More than happy to help and play that small role!

Thanks, Beth!

Thanks, Sofiya! We found that roughly half of all prelimbic SST neurons co-express cortistatin. I don't currently have a definitive answer for you on the % in humans, but it looks similar. Hopefully can answer that better soon!

Thanks, Tom!

Thanks, I looked for Andrew's account but couldn't find it! Major shout out to @aejaffe.bsky.social for leading the original study that led the ideas for this paper!

And a massive thanks to my advisor @martinowk.bsky.social for allowing me to mentor Aaron and lead the direction of this project as senior author. These ideas started as part of my F32 award ~4 years ago and it's exciting to be able to share them all with you now!

We're very excited to share this paper with you all and welcome all thoughts and feedback you might have! And please help me in congratulating @aaronsalisbury.bsky.social on this massive effort!

Given the comorbidity of epilepsy with PTSD and MDD, and the implication of SST+ neurons in each disorder, we speculate that dysfuntion of CST+ neurons might be common neural mechanism underying epilepsy and stress-related psychiatric disorders.

Aaron also characterized CST+ in the PrL and found that they are largely a subset of SST+ neurons (~50%), but CST is also found in a small subset of PVALB neurons (~20%).

Prior work by the @martinowk.bsky.social lab and others have shown that CST (along with other neuropeptides) are regulated by BDNF-TrkB signaling. Indeed, Aaron found that disrupting TrkB signaling in CST neurons is sufficient to reproduce the sex-specific effect of accelerated kindling rate.

Naturally we were blown away by this and decided to follow up onit. Aaron went on to show that DREADD inhibition of PrL CST+ neurons results in increased kindling rate ~exclusively~ in female mice. Another surprising finding.

Just to repeat that - a SUBTHRESHOLD dose of a chemoconvulsant which normally has no effect resulted in fatal seizures due to the ablation of CST+ cells in just the prelimbic cortex!

Surprisingly, Aaron noticed that a few of mice were having spontaneous seizures. So he gave the ablation and control mice a subthreshold dose of a chemoconvulsant (PTZ). Control mice showed no/minimal effects, but all ablation mice resulted in fatal seizures.

Lead by senior JHU PhD student Aaron Salisbury, he ablated all CST+ neurons in the prelimbic cortex and found that fear learning and extinction were unaffected, but mice showed a deficit in fear renewal.

However, cortistatin (CST) has largely flown under the radar and the function of CST+ neurons has been mostly unexplored. Given the PTSD implications, we sought to determine it's potential role in fear regulation

What is cortistatin? It's is an analogue of somatostatin that is localized primarily to the cortex, hippocampus, and amygdala. Binds to all 5 SST receptors but also has distinct functions. pubmed.ncbi.nlm.nih.gov/18374474/

The Lieber Institute (@martinowk.bsky.social + others) recently found that the gene encoding cortistatin (CORT) was among the most strongly downregulated genes across multiple prefrontal and amygdala postmortem brain regions in MDD and PTSD. pubmed.ncbi.nlm.nih.gov/35791611/

So functional cell types certainly exist in the spatial system. There is no doubt about this. However, this paper shows that you cannot know that you have found them by just decoding space, or even by showing spatial selectivity! This is a very important thing to tell the field.