The remarkably long-lasting fragments of memory

It was a whirlwind 2018. Irina and I are just now catching our breath and finding some time to update the lab website.

One awesome piece of news we forgot to publicize is that our latest paper came out in the August issue of Neurobiology of Learning and Memory (Patel et al., 2018).   This paper continues our work of tracking the molecular fragments of a memory as it is forgotten.  Specifically, we tracked 11 genes we suspected of being regulated *after* forgetting (Perez, Patel, Rivota, Calin-Jageman, & Calin-Jageman, 2017).  Things didn’t work out quite as well as we had expected: of our 11 candidate genes 4 didn’t show much regulation, meaning that our previous results with these genes were probably over-estimating their importance (curse you, sampling error!).  On the other hand, we replicated the results with the other genes and found that some of them are actually regulated for up to 2 weeks after the memory is induced, long after it seems forgotten.

Here are two key figures.  The first is the memory curve for sensitization in our Aplysia -it shows that after memory induction there is strong sensitization recall that decays within a week back to baseline.  Even though the memory seems gone, giving a reminder 2 weeks after learning rekindles a weak re-expression of the memory. That’s a classic “savings” effect.  

The next figure traces the time-course of memory-induced gene expression (levels of mRNA) for 6 specific genes, measured in the pleural ganglia that contains neurons known to be important for storing sensitization memory.  You can see that each of these transcripts is up- or down-regulated within 24 hours of learning, and that in each case this regulation lasts at least a week and sometimes out to 2 weeks.  So, just as the behavioral level of the memory fades but isn’t really completely gone, the some of the transcriptional events that accompany learning also seem to persist for quite some time. 

Why would this occur?  Perhaps these transcripts are part of savings…maybe they set the stage for re-expressing the memory?  Or maybe they are actually part of forgetting, working to remove the memory?  Or maybe both?  For example, one of the transcripts is encodes an inhibitory transmitter named FMRFamide.  It is really up-regulated by learning, which would normally work against the expression of sensitization memory.  So perhaps this helps suppress the memory (forgetting), but in a way that can be easily overcome with sufficient excitation (savings)… that’s an exciting maybe, and it’s the thing we’ll be working this summer to test.

As usual, we’re so proud that this paper was made possible through exceptional hard work from some outstanding DU student researchers: Ushma Patel, Leticia Perez, Steven Farrell, Derek Steck, Athira Jacob, Tania Rosiles, and Melissa Nguyen.  Go slug squad!

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. Neurobiology of Learning and Memory, 155, 474–485. doi:10.1016/j.nlm.2018.09.007
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. Learning & Memory, 25(1), 45–48. doi:10.1101/lm.046250.117

New preprint on the very long-lasting transcriptional response to learning

The sluglab has a new preprint out, currently under review at the Neurobiology of Learning and Memory.  We shows that both transcription and savings can persist for as long as 2 weeks after the induction of long-term sensitization, way beyond the decay of recall.  Interestingly, all the long-lasting transcriptional changes start within 1 day of training.  Lots of student co-authors on this one; it was a *lot* of work.  Looking forward to the reviews.

Slug Lab Triumph! First place in the cSFN undergraduate poster competition for Leticia Perez and Ushma Patel

So pleased and proud to announce that Leticia Perez and Ushma Patel have won first place in the Chicago Society for Neuroscience undergraduate poster competition.   Congrats Leticia and Ushma on a great presentation on the work you’ve been doing in the slug lab on the transcriptional correlates of forgetting and savings memory.

Leticia and Ushma are following up their spectacular win with exciting post-graduation plans.  Leticia is enrolling at the University of Illinois School of Vetrinary Medicine (and had her choice of programs!).  Ushma is enrolling at UIC’s prestigious medical illustration MA program (and also had her choice of programs!).  Congrats to both on all the hard work they put into collecting data, analyzing results, and presenting their exciting research.

Want to know more about the research Leticia and Ushma presented?  See their paper in Learning and Memory here: (Perez, Patel, Rivota, Calin-Jageman, & Calin-Jageman, 2017)

Not to brag, but this is the 3rd time a DU student has placed in this competition in the past 10 years (Kristine Bonnic had a 3rd place win and Tim Lazicki had a first place win).  That means DU neuroscience students have earned 1/3 of all the awards given out for undergraduate research by the Chicago Society for Neuroscience–an organization that includes Northwestern, Loyola, University of Chicago, DePaul, Midwestern, Roosevelt, North Central, and more…. relative to our student body we’re punching way above our weight!

Perez, L., Patel, U., Rivota, M., Calin-Jageman, I., & Calin-Jageman, R. (2017). Savings memory is accompanied by transcriptional changes that persist beyond the decay of recall. Learning & Memory (Cold Spring Harbor, N.Y.), 25(1), 45–48. [PubMed]

Memories fade..but something remains

Most long-term memories are ‘forgotten’–meaning that it becomes harder and harder to recall the memory.  Psychologists have long known, though, that forgetting is complex, and that fragments of a memory can remain.  For example, even after a memory seems forgotten it can be easier to re-learn the same material, something called ‘savings memory’.  That suggests that there is at least some fragment of a memory that persists in the brain even after it seems forgotten…but what?

Today our lab has published a paper shedding a bit of light on this long-standing mystery (Perez, Patel, Rivota, Calin-Jageman, & Calin-Jageman, 2017).  We tracked a sensitization memory in our beloved sea slugs.  As expected, memories faded–within a week animals had no recall of the prior sensitization.  Even more exciting, we found similar fragments of memory at the molecular level–there was a small set of genes very strongly regulated by the original training even though recall had fully decayed.

Why?  Do these persistent transcriptional changes help keep a remnant of the memory going?  Or are they actually doing the work of fully erasing the memory?  Or do they serve some other function entirely (or no function at all)?  These are some of the exciting questions we now get to investigate.  But for now, we have these fascinating foothold into exploring what, exactly, forgetting is all about in the brain.

As usual, we are enormously proud of the undergraduate students who helped make this research possible: Leticia Perez, Ushma Patel, and Marissa Rivota. Ushma, who wants to do science illustration, is making an incredible piece of artwork representing these findings.  A draft is shown above.  She submitted it for the cover of the journal, but sadly they journal selected a different image (boo!).  Still, a very exciting and proud day for the slug lab!

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. Learning & Memory, 25(1), 45–48. doi: 10.1101/lm.046250117

Workshop at the Society for Neuroscience Meeting

This year was a big year for our lab at the Society for Neuroscience conference.  Leticia Perez, who has been in the lab for the past two summers, gave an amazing talk on our work on forgetting.  In addition, I (Bob) helped organize a Professional Development Workshop on doing better neuroscience.

It was a huge honor to get to lead this workshop.  I gave a presentation on sample-size planning (which is sooo vital to doing good science).  David Mellor at the Open Science Framework spoke about pre-registration.  And Richard Ball, who co-directs project Tier, spoke about reproducible data analysis.  Like the good Open Scientists we are, we used the Open Science Framework to post all our slides and resources: https://osf.io/5awp4/.  SFN also made a video, which should be posted soon.

SFN staff told us it was the best attended workshop for the meeting.  Hooray!  Hope all our attendees will go forth to spread the good word about these small tweaks that can have such a big impact on scientific quality.

Here’s what it looked like from my perspective:

An unforgettable experience talking about forgetting

Wow! Our lab just returned from the 2017 Society for Neuroscience meeting.  It was the typical maelstrom of neuroscience–with more than 20,000 neuroscientists bustling about trying to share the latest and greatest about their research.

This turned out to be an especially great year for the Slug Lab.  Leticia Perez, who has been working in our lab for the past two summers, submitted an abstract to present the work she and others in the lab have been doing on forgetting.  We’ve been really excited about the results of this project.  It turns out the SFN organizers were excited, too–they selected Leticia’s abstract for a 10 minute talk during a mini-symposium on the mechanisms of learning and memory.

Leticia absolutely crushed it–she gave a concise, clear, and exciting presentation on what happens in the Aplysia nervous system as a long-term memory is forgotten.  She handled the questions wonderfully, and was soundly congratulated by many researchers in the learning and memory community.  Of the 20,000+ in attendance, I’m willing to be she was the only undergraduate to give a talk at this year’s meeting.  It was *such* an accomplishment.

In case that wasn’t enough, Leticia also brought along a poster presenting the research.  She gave the poster at the pre-meeting on molecular and cellular neuroscience and at the undergraduate poster session.  Yes, that means she gave 3 presentations last weekend!  Wow!  And, again, all went wonderfully.

Part of the reason Leticia was able to attend the meeting to earn all this acclaim is that she was awarded an Excel scholarship through Dominican University–this paid her registration, hotel, and airfare to make it affordable to attend the meeting.  She still had to work like crazy to collect the data, refine the presentation, and clear her class schedule to attend.  Lab alumnnus Marissa Rivota also attended–so her and Leticia also got to see the capital and the White house.

We’re so proud of Leticia, and of the many other students who have worked so hard in the lab for the past summers to make this forgetting project such a success.  There will be a paper on it coming out very soon in Learning and Memory.  It’s tremendous work to do good science–we’re so happy to have wonderful students who want to get involved and excel.

Below are photos of Leticia giving her talk, giving her poster, and celebrating with me, Irina, and Marissa.  Congrats, Leticia!

Slug Lab – Distinguished Service Awards from the Faculty for Undergraduate Neuroscience

At this year’s Society for Neuroscience meeting, Irina and I were honored for our contributions to the Faculty for Undergraduate Neuroscience (FUN).  Specifically, we were both given the annual Distinguished Service Award.  The honors were bestowed for our work organizing the FUN conference this past summer and for other work supporting the mission of undergraduate neuroscience education.

We’re so fortunate to be a part of FUN–it’s our favorite people all working towards a mission that is so very important.  Thanks for the great honor, and we’re looking forward to staying very involved with FUN.

Here’s a photo of Irina’s award.

 

 

The New Statistics for Neuroscience Education.

This summer I (Bob) was asked to write a series of perspective pieces on statistical issues for the Journal of Undergraduate Neuroscience.

My first effort has just been published–it is a call for neuroscience education to shift away from p values, and an explanation of the basic principles of the New Statistics with an example drawn from neuroscience.

It turns out that the paper was published just before the annual meeting of the Society for Neuroscience, which I am currently attending.  It’s been very gratifying to see the paper is already sparking some discussion.

Here’s the key figure from the paper comparing/contrasting the NHST approach with the New Statistics approach with data from a paper in Nature Neuroscience.

Getting Started with the New Statistics – A talk at Indiana University

This fall I (Bob) was invited to give a talk at Indiana University as part of a series on good science and statistical practice organized by the university’s Social Science Research Commons (which is like a core facility for getting advice on statistics and experimental design…what a cool thing for a university to have!).

I really enjoyed my visit (thanks Emily, Cami, and Patricia)–good conversation with fascinating people in a beautiful setting.  The series has a video archive, so my talk is now posted online as a video and as a powerpoint. Here’s the link–take a look if you want to know more about how to get started using Open Science practices and the New Statistics:  https://media.dlib.indiana.edu/media_objects/gt54kp23k

Maintaining Memories, Changing Transcription

Under the right circumstances, a memory can last a lifetime.  Yet at the molecular level the brain is constantly in flux: the typical protein has a half-life of only a few hours to days; for mRNA a half-life of 2 days is considered extraordinarily long.   If the important biological molecules in the brain are constantly undergoing decay and renewal, how can memories persist?

The Slug Lab has a bit of new light to shed on this issue today.  We’ve just published the next in our series of studies elucidating the transcriptional changes that accompany long-term memory for sensitization in Aplysia.  In a previous paper, we looked at transcription 1 hour after a memory was induced, a point at which the nervous system is first encoding the memory.  We found that there is rapid up-regulation of about 80 transcripts, many of which function as transcription factors (Herdegen, Holmes, Cyriac, Calin-Jageman, & Calin-Jageman, 2014).

For the latest paper (Conte et al., 2017), we examined changes 1 day after training, a point when the memory is now being maintained (and will last for another 5 days or so).  What we found is pretty amazing.  We found that the transcriptional response during maintenance is very complex, involving up-regulation of >700 transcripts and down-regulation of <400 transcripts.  Given that there are currently 21,000 gene models in the draft of the Aplysia genome, this means more than 5% of all genes are affected (probably more due to the likelihood of some false negatives and the fact that our microarray doesn’t cover the entire Aplysia genome).   That’s a lot of upheaval… what exactly is changing?  It was daunting to make sense of such a long list of transcripts, but we noticed some very clear patterns.  First, there is regulation influencing growth: an overall up-regulation of transcripts related to producing, packaging, and transporting proteins and a down-regulation of transcripts related to catabolism.  Second, we observed lots of changes which could be related to meta-plasticity.  Specifically, we observed down regulation in isoforms of PKA, in some serotonin receptors, and in a phosphodiesterase.  All of these changes might be expected to limit the ability to induce sensitization, which would be consistent with the BCM rule (once synapses are facilitated, raise the threshold for further facilitation).  (Bienenstock, Cooper, & Munro, 1982).

One of the very intriguing findings to come out of this study is that the transcriptional changes occuring during encoding are very distinct from those occuring during maintenance.  We found only about 20 transcripts regulated during both time points.  We think those transcripts might be especially important, as they could play a key regulatory/organizing role that spans from induction through maintenance.  One of these transcripts encoded a peptide transmitter called FMRF-amide.  This is an inhibitory transmitter, which raises the possibility that as the memory is encoded, inhibitory processes are simultaneously working to limit or even erode the expression of the memory (a form of active forgetting).

There are lots of exciting pathways for us to explore from this intriguing data set.  We feel confident heading down these paths because a) we used a reasonable sample size for the microarray, and b) we found incredibly strong convergent validity in an independent set of samples using qPCR.

This is a big day for the Slug Lab, and a wonderful moment of celebration for the many students who helped bring this project to fruition: Catherine Conte (applying to PT schools), Samantha Herdegen (in pharmacy school), Saman Kamal (in medical school), Jency Patel (about to graduate), Ushma Patel (about to graduate), Leticia Perez (about to graduate), and Marissa Rivota (just graduated).  We’re so proud of these students and so fortunate to work with such a talented and fun group.

Bienenstock, E., Cooper, L., & Munro, P. (1982). Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience, 2(1), 32–48. [PubMed]
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. Learning and Memory, 24, 502–515. doi: 10.1101/lm.045450117 [Source]
Herdegen, S., Holmes, G., Cyriac, A., Calin-Jageman, I. E., & Calin-Jageman, R. J. (2014). Characterization of the rapid transcriptional response to long-term sensitization training in Aplysia californica. Neurobiology of Learning and Memory, 116, 27–35. doi: 10.1016/j.nlm.2014.07009