Björn Brembs

[*During my [flyfishing vacation last
year](http://blogarchive.brembs.net/comment-n862.html), pretty much
nothing was happening on this blog. Now that I've migrated the blog to
WordPress, I can actually schedule posts to appear when in fact I'm not
even at the computer. I want to use this functionality to re-blog a few
posts from the [archives](http://blogarchive.brembs.net) during the
month of august while I'm away. This is the first post in this series,
just to see if it works and what needs to be tweaked. This post is from
[October 31,
2011](http://blogarchive.brembs.net/news794.html):*]{style="font-size: 12px;"}

 

It's been a while since I've last been so excited about [a new finding
by someone
else](https://www.sciencemag.org/content/334/6054/385.full){target="_blank"
rel="external"}
![](http://blogarchive.brembs.net/e107_images/emotes/yellow/smile.png){decoding="async"}
And until today, this paper from last week even flew completely under my
radar. I had seen the title and decided it's not relevant. A
collaborator of mine sent it to me after she found it searching for a
current affiliation of a former postdoc of hers -- which was how she
realized how pertinent this work was to our research and sent it to me
(which says something about the way scientists are able to stay on top
of the literature. Note to self: write separate post!).

This paper detailing experiments in transgenic mice joins a pair of
papers in invertebrate model systems (
*[Aplysia](http://brembs.net/learning/aplysia/){target="_blank"
rel="external"}* and
*[Drosophila](http://brembs.net/learning/drosophila/){target="_blank"
rel="external"}*), suggesting that brains have two distinct molecular
learning mechanisms, one to learn about relationships among events in
the world around them and one to learn about the effects of their own
behavior on the world. This distinction shares several conceptual
features with the distinctions that have been made between [operant
conditioning](http://brembs.net/learning/operant.html){target="_blank"
rel="external"} and [classical
conditioning](http://brembs.net/learning/classical.html){target="_blank"
rel="external"} or between declarative and procedural memory, and
several other related dichotomies, but is yet slightly different.

Here's a drastically simplified diagram of what the current canonical
pathway looks like for 'synaptic plasticity', the kind of physiological
process that modifies the connections between neurons in order to store
memories (screenshot from one of my talks):

[![canonical_small.png](http://blogarchive.brembs.net/e107_images/newspost_images/canonical_small.png){decoding="async"}](http://blogarchive.brembs.net/e107_images/newspost_images/canonical.png){target="_blank"}

Briefly, the to-be-remembered information is translated into neuronal
signals which are eventually translocated into the memory-storing
neuron, where an adenylyl cyclase (encoded by the *rutabaga* gene in
flies) generates cAMP, which activates Protein Kinase A (PKA), which in
turn eventually activates a protein with the acronym CREB. CREB is a
transcription-factor switching on genes which modify the neuron, storing
the memory. Not shown is how PKA can itself also modify the neuron to
allow memories to form almost instantaneously, without the need for
protein synthesis (which takes a while). OK, this is really extremely
simplified, but the important point here is that there is no Protein
Kinase C (PKC) involved. In fact, PKC has been shown to either not be
involved at all, or only to maintain the memory, long after it's been
formed. The cool thing about this learning mechanism (and why its
discovery got the [Nobel Prize in
2000](https://www.nobelprize.org/nobel_prizes/medicine/laureates/2000){target="_blank"})
is that you find it in all bilaterian animals, e.g. flies, snails and
mice.

In 2008 I
[wrote](http://blogarchive.brembs.net/comment-n400.html){target="_self"}
here about one of our publications that we had discovered a
'[Skinnerian](http://brembs.net/rut-pkc){target="_self"}' learning
mechanism, which did not require the *rutabaga* gene, but PKC. Back then
we couched the discovery in terms of the 70-something year-old debate
about whether operant and [classical
conditioning](http://brembs.net/learning/classical.html){target="_blank"
rel="external"} share a common learning mechanism or not. The idea was
that [operant
conditioning](http://brembs.net/learning/operant.html){target="_blank"
rel="external"} involves learning about the consequences of one's
behavior while [classical
conditioning](http://brembs.net/learning/classical.html){target="_blank"
rel="external"} involves learning about the ring of a bell being
followed by food
![](http://blogarchive.brembs.net/e107_images/emotes/yellow/smile.png){decoding="async"}
For this experiment, we used the genetic toolkit of
*[Drosophila](http://brembs.net/learning/drosophila/){target="_blank"
rel="external"}* to express an inhibitor of PKC (PKCi) in all cells of
the fly only during the experiment. These flies had trouble learning an
operant task in which all external cues had been removed, but as soon as
'classical' cues were added, they learned just fine.

This discovery was followed in the same year by [a
paper](https://www.sciencedirect.com/science/article/pii/S0896627308005928){target="_blank"}
from my postdoctoral lab that showed basically the analogous outcomes in
the marine snail
*[Aplysia](http://brembs.net/learning/aplysia/){target="_blank"
rel="external"}*. This got me very excited: flies and snails? What about
the chordates?

[![conservation_small.png](http://blogarchive.brembs.net/e107_images/newspost_images/conservation_small.png){decoding="async"}](http://blogarchive.brembs.net/e107_images/newspost_images/conservation.png)

In their new paper, Rochefort *et al.* express the same PKCi peptide
that we had used in our fly study in the cerebellum of mice. They use
these mice to perform orientation and navigation experiments in which
the animals either have to rely on self-motion cues (procedural
learning) or on the position and identity of external cues (declarative
learning) to find a particular location. It turned out that in all three
of their experiments, whenever the animals could rely on external cues,
they learned to find the location just fine. However, when the cues
either were removed or arranged in a way to conflict with each other,
the mice showed a severe decrement in performance. In other words, also
these colleagues found a PKC-dependent form of learning which is mainly
concerned with the behavior of the animal itself and less with learning
about events in its environment.

Are these experiments in three model systems enough to make a strong
claim there we are in the process of opening up a new field of research,
the study of
'[self-learning](http://brembs.net/learning/drosophila/behavproc11/){target="_self"}'?
I wouldn't think so if we wouldn't have yet another piece of evidence up
our sleeves: we are currently in the process of submitting a manuscript
that details our
[results](http://blogarchive.brembs.net/request99.html){target="_self"}
on the fly gene most closely related to the '[language
gene](https://discovermagazine.com/2011/oct/08-the-brain-language-fossils-buried-in-your-cells/){target="_blank"}'
([that
wasn't](https://mindhacks.com/2011/10/26/ten-years-of-the-language-gene-that-wasnt/){target="_blank"}),
FOXP2. Briefly, language acquisition can be thought of as an operant
process: babies babble and use the auditory feedback of what it sounded
like when they babbled to change their babbling -- eventually into
language. Songbirds learn their songs in a quite similar way. Both
humans and songbirds have trouble learning their respective
vocalizations if the gene FoxP2 is not intact. So we went and looked for
a homologous gene in
*[Drosophila](http://brembs.net/learning/drosophila/){target="_blank"
rel="external"}*, found it (*dFoxP*), manipulated it and found that the
manipulations had the same effect as the PKCi expression: self-learning
was affected and world-learning wasn't.

Thus, we (several different labs independently) now appear to have
discovered not one, but two components of this new self-learning
mechanism, PKC and FoxP:

[![nuplast_small.png](http://blogarchive.brembs.net/e107_images/newspost_images/nuplast_small.png){decoding="async"}](http://blogarchive.brembs.net/e107_images/newspost_images/nuplast.png){target="_blank"}

In fact, evidence from
*[Aplysia](http://brembs.net/learning/aplysia/){target="_blank"
rel="external"}* suggests that this mechanism also includes cAMP, but
form a different cyclase and activating a different sort of PKA.
However, this has not been tested in the other systems, so far.  
Thus, I think there now are too many converging results from very
disparate experiments to just be chance. I now have the very strong
suspicion that we are on the cusp of the birth of a new research field:
the neurobiology of self-learning.

------------------------------------------------------------------------

Rochefort, C., Arabo, A., Andre, M., Poucet, B., Save, E., & Rondi-Reig,
L. (2011). Cerebellum Shapes Hippocampal Spatial Code Science, 334
(6054), 385-389 DOI:
[10.1126/science.1207403](https://dx.doi.org/10.1126/science.1207403){rev="review"}


<em>
 During my flyfishing vacation last year, pretty much nothing was happening on this blog. Now that I’ve migrated the blog to WordPress, I can actually schedule posts to appear when in fact I’m not even at the computer. I want to use this functionality to re-blog a few posts from the archives during the month of august while I’m away. This is the first post in this series, just to see if it works and what needs to be tweaked.
</em>

Publicaciones de Rogue Scholar

Flashback: The neurobiology of self-learning