Lewis Holt

Thanks! 😄 @joscience.bsky.social

This all came online while we were at @gliameeting.bsky.social 2025 meeting! I couldn't think of a better community to celebrate it with and in a better setting than the south of France!

I want to give a big shout out to all the people in the CMR lab that helped with this project over the past few years, including those not on the paper. 💙

10. Astrocytic glucocorticoid receptor deletion correct the excitability changes we saw after ELS in a sex specific manner! The remarkable thing was that these changes were sufficient enough to rescue the behavioural deficits caused by ELS back in Fig.1!

9. Given the changes in blood CORT, we questioned if all these changes in running activity, firing rates and morphology could be a result of stress signalling in astrocytes? To get at this we selectively delete glucocorticoid receptors in astrocytes.

8. In ELS female mice we observed deficits in lactate availability. We also used some cool intracellular sensors to look at lactate dynamics in LH neurons after ELS!

7. We then got into what was underlying the divergent effects on orexin neuron firing in male and female mice. – Males first. Long story short, we saw elevated P2X receptor signalling was driving the hyper-excitability after ELS.

6. By chemogenetically manipulating astrocyte activity, we could recapitulate the behavioural and cellular phenotypes we saw after ELS - see paper for all the data!

5. But what about astrocytes after ELS? We saw changes in GFAP and Cx43. But to look at astrocyte morphology we developed a sparse viral labeling technique, which gave beautiful reconstructions of astrocytes in the LH. ELS shrunk astrocytes with a pronounced effect on branching in females!

4. This behavioural phenotype was nicely reflected at the neuronal level in the lateral hypothalamus, where ELS male orexin neurons had increased firing rates and hyper-excitability and ELS female orexin neurons had reduced firing rates and hypo-excitability.

3. We next found that ELS had opposing effects on running wheel behaviour across the light-dark cycle. Males ran more in their light phase and females ran less in their dark phase!

2. Firstly, replicating the findings from previous work in the lab, we see mice that experience ELS (maternal separation 4hr / day + limited bedding) display much higher nadir levels of blood corticosterone, the primary stress hormone in rodents!

1. Globally, this work builds on the growing body of literature investigating the effects of Early-Life Stress (ELS) on astrocytes, neuronal excitability and behaviour. This time we focused on astrocytes in the lateral hypothalamus.

A divergent astrocytic response to stress alters activity patterns via distinct mechanisms in male and female mice - Nature Communications Early-life stress has lifelong impacts on neuronal function and behavior. Here, the authors show that astrocytic glucocorticoid receptor signaling drives stress-induced neuronal and behavioral change ...

Absolutely thrilled to share the first half of my PhD work! Super proud to see it finally out!
www.nature.com/articles/s41...

Thread below for a quick (10 point) recap of what we found!
🧵🧪🧠

Thanks!! @dibenedetto-lab.bsky.social

Final leg of the Tour de France done with an excellent @gliameeting.bsky.social !
Amazing science in a great city, (despite some smoke!) and a nice travel award for @lewisholt.bsky.social 🥳

Going to make sure we come back to this meeting again next time! #glia2025

Have to get you an above-ground pool to finish off that QC aesthetic!

Thanks @paulsheppard.bsky.social !

Was great to present at @canglia.bsky.social today!
Cool to see all the glial research happening across Canada!

Norepinephrine changes behavioral state through astroglial purinergic signaling Both neurons and glia communicate through diffusible neuromodulators; however, how neuron-glial interactions in such neuromodulatory networks influence circuit computation and behavior is unclear. Dur...

Excited to share that the astrocyte-centered half of my thesis work is now out @science.org ! With @mishaahrens.bsky.social and @marcduque.bsky.social
science.org/doi/10.1126/... 1/8

Norepinephrine signals through astrocytes to modulate synapses Locus ceruleus (LC)–derived norepinephrine (NE) drives network and behavioral adaptations to environmental saliencies by reconfiguring circuit functional connectivity, but the underlying synapse-level...

Thought this would be a nice way to enter the bsky community👇Delighted for Katie (now in Chris Dulla's lab at Tufts). Thank you to our collaborators, to the reviewers and to Cagla Eroglu for the highlight!
www.science.org/doi/10.1126/...

Indeed! It's something that appears across various brain "pathology states", arrested C-like mitoses and multinucleation. These two were 'joined at the hip', if astrocytes have hips...

Super cool that these are finally out!! Check out some of the protocols we've been using to investigate the role of astrocytes in stress!

Multinucleated astrocytes always look so cool! #FluorescenceFriday

Diversifying my portfolio with some Iba-1 staining. #fluorescentfriday

Early-life stress induces persistent astrocyte dysfunction associated with fear generalisation Amygdala astrocytes play a critical role in mediating the effects of stress during infancy on neuronal excitability, synaptic plasticity, and memory.

Version of Record of our work at @elife.bsky.social has been published! Super proud of this one after all the hard work of the lab seeing it to the end.

Make sure to click through figure supplements as there is so much good stuff in there - sex differences, etc.

elifesciences.org/articles/99988

technical question. Can anyone recommend a good commercially available SOX9 antibody for fixed tissue IHC? #astrosky #astrocytes

What a year! #DLC3🔥 is up tested by many of you (👀 watch out for a paper in 2025), we hit 750K downloads, and have over 120 contributors to the code! @deeplabcut.bsky.social

❄️⛷just dropped: new human pose models & high perf. models!

Early-life stress induces persistent astrocyte dysfunction associated with fear generalisation Early-life stress can have lifelong consequences, enhancing stress susceptibility and resulting in behavioural and cognitive deficits. While the effects of early-life stress on neuronal function have ...

Delighted to share an update to our preprint, reviewed at @elife.bsky.social, and now sent back for re-review.
Colossal work by the team and driven home by @mathiasgua.bsky.social
Quick 🧵 of what's new -
www.biorxiv.org/content/10.1...

Leveraging research into sex differences and steroid hormones to improve brain health - Nature Reviews Endocrinology This Review outlines how the effects of steroid hormones on hippocampal neuroplasticity across the adult lifespan differ between the sexes, highlighting the importance of considering sex and steroid h...

Our latest review-with @bonniee-leee.bsky.social where we pour our ❤️🧠 & soul to outline our position on why we are so passionate about harnessing the power of sex differences & within sex diff to propel precision medicine forward let us know if we convince you www.nature.com/articles/s41...