Sleep and Wake Affect Glycogen Content and Turnover at Perisynaptic Astrocytic Processes.

Giulio Tononi,Michele Bellesi,Samuel Koebe,Chiara Cirelli,Luisa De Vivo

doi:10.3389/fncel.2018.00308

Giulio Tononi, Michele Bellesi + Show 3 more

Open Access

https://doi.org/10.3389/fncel.2018.00308

Copy DOI

Abstract

Astrocytic glycogen represents the only form of glucose storage in the brain, and one of the outcomes of its breakdown is the production of lactate that can be used by neurons as an alternative energetic substrate. Since brain metabolism is higher in wake than in sleep, it was hypothesized that glycogen stores are depleted during wake and replenished during sleep. Furthermore, it was proposed that glycogen depletion leads to the progressive increase in adenosine levels during wake, providing a homeostatic signal that reflects the buildup of sleep pressure. However, previous studies that measured glycogen dynamics across the sleep/wake cycle obtained inconsistent results, and only measured glycogen in whole tissue. Since most energy in the brain is used to sustain synaptic activity, here we employed tridimensional electron microscopy to quantify glycogen content in the astrocytic processes surrounding the synapse. We studied axon-spine synapses in the frontal cortex of young mice after ~7 h of sleep, 7–8 h of spontaneous or forced wake, or 4.5 days of sleep restriction. Relative to sleep, all wake conditions increased the number of glycogen granules around the synapses to a similar extent. However, progressively longer periods of wake were associated with progressively smaller glycogen granules, suggesting increased turnover. Despite the increased number of granules, in all wake conditions the estimated amount of glucose within the granules was lower than in sleep, indicating that sleep may favor glucose storage. Finally, chronic sleep restriction moved glycogen granules closer to the synaptic cleft. Thus, both short and long wake lead to increased glycogen turnover around cortical synapses, whereas sleep promotes glycogen accumulation.

Highlights

The human brain has remarkably high energy demands, accounting for ∼20% of the body metabolism (Attwell and Laughlin, 2001)
To study the effects of sleep and wake on glycogen granule dynamics, we focused on cortical synapses of layers II/III of the mouse primary motor cortex
We find that glycogen turnover in perisynaptic astrocytic processes (PAPs) increases during wake while sleep promotes glycogen accumulation

Summary

Introduction

The human brain has remarkably high energy demands, accounting for ∼20% of the body metabolism (Attwell and Laughlin, 2001). Glucose is the main energetic substrate of the brain, and increases in local blood flow and glucose utilization typically follow changes in brain activity (Bélanger et al, 2011). While local increases in cerebral blood flow are well recognized phenomena, the cellular responses to energy demand remain controversial. Nerve endings can directly uptake and oxidize glucose under both resting and activated conditions (Patel et al, 2014). Consistent with these findings, a recent study used two-photon imaging of a near-infrared 2-deoxyglucose analog. Using genetically-encoded fluorescent biosensors, another study assessed the metabolic responses of individual neurons to stimulation and found increased direct glucose consumption by neurons, confirming that neurons can directly utilize glucose as needed (Díaz-García et al, 2017). The exclusive compartmentalization of glycogen in astrocytes, together with the robust production of lactate upon glycogenolysis, potentially enables the astrocytes to buffer sudden increases in energy requirements (Bouzier-Sore and Pellerin, 2013)

Methods

Results

Conclusion