Congrats! Looking forward to seeing the research program that you build!

Thanks Liisa! 😁

This wouldn’t have been possible without the contributions of my incredible lab mates and collaborators.

Many thanks to Yi Ren, Kabirat Adigun, the @ucalgarymed.bsky.social ASOC (Heewon Seo & Bo Young Ahn), @liisagalea.bsky.social, @deryasargin.bsky.social, and Jonathan Epp.

15/15

In summary, we:

Found sex-specific impairments in RSC PV-IN presentation in AD 👫

Characterized consequences locally and brain-wide 🌎

Demonstrated the clinical relevance of this phenotype 🏥

Improved cognitive performance by promoting the activity of RSC PV-INs 🎓

14/15

If dampening RSC PV-INs impairs cognition, can we improve memory performance by increasing the activity of these cells? 📈

By chemogenetically promoting the activity of RSC PV-INs, we improved contextual memory performance in aged female
5xFAD mice

13/15

How does this carry over to the clinic?

At rest, RSC activity should be highly correlated with the rest of the default mode network (DMN). Via clinical rs-fMRI scans, we noted increased density of anti-correlated RSC connections with DMN regions in AD.

(👀 the slopes of males vs females…)

12/15

Does dampening the activity of these cells induce similar changes to those seen in AD? 📉

Turns out, yes. With chemogenetic dampening, we impaired memory performance and increased the density of RSC anti-correlations (shown here in 🟢)

11/15

With c-Fos as a proxy of neuronal activity, we can study brain-wide functional connectivity (see: www.mdpi.com/2079-7737/12...).

In female 5xFAD mice, the density of anti-correlated RSC functional connections increases drastically (shown here in 🟢)

10/15

Let’s focus on memory impairments, such as those observed in 5xFAD mice.

Memory processes depend on networks of brain-wide activity. The RSC is involved in many such networks. PV-IN dysfunction may alter RSC connectivity - but how can we study this in freely-behaving mice? 🤔…

9/15

But what about in freely-behaving mice? 🐁

In vivo, my lab mate Yi Ren and I examined RSC PV-IN dynamics at both a population- and single cell-level. During a working memory task, we identified impaired RSC PV-IN activity in 5xFAD mice.

8/15

These transcriptional changes prompted electrophysiological characterization of RSC PV-INs ⚡️

These experiments were conducted by @deryasargin.bsky.social, who found impaired inhibitory control in RSC PV-INs of female 5xFAD mice.

7/15

But back to the paper:

Let’s dive deeper via gene-expression within PV-INs (GeoMx DSP) 🧬

Many genes critical to PV-IN function are down-regulated in female 5xFAD mice, particularly relating to GABA signalling and potassium transport

6/15

Maybe this female-specific vulnerability of PV-INs to AD shouldn’t have come as a surprise?

From our recent review, these cells are highly sensitive to changes in circulating estrogens and are very vulnerable to metabolic disruption prevalent in AD 👫

www.sciencedirect.com/science/arti...

5/15

Gene expression does not always align with protein expression, so next we assessed PV-IN immunohistochemistry 🔬

Here, we noted earlier impairments in PV-IN presentation in female 5xFAD and similar patterns of impairment in human tissue samples

4/15

Altered metabolic activity often coincides with impairments to local neuronal and glial populations

With single-cell spatial transcriptomics (Xenium), we noted down-regulation of Pvalb and other PV-IN-related genes in the RSC of 5xFAD mice 🧬

3/15

So, why the retrosplenial cortex (RSC)?

The RSC is involved in many learning and memory processes. Furthermore, as we previously demonstrated via clinical FDG-PET, hypometabolic activity in this region predicts cognitive decline 🧠

alz-journals.onlinelibrary.wiley.com/doi/10.1002/...

2/15