Ethanol abolishes vigilance-dependent astroglia network activation in mice by inhibiting norepinephrine release

Liang Ye,Amit Agarwal,Dwight E Bergles,Murat Orynbayev,Eunice Y Lim,Manzoor A Bhat,Xiangyu Zhu,Ram R Dereddi,Martin Paukert

doi:10.1038/s41467-020-19475-5

Abstract

Norepinephrine adjusts sensory processing in cortical networks and gates plasticity enabling adaptive behavior. The actions of norepinephrine are profoundly altered by recreational drugs like ethanol, but the consequences of these changes on distinct targets such as astrocytes, which exhibit norepinephrine-dependent Ca2+ elevations during vigilance, are not well understood. Using in vivo two-photon imaging, we show that locomotion-induced Ca2+ elevations in mouse astroglia are profoundly inhibited by ethanol, an effect that can be reversed by enhancing norepinephrine release. Vigilance-dependent astroglial activation is abolished by deletion of α1A-adrenergic receptor from astroglia, indicating that norepinephrine acts directly on these ubiquitous glial cells. Ethanol reduces vigilance-dependent Ca2+ transients in noradrenergic terminals, but has little effect on astroglial responsiveness to norepinephrine, suggesting that ethanol suppresses their activation by inhibiting norepinephrine release. Since abolition of astroglia Ca2+ activation does not affect motor coordination, global suppression of astroglial networks may contribute to the cognitive effects of alcohol intoxication.

Highlights

Norepinephrine adjusts sensory processing in cortical networks and gates plasticity enabling adaptive behavior
Ethanol inhibition of Bergmann glia (BG) activation was dose-dependent, reaching almost complete inhibition at 1.5 g/kg (i.p.). This ethanol dosage is within the range used for acute ethanol exposure studies of rodents[23,28,37], and caused temporary ataxic motor coordination as discussed below, but did not impair their ability to walk on the treadmill while head restrained (Fig. 1d)
The considerable variability of voluntary locomotion-induced astroglia activation[7] suggests that adrenergic receptors are not saturated by NE released during natural behavior

Summary

Introduction

Norepinephrine adjusts sensory processing in cortical networks and gates plasticity enabling adaptive behavior. Voluntary and enforced locomotion induces global and coordinated Ca2+ activation in cerebellar Bergmann glia (BG) and in cortical astrocytes that is dependent on α1-adrenergic receptors[7,8,9], despite an abundance in other neurotransmitter receptors leading to intracellular Ca2+ release in astroglia in culture or slice preparations[10]. These signals can be evoked by sensory and aversive stimuli[9,11], a feature that is anatomically supported by the multitude of inputs to the LC from cortex, amygdala, and cerebellar Purkinje cells[2]. Together these findings suggest that ethanol can have acute as well as longlasting effects on astroglia biology; little is known about the effects of ethanol on vigilance-dependent, noradrenergic responses in astroglia in awake behaving animals

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Results

Conclusion