytes

“…As these sensors are proteins which can be genetically encoded, they allow cell type specific expression using specific promoters as well as subcellular targeting using appropriate targeting sequences. Combined with different stateof-the art microscopy technologies, the dynamics of metabolites can be followed in cultured cells, in tissue preparations like brain slices or the isolated optic nerve, but also in vivo in living and even awake animals (Bittner et al, 2011;Ruminot et al, 2011;Mächler et al, 2016;Díaz-García et al, 2017, 2019Trevisiol et al, 2017;Köhler et al, 2018;Baeza-Lehnert et al, 2019;Gerkau et al, 2019;Lerchundi et al, 2019;Arce-Molina et al, 2020;Zuend et al, 2020). However, while these nanosensors readily allow for monitoring relative changes of the metabolite concentration, deduction of absolute concentrations and absolute concentration changes (i.e., in mol/l) during treatments has remained challenging as calibration of the signal of the nanosensors to the actual concentration of the metabolite is hampered by both, theoretical and practical problems (Barros et al, 2018a).…”

“…The metabolism of the brain is realized by a joint effort of all cell types including neurons, glial cells as well as cells constituting the blood vessels. Almost all aspects of metabolism in the brain involve several types of cells, including energy metabolism (Pellerin and Magistretti, 1994;Guzmán and Blázquez, 2001; Barros and Deitmer, 2010;Nave, 2010a;Hirrlinger and Nave, 2014;Barros et al, 2018b;Díaz-García and Yellen, 2019;Vicente-Gutierrez et al, 2019;Zuend et al, 2020), and neurotransmitter metabolism (van den Berg et al, 1978;Waagepetersen et al, 2003;Bak et al, 2006;Le Douce et al, 2020). Furthermore, brain cells are structurally intermingled, heavily interdigitating their numerous cellular processes (Somjen, 1988;Grosche et al, 1999;Bushong et al, 2002;Nave, 2010b).…”

“…However, fluorescence nanosensors for metabolites are well suited to follow the concentration of a growing set of metabolites at high spatial and temporal resolution in vitro, in situ, and in vivo (Imamura et al, 2009;Hung et al, 2011;San Martin et al, 2014;Lange et al, 2015;Mächler et al, 2016;Mongeon et al, 2016;Trevisiol et al, 2017;Winkler et al, 2017;Köhler et al, 2018;Barros et al, 2018a;Zuend et al, 2020). Conceptually, these sensors are proteins composed of a domain which specifically binds the metabolite of interest as well as one or more fluorescent proteins, which change their fluorescent properties upon metabolite binding.…”

Distinct signatures of calcium activity in brain pericytes

“…To compare the calcium dynamics between EPs and CPs, we measured frequency, amplitude and duration of calcium transients using semi-automated image analysis as described and employed earlier by our lab (Zuend et al, 2020. Regions of interest (ROI) for pericyte somata (S) were selected by hand and ROIs for pericyte processes (P) were automatically detected with an unbiased algorithm (Ellefsen et al, 2014) implemented in our MATLAB toolbox, CHIPS (Barrett et al, 2018).…”

Lactate Transporters Mediate Glia-Neuron Metabolic Crosstalk in Homeostasis and Disease

“…Furthermore, one study suggests that neuronal stimulation, at least in the hippocampus, triggers neuronal glycolysis and the release of lactate from neurons ( Diaz-Garcia et al, 2017 ). In contrast, many others provide evidence that lactate is released from astrocytes and delivered to neurons, both in response to cortical activation by arousal triggers ( Zuend et al, 2020 ) or stimulation with cannabinoids ( Jimenez-Blasco et al, 2020 ). As with most complicated systems in neuroscience, it is likely that all of these processes can occur depending on the exact stimulus, environment, and cells involved.…”