Astrocyte glucocorticoid receptors mediate sex-specific changes in activity following stress

Interactions between orexin neurons and astrocytes in the lateral hypothalamus influence activity levels including circadian and motivated behaviour. These behaviors are disrupted by stress in rodents and form a hallmark of stress-related neuropsychiatric disorders. Here we set out to understand how stress influences activity and the underlying cellular mechanisms. We report that the long-term effects of stress on activity levels correlate with spontaneous firing of orexin neurons with hyperactivity in males and hypoactivity presented by female mice. These neuronal changes were accompanied by extensive astrocyte remodelling. Causal manipulations identified lateral hypothalamic astrocytes as key regulators of activity patterns. In the context of stress, genetic deletion of glucocorticoid receptors in lateral hypothalamic astrocytes rescued the effects of stress on orexin neuron firing, restoring activity to control levels in both males and females. Overall, these data suggest that astrocytic regulation of orexin neuron firing enables the maintenance of activity levels, and their dysfunction drives stress-induced activity dysregulation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=185 HEIGHT=200 SRC="FIGDIR/small/613499v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@1e4b3b9org.highwire.dtl.DTLVardef@1d35774org.highwire.dtl.DTLVardef@12a168org.highwire.dtl.DTLVardef@122d9dc_HPS_FORMAT_FIGEXP M_FIG C_FIG