Michael Totty

Very excited to get to share culmination of this large-scale project to understand spatial gene expression in schizophrenia. Really proud of the amazing team work here working out lots of roadblocks to deploy these spatial strategies and analysis methods at scale!

A dorsal hippocampus-prodynorphinergic dorsolateral septum-to-lateral hypothalamus circuit mediates contextual gating of feeding Goode et al. show that prodynorphin (Pdyn)-expressing neurons of the dorsolateral septum (DLS) receive substantial dorsal hippocampal (DHPC) input and inhibit lateral hypothalamic (LHA) GABAergic neur...

Restaurants, billboards, commercials… what brain circuits link context to appetite? 🧠🌎🍽️

Very happy to finally share a major update in our work exploring the hippocampus and lateral septum in calibrating food consumption! 🍩

Major thanks to our lab and collaborators! ⭐️⭐️

www.cell.com/neuron/fullt...

More than happy to help and play that small role!

Major congratulations to @travisgoode.bsky.social and team on this!! This work was years in the making and is an absolute tour de force uncovering the neural circuitry of context-dependent feeding.

Excited to share our study in Neuron led by
@travisgoode.bsky.social, a K99 PDF (interviewing for Faculty) and Sahay lab team with collaborators at BROAD, Hopkins, and UW Seattle, defining a neural circuit that links prior experience with feeding behavior. Open Access: sahaylab.com/publications

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!

Congrats to @aaronsalisbury.bsky.social and @mictott.bsky.social on this exciting project initially designed to mechanistically investigate a molecular association with PTSD that we observed in postmortem human brain tissue. Fun🧵below explaining the scientific rational and findings from Michael!

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

Cortistatin--functions in the central nervous system - PubMed Cortistatin (CST) is a neuropeptide from the somatostatin (SRIF)/urotensin (UII) family named after its predominantly cortical expression and ability to depress cortical activity, which was discovered a decade ago. In vitro assays show CST is able to bind all five cloned somatostatin receptors and s …

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/

Decoding Shared Versus Divergent Transcriptomic Signatures Across Cortico-Amygdala Circuitry in PTSD and Depressive Disorders - PubMed These findings provide supporting evidence for involvement of decreased immune signaling and neuroinflammation in MDD and PTSD pathophysiology, and extend evidence that GABAergic neurons have functional significance in PTSD.

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/

New paper out on cortistatin neurons and their role in regulating fear and cortical hyperexcitability in the prelimbic cortex! This one has been a fun ride 🧵 www.biorxiv.org/content/10.6...

Spatially resolved molecular sex differences at single-cell resolution in the adult human ventromedial and arcuate hypothalamus The ventromedial hypothalamus (VMH) and arcuate (ARC) nuclei of the hypothalamus play critical roles in regulating metabolism and behavior. Here, Mulvey et al. create a focused spatial transcriptomic ...

Now online! @lieberinstitute.bsky.social & @jhubiostat.bsky.social collaboration generating important resource (Visium & Xenium) on molecular organization of human hypothalamus w/ cool findings associating sex differential expression to neuropsychiatric disorders 🧠🔬🧪
www.cell.com/cell-reports...

Altered Dopamine Signaling in Extinction-Deficient Mice A central mechanism of exposure-based cognitive behavioral therapy for anxiety and trauma-related disorders is fear extinction. However, the mechanisms underlying fear extinction are deficient in some...

1/4 New Paper 🧠🐭 #Neuroscience #Dopamine #FearExtinction
#eNeuro
Altered Dopamine Signaling in Extinction-Deficient Mice www.eneuro.org/content/12/1...

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.

"The inevitability and superfluousness of cell types in spatial cognition". Intuitive cell types are found in random artificial networks using the same selection criteria neuroscientists use with actual data. elifesciences.org/reviewed-pre... 1/2

Getting the most of out a scientific conference A slightly unconventional guide to your first time

A great intro to academic conferencing.
Not sure how I missed this one.

scienceforeveryone.science/getting-the-...

We are excited to share our online book and preprint on “Orchestrating Spatial Transcriptomics Analysis with Bioconductor”!

Whether you're new to bioinformatics or a seasoned pro, OSTA covers everything that you need to know about spatial transcriptomics data analysis spanning both sequencing and imaging-based technologies within the Bioconductor framework 👨‍💻🧬

Congrats to all the authors on this huge effort!