A divergent astrocytic response to stress alters activity patterns via distinct mechanisms in male and female mice

Lewis R. Depaauw-Holt, Manon Duquenne, Sarah Hamane, Sarah Peyrard, Benjamin Rogers, Clara Ireland, Yusuke Nasu, Stephanie Fulton, Anthony Bosson, Thierry Alquier and Ciaran Murphy-Royal ()
Additional contact information
Lewis R. Depaauw-Holt: Université de Montréal
Manon Duquenne: Université de Montréal
Sarah Hamane: Hospitalier de l’Université de Montréal (CRCHUM)
Sarah Peyrard: Hospitalier de l’Université de Montréal (CRCHUM)
Benjamin Rogers: Université de Montréal
Clara Ireland: Université de Montréal
Yusuke Nasu: Nankang
Stephanie Fulton: Hospitalier de l’Université de Montréal (CRCHUM)
Anthony Bosson: Hospitalier de l’Université de Montréal (CRCHUM)
Thierry Alquier: Hospitalier de l’Université de Montréal (CRCHUM)
Ciaran Murphy-Royal: Université de Montréal

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract The lateral hypothalamus is a brain region that regulates activity levels, circadian, and motivated behaviour. While disruption of these behaviours forms a hallmark of stress-related neuropsychiatric disorders, the underlying cellular mechanisms of how stress affects this brain region remain poorly understood. Here, we report that the effects of stress on behavioural activity levels correlate with spontaneous firing of orexin neurons, inducing hyperactivity in males and hypoactivity in female mice. These neuronal changes are accompanied by astrocyte remodelling, with causal manipulations identifying lateral hypothalamic astrocytes as key regulators of neuronal firing and physical activity patterns. In the context of stress, sex-specific changes in orexin neuron firing were driven by distinct astrocytic mechanisms with elevated purinergic signaling in male mice and reduced extracellular L-lactate in female mice. Finally, we show that genetic deletion of glucocorticoid receptors in lateral hypothalamic astrocytes restores key aspects of astrocyte morphology, rescues the effects of stress on orexin neuron firing, and recovers activity levels in both males and females. Overall, these data causally implicate astrocytes in the regulation of orexin neuron firing, behavioural activity patterns, and reveal that astrocytes are primary drivers of stress-induced behavioural change.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-61643-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61643-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-61643-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().