Is forgetting an active process? Some new evidence from Aplysia

The SlugLab has a new preprint from a really cool experiment we conducted this summer (2023). Check it out here ​(Calin-Jageman et al., 2023)​: https://osf.io/preprints/psyarxiv/xgfdk.

The results are a bit equivocal, but that’s the messiness of doing good science (“the data is the data”, as Bob’s PhD advisor was always fond of saying). In addition, we’re proud that this work has so many excellent student co-authors — well done Bryan, Elise, Zayra, Anna, Nelly, Leslie, Zayra, Jash, Elise, Dina and Theresa!

Now to the science. We’ve been studying the transcriptional changes that occur when Aplysia form long-term sensitization memories. One intriguing thing we’ve found, is that some of the transcriptional changes we observe would seem to work against the expression of sensitization ​(Conte et al., 2017)​. Specifically, one of the strongest transcriptional changes that occurs when sea slugs form a new sensitization memory is a strong and long-lasting up-regulation of a transcript encoding FMRFamide (FMRFa), a peptide neurotransmitter ​(Patel et al., 2018; Perez, Patel, Rivota, Calin-Jageman, & Calin-Jageman, 2017)​. This is strange begauce FMRFa is inhibitory and it generally works to depress synapses and specifically undoes the types of synaptic changes that help encode sensitization. Why would this be happening?

We’ve proposed the FMRFa is up-regulated because it is part of an active forgetting process — meaning a specific, biological pathway designed to erode/prune away memories. The idea would be that training produces transcriptional changes that encode sensitization but also produces a slower-developing increase in FMRFa, and that as FMRFa signalling increases it wears away the changes that maintain a sensitization memory, producing memory. Consistent with this hypothesis, we’ve found that FMRFa transcripts are up-regulated for a long time, even after sensitization memory seems completely forgotten.

To test the role of FMRFa signalling in forgetting, we gave animals sensitization training and then manipulated FMRFa signalling: boosting it with direct injections or blocking it with injections of a drug (4-BPB) that prevents arachidonic acide release, a key step in the G-protein-coupled-signaling that FMRFa triggers in Aplysia neurons. After these injections, we tracked forgetting of sensitization, measuring the strength of memory 4, 6, and 13 days after training.

What did we find? Well, inconsistent with our hypothesis we found that direct injection of FMRFa did alter forgetting at all. Bummer — sometimes you’re wrong! Or maybe we just didn’t use a strong enough dose, or the FMRFa didn’t get to the nervous system…. not sure. On the other hand, we found that 4-BPB slowed forgetting — animals in this condition had a stronger senstization memory 6-days after training than controls, and even had detectable levels of sensitization at day 13 (though no longer a clear difference from controls).

So, what does this mean? Well, it seems pretty clear that arachidonic acid plays some type of role in forgetting of sensitization. But FMRFa may not… or maybe it does but our FMRFa condition just wasn’t strong/direct enough. We’re going to repeat the study in reduced preps where we can control the drug application just a bit more strongly (though where we’ll have to rely on a physiological measure of memory strength). Excited to see where this goes.

  1. Calin-Jageman, R., Delgadillo, B. G., Gamino, E., Juarez, Z., Kurkowski, A., Musajeva, N., … Calin-Jageman, I. (2023). Evidence of Active-Forgetting Mechanisms:  Blocking Arachidonic Acid Release May Slow Forgetting of Sensitization in Aplysia. Center for Open Science. doi: 10.31234/osf.io/xgfdk
  2. Conte, C., Herdegen, S., Kamal, S., Patel, J., Patel, U., Perez, L., … Calin-Jageman, I. E. (2017). Transcriptional correlates of memory maintenance following long-term sensitization of Aplysia californica. Cold Spring Harbor Laboratory. doi: 10.1101/lm.045450.117
  3. Patel, U., Perez, L., Farrell, S., Steck, D., Jacob, A., Rosiles, T., … Calin-Jageman, I. E. (2018). Transcriptional changes before and after forgetting of a long-term sensitization memory in Aplysia californica. Elsevier BV. doi: 10.1016/j.nlm.2018.09.007
  4. Perez, L., Patel, U., Rivota, M., Calin-Jageman, I. E., & Calin-Jageman, R. J. (2017). Savings memory is accompanied by transcriptional changes that persist beyond the decay of recall. Cold Spring Harbor Laboratory. doi: 10.1101/lm.046250.117

New Review Article: Transcriptional Mechanisms of Long-Term Sensitization

Psychologists and neuroscientists have long been fascinated by memory: how do we learn and carry with us new skills and memories? One key insight is that lasting memories require both transcriptional change and neural plasticity.

Much of what we know abou tthe links between transcription and memory has been revealed through the study of long-term sensitization in Aplysia.

The sluglab has a a new review paper reviwing what we’ve learned from Aplysia, summarizing the state of the art of how sensitization memories are induced, encoded, and maintained . You can check it out here: https://osf.io/preprints/osf/urxk2

This review was a lot of work — but also a lot of fun to work on. This is a topic we know well — it’s the main thing the sluglab has studied over the past 15 years. But it was still incredible (and overwhelming) to get a chance to sit down and intensely re-read the many amazing papers that have explored this topic. Pulling it all together was tough, but rewarding; we especially appreciated being able to carefully explain the evidence behind the synchronization model of the induction of sensitization memory that has emerged from recent empirical an computational work.

Writing this review re-newed our appreciation for the incredible work of Gary Philips, the lab of Jack Byrne, Eric Kandel, and the many other folks who have studied sensitization in Aplysia. It was a real honor to be asked to write about all this work; we hope we’ve done it justice.

Writing this review was also fun because Theresa Wilsterman (DU class of 2023) worked up some really amazing figures — nice work, Theresa, and congrats on graduating!

Oh – it was also fun to make a preprint of this review using Quarto and RStudio — it was easy to produce a really beautiful document.

Sluglab at SFN 2023

The Annual Meeting of the Society for Neuroscience is a dizzying conference — it is a multi-day science extravaganza attended by over 30,000 people. The main meeting has a talks on the latest and greatest in neuroscience, an endless series of poster sessions, and a huge exhibitors section where you can check out the newest in techniques. In addition, there are many sattelite meetings and socials. The Faculty for Undergraudate Neuroscience puts on a lot of great events: an undergraduate poster session, a social, and usually a teaching of neuroscience workshop as well.

Although the neuroscience meeting is overhwhelming (it’s a bit like the Total Perspective Machine that Douglas Adams imagined for The Hitchhiker’s Guide), we really missed being able to attend the conference during the covid years.

This year (2023), the sluglab got to return to the Society for Neuroscience conference in style. We presented 2 posters at the Molecular and Celluar Cognition Sattelite Meeting, 2 posters at the undergraduate poster session, and 1 poster on the main foor! All in all, that involved 7 students from the slug lab, all of whom got to travel to D.C. and drink from the science firehose that is SFN.

Here’s Theresa and Elise getting a bright idea while presenting their posters at the Mollecular and Cellular Cognition meeting.

Here is Jash presenting at the undergrad session:

And Anna:

Andd Zayra:

And Leslie:

And Bryan:

So proud of the sluglab; it was a fantastic conference and they kicked a**.

Here is the whole gallery: