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

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.

Astrocytes, Noradrenaline, α1-Adrenoreceptors, and Neuromodulation: Evidence and Unanswered Questions

“…Two recent studies independently generated transgenic mouse lines with LoxP sites flanking Adra1a , allowing conditional deletion of the gene in astrocytes by crossing to appropriate Cre drivers. Both found a loss of calcium transients evoked by enforced locomotion (i.e., a form of startling), or noxious stimuli, in cerebellar ( Ye et al, 2020 ) and spinal cord astrocytes ( Kohro et al, 2020 ), respectively. This is consistent with the transcriptome data from astrocytes isolated from these regions ( Anderson et al, 2016 ; Boisvert et al, 2018 ).…”

“…It should also be noted that none of the studies performed in mouse visual cortex that we cite unambiguously demonstrate the direct activation of astrocyte α1-NAR to be central to the observed effects. Even if this is the most likely explanation, it remains to be explored in future studies, likely employing the Adra1a -floxed mouse lines that were recently reported ( Kohro et al, 2020 ; Ye et al, 2020 ).…”

“…While other studies suggest a role for α1-NAR signaling in astrocytes, sometimes using multiple lines of evidence ( Pankratov and Lalo, 2015 ), we believe cell-type specific gene ablation approaches are the cleanest way to understand the role of α1-NAR signaling in the CNS. We believe that the recent publication of two Adra1a -floxed mouse lines, enabling such experiments ( Kohro et al, 2020 ; Ye et al, 2020 ), will prove crucial in this endeavor and be a valuable resource for the neuroscience community.…”

“…This typically uses simultaneous activation of multiple promoters to achieve selective transgene expression in the desired cell subtype. An obvious example is the split Cre system ( Hirrlinger et al, 2009 ), which could, for example, be used in combination with Adra1a -floxed mice to delete α1A-NAR in specific astrocyte subtypes ( Kohro et al, 2020 ; Ye et al, 2020 ), or induce expression of a fluorescent protein (or genetically encoded sensor) in cells using existing mouse lines (such as GCaMP6f in the Ai95D line 2 ).…”

Voluntary alcohol consumption disrupts coupling of prefrontal cortical activity to arousal

“…Similarly, two-photon calcium imaging is beginning to identify how systemically injected ethanol modulates neuromodulator release and non-neuronal cell types 75 .…”