Dr. Lewis Depaauw-Holt
Work done at Université de Montréal – CRCHUM
Article citation
Depaauw-Holt, L.R., Duquenne, M., Hamane, S., Peyrard, S., Rogers, B., Ireland, C., Nasu, Y., Fulton, S., Bosson, A., Alquier, T. and Murphy-Royal, C., 2025. A divergent astrocytic response to stress alters activity patterns via distinct mechanisms in male and female mice. Nature Communications, 16(1), p.6372.
Astrocytes play key roles in sex-specific changes in brain and behaviour caused by early-life stress
In this study, Lewis Depaauw-Holt, working in the laboratory of Dr. Ciaran Murphy-Royal at Université de Montréal, investigated how early life stress influences brain and behaviour. They specifically aimed to elucidate the role of a non-neuronal brain cell, the astrocyte. The researchers showed striking differences in the response of males and females to early-life stress, differences that they could replicate in non-stressed mice by manipulating astrocytes chemically and genetically. These results suggest a perspective shift in our models of stress by directly implicating astrocytes in the behavioural, cellular, and synaptic response to stress.
Using a rodent model of early-life stress (ELS), the researchers showed that stress leads to opposite behaviour changes in male and female mice: ELS male mice exhibited hyperactivity, running more than controls, while ELS female mice display hypoactivity, running less. Interestingly, these behavioural changes were correlated with changes in astrocyte morphology and excitability of a type of neurons called orexin neurons. ELS male neurons displayed increased firing rates indicative of hyper-excitability and ELS female neurons displayed attenuated firing rates indicative of hypo-excitability. Remarkably, by chemogenetically manipulating astrocytes in naïve conditions, the researchers could recapitulate the behavioural, cellular and synaptic effects of ELS in both sexes. The researchers also found they could revert the effects of ELS by deleting the glucocorticoid receptor in astrocytes, thereby showing astrocytes are not bystander cells, but rather the primary mediators of the psychological effects of stress.
This work highlights the important role of astrocytes in the behavioural, cellular, and synaptic response to ELS and paves the way to a more comprehensive multicellular models of brain function.
Given the profound sex-based differences observed under both naïve and stress conditions, this article underscores the importance and necessity of incorporating both biological sexes in fundamental neuroscience research.
About Lewis Depaauw-Holt
Lewis is a British neuroscientist with a passion for studying the complex roles of astrocytes in regulating brain circuits to drive behavior. He completed his master’s research at UCL in London, U.K., where he studied the role of glia in disorders of autophagy, the body’s natural cellular recycling system. For his PhD, Lewis trained with Prof. Murphy-Royal in Montreal, Quebec, to delve deeper into the role of astrocytes in the behavioral and synaptic response to stress.
Today, Lewis is a postdoctoral researcher in the Laboratory of Behavioral Genetics, headed by Prof. Carmen Sandi at EPFL in Lausanne, Switzerland. His current research focuses on the diverse effects of steroid hormones on astrocyte metabolism and synaptic function across a range of brain regions. In his spare time, Lewis enjoys music, spending time in the mountains, and is an endurance athletics enthusiast.
Sources of funding
Fonds de Recherche du Québec (FRQ) – Santé (2024-2026) – Doctoral training Fellowship
This project was supported by
Réseau Québécois sur le Suicide, les troubles de l’humeur et les troubles Associées (RQSHA) Early Career Researcher Pilot Grant (2021-2022)
Scottish Rite Charitable Foundation of Canada (2024-2027)
NSERC Discovery Grant (2021-2027)