Björn Brembs

[[![ResearchBlogging.org](https://www.researchblogging.org/public/citation_icons/rb2_mid.png){decoding="async"
style="border: 0;"}](https://www.researchblogging.org)]{style="float: left; padding: 5px;"}[The
data clearly
show](https://journal.frontiersin.org/Journal/10.3389/fnhum.2013.00291/full)
that publications in *Cell*, *Nature* or *Science* (*CNS* for short), on
average, cannot be distinguished from other publications, be it by
methodology, reproducibility or other measures of quality. Even their
citation advantage, while statistically significant, is so small that it
is practically negligible. Regardless of all the data, individual
examples sometimes serve to illuminate the data and drive some facts
home. There are more or less extreme examples of *CNS* publications not
meeting the expectations to which they are commonly held. It's needless
to mention all the examples that went through the media, but I would
instead [cite a paper from my
field](http://blogarchive.brembs.net/news.php?item.519.3) (where I feel
reasonably competent) as an instance of an extreme case of an obviously
flawed paper making in into the journal *Nature*.

However, one doesn't even need to look at the extreme cases. Let's look
at a [paper in *Science
Magazine*](https://www.sciencemag.org/content/344/6186/901.full) I
actually quite like. It's an interesting topic, a beautiful experimental
paradigm and the results in the wildtype flies are truly exciting. Their
mutant and transgenic results, if correct, are tantalizing as they run
counter to essentially all available literature on the gene in question.
I personally know and like the senior author of the paper, Gero
Miesenböck, and appreciate all of his work, including this publication.
All I'll try to do here is to make the case, that this paper is an
average paper in terms of the level of evidence provided to support the
claims made by the authors. Not obviously worse than most papers in our
field, but definitely nowhere near the level of evidence those
colleagues ignorant of the data would assume to be required for a *CNS*
paper. All papers have strengths and weaknesses, some have more
uncertainty associated with their results, others less. The data suggest
that there isn't much difference between journals, on average, and I'll
try to use some details in this *Science* paper to exemplify the data.

The authors state in their title that the gene *dFoxP* influences the
speed of perceptual decision-making in *Drosophila* fruit flies. They
test the flies by first conditioning them to avoid a given odor using
electric shocks. The choice test is then done in a chamber on individual
flies. Two odors enter the chamber from opposite ends and exit the
chamber in the middle. The fly then walks back and forth between the
ends of the chamber and avoidance is measured by where the fly spends
most of the time: in the half with the odor associated with electric
shock, or in the half with the control odor. In the current study, the
authors made the control odor increasingly similar to the one associated
with shock and found that wildtype flies spent more time in the middle
of the chamber, where they had to decide of whether to keep walking or
make a turn, the more similar the odors were. That is definitely an
exciting finding, suggesting that more similar odors require more
processing time for an avoidance decision than less similar odors.

In order to get a handle on the biological processes underlying this
interesting phenomenon, the authors have conducted a screen of
genetically modified flies, looking for mutants with longer decision
times than the wildtype flies. One of the candidates that showed up in
the screen, is the *Drosophila* orthologue of a gene involved in
language in humans, *FoxP*. It seems hard to understand what a gene
generally thought to be involved in motor learning has to do with this
perceptual task, but data are data, unless there are alternative
explanations. There are three main concerns that raise the suspicion
that the involvement of *dFoxP* in this task may not be as
straightforward as suggested in the title of this paper.

1.  It s common practice to homogenize the genetic background of mutants
    with that of the control strain to which the mutants are compared.
    This is done to exclude variations other than in the gene of
    interest to be responsible for any differences. However, the authors
    do not state whether and if so for how many generations the mutant
    flies were outcrossed to the proper wildtype genetic background.
    Given that the flies came from a screen, it is unlikely that all
    strains tested in the screen were outcrossed. For instance, the
    alleles described in the paper show significant lethality which
    disappears when outcrossed for six generations, suggesting that
    their general level of fitness and health appears to be affected by
    their genetic background. It is thus possible that factors in the
    genetic background and not *dFoxP* may be responsible for the
    phenotype. Given the track record of the Miesenböck lab, it is
    unlikely they did not outcross the flies, but at the very least, the
    number of generations for which the outcrossing has taken place
    would have to be listed in the paper.

2.  A common procedure to test for genetic background effects, in
    addition to outcrossing which can reduce but not eliminate genetic
    background effects, is to use an additional method to manipulate the
    gene in question. The authors used RNA interference (RNAi) to
    attempt to down-regulate the expression of *dFoxP*. It is common
    practice to use quantitative PCR to test the effectiveness of this
    method, as a) RNAi usually does not abolish gene expression
    completely and b) it is known to have off-target effects, i.e., it
    may affect the expression of other genes besides/instead of the
    target gene. The line used in this study comes from a collection
    known to have problems with off-target effects, so testing
    effectiveness is especially important. However, no evidence that
    such a test was performed is described. Below is what such data
    would look like, if you were to order all RNAi constructs currently
    available, drive their expression in all neurons (with nSyb-GAL4)
    and then have an undergraduate student run a whole slew of qPCR
    reactions to compare the expression (in fly heads) of all three
    *dFoxP* isoforms to the respective control strain (many thanks Joel
    and postdoc [Axel](https://lab.brembs.net/author/axel/) for all that
    work!): No effect!

    ::: {#attachment_596 .wp-caption .alignnone style="width: 530px"}
    [![relative expression of dFoxP isoforms in six different RNAi
    lines](https://bjoern.brembs.net/wp/wp-content/uploads/2014/06/foxp_qpcr-1024x429.jpg){.wp-image-596
    .size-large decoding="async"
    aria-describedby="caption-attachment-596" width="520" height="217"
    srcset="https://bjoern.brembs.net/wp/wp-content/uploads/2014/06/foxp_qpcr-1024x429.jpg 1024w, https://bjoern.brembs.net/wp/wp-content/uploads/2014/06/foxp_qpcr-300x125.jpg 300w, https://bjoern.brembs.net/wp/wp-content/uploads/2014/06/foxp_qpcr.jpg 1808w"
    sizes="(max-width: 520px) 100vw, 520px"}](https://bjoern.brembs.net/wp/wp-content/uploads/2014/06/foxp_qpcr.jpg)
    relative expression of dFoxP isoforms in six different RNAi lines
    :::

    I cannot emphasize enough that the graph above represents [very
    preliminary data]{style="text-decoration: underline;"}. It's data
    from one undergraduate student who had prior experience with qPCR
    before coming to our lab, but who did not do this work full-time.
    There definitely need to be more biological replicates and some
    additional drivers need to be used (e.g. an actin driver to drive
    RNAi in all cells). On the other hand, the results match my own qPCR
    results with these lines and results from another laboratory that we
    collaborate with. So while I would not exclude that we may see
    significant reduction in *dFoxP* expression with some technical
    tweak, the currently available data suggest that none of the
    available dFoxP RNAi lines significantly knocks down *dFoxP*
    expression, including the one tested by DasGupta *et al*. (15732V).
    Our work also points to a reason why none of the lines seems to have
    a detrimental effect on *dFoxP* expression: we have localized
    polymorphisms in the *dFoxP* gene which could bias the RNAi process
    towards sequestration, rather than degradation of the mRNA,
    potentially explaining some of the very high values in the plot
    above. Thus, it is possible (and we consider it even very likely)
    that some or all of these lines actually do affect *dFoxP*
    expression in the way intended. However, we currently have little
    possibility to ensure it's not an off-target effect after all.  
    I'd thus tentatively conclude that the phenotype DasGupta *et al.*
    have discovered can indeed be ascribed to *dFoxP* action in this
    task. However, at this point, there is insufficient data to make
    that statement with any reasonable certainty (no matter how likely I
    personally find that to be the case!).

3.  Finally, previous work on *FoxP* both in other animals and in flies
    (including our own paper coming out tomorrow, watch this space after
    5pm EST on June 25) suggests an involvement of *dFoxP* in motor
    learning and perhaps also (consequently?) motor coordination. In
    fact, [our](http://blogarchive.brembs.net/comment-n632.html)
    [work](http://blogarchive.brembs.net/comment-n678.html) shows that
    learning about external stimuli is fine in *FoxP* mutant flies. It
    is thus critical to make sure that any animals showing a deficit in
    this task can perform the required movements (walking, turning,
    starting, stopping) accurately. The authors here attempted to ensure
    this by measuring the time spent in sections of the chamber other
    than the decision section in the middle. However, one would assume
    that flies will mostly turn or sit at the ends of the chamber and in
    the decision sector, with fewer turns and pauses in the sectors
    in-between. Thus, by evaluating sectors in which the flies mainly
    walk straight, the authors may be underestimating the contribution
    of turns and no-movement episodes to the decision-making process. If
    that is correct (and the brief explanations in the methods section
    make it very difficult to be entirely sure about how precisely and
    on which sectors they have performed the calculations),
    *dFoxP*-manipulated flies may either have a problem starting to walk
    from a stop, or have difficulty turning in the chamber and the
    authors would interpret this as an increased decision-time, rather
    than a motor problem.

In summary, it may well be that *dFoxP* entails all the functions
reported by DasGupta *et al*. and this would indeed make for a giant
head-scratcher about the (ancestral) functions of *FoxP*, given all the
mountain of work involving it in motor, rather than perceptual
processes. However, at this point, some more work (at least some more
detailed method explanations!) is required to be reasonably certain
about the existence of such a problem. Personally, I do think that the
phenotype is due to the authors' *FoxP* manipulations, but I may be
wrong, the evidence is not strong enough either way. I do have my
doubts, however, about the phenotype not being due to motor defects, but
I could be wrong there as well, as the data is inconclusive. At this
point, we need more experiments and/or data analysis to show who is
wrong. Again, I still like the paper, it's the kind of work that drives
our field forward.

Speaking more generally: there is no need for any researcher to wait
(perhaps indefinitely?) until they have the perfect data set, with the
unambiguous results and the foolproof conclusions. Just send your plain
decent work to *CNS* magazines as well! If they publish it, you will get
a job and nobody but some lone blogger will ever ask about the content
of that paper ever again.

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

[DasGupta, S., Ferreira, C., & Miesenbock, G. (2014). FoxP influences
the speed and accuracy of a perceptual decision in Drosophila [Science,
344]{style="font-style: italic;"} (6186), 901-904 DOI:
[10.1126/science.1252114](https://dx.doi.org/10.1126/science.1252114){rev="review"}]{.Z3988
title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Science&rft_id=info%3Adoi%2F10.1126%2Fscience.1252114&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=FoxP+influences+the+speed+and+accuracy+of+a+perceptual+decision+in+Drosophila&rft.issn=0036-8075&rft.date=2014&rft.volume=344&rft.issue=6186&rft.spage=901&rft.epage=904&rft.artnum=http%3A%2F%2Fwww.sciencemag.org%2Fcgi%2Fdoi%2F10.1126%2Fscience.1252114&rft.au=DasGupta%2C+S.&rft.au=Ferreira%2C+C.&rft.au=Miesenbock%2C+G.&rfe_dat=bpr3.included=1;bpr3.tags=Anthropology%2CBiology%2CPsychology%2CNeuroscience%2CBehavioral+Biology%2C+Ecology%2C+Evolutionary+Biology%2C+Genetics%2C+Zoology%2C+Biological+Anthropology%2C+Evolutionary+Anthropology%2C+Behavioral+Neuroscience%2C+Cognitive+Neuroscience%2C+Neurolinguistics%2C+Comparative+Psycholog"}


The data clearly show that publications in
<em>
 Cell
</em>
,
<em>
 Nature
</em>
or
<em>
 Science
</em>
(
<em>
 CNS
</em>
for short), on average, cannot be distinguished from other publications, be it by methodology, reproducibility or other measures of quality. Even their citation advantage, while statistically significant, is so small that it is practically negligible.

No need to only send your best work to Science Magazine

Genetically Separable\"
href=\"https://www.slideshare.net/brembs/wcalb14\"
target=\"\_blank\"\>Pavlovian and Skinnerian Processes are Genetically
Separable


Genetically Separable" href="https://www.slideshare.net/brembs/wcalb14" target="_blank"&gt;Pavlovian and Skinnerian Processes are Genetically Separable

Two evolutionary conserved, fundamental learning mechanisms

[[![ResearchBlogging.org](https://www.researchblogging.org/public/citation_icons/rb2_mid.png){decoding="async"
style="border: 0;"}](https://www.researchblogging.org)]{style="float: left; padding: 5px;"}This
year's Winter Conference on Animal Learning and Behavior
([WCALB](https://www.american.edu/cas/psychology/wcalb/)) will be on one
of my oldest and most central research projects, the commonalities and
differences between [operant](http://brembs.net/learning/operant.html)
and [classical](http://brembs.net/learning/classical.html) conditioning.
I picked this project for my [Diploma (Master's)
thesis](http://brembs.net/diploma/) way back in 1995, because I had
learned about these forms of conditioning in high-school and couldn't
believe it when I heard that nobody knew how the brain was doing it.

Little did I know back then, that already in the 1930s [B.F.
Skinner](https://en.wikipedia.org/wiki/B._F._Skinner) and the students
of [Ivan Pavlov](https://en.wikipedia.org/wiki/Ivan_Pavlov), Konorski
and Miller,
[had](https://psychclassics.yorku.ca/Skinner/Twotypes/twotypes.htm)
[started](https://psychclassics.yorku.ca/Skinner/Konorski/)
[discussing](https://psychclassics.yorku.ca/Skinner/ReplytoK/reply.htm)
[how](https://www.tandfonline.com/doi/abs/10.1080/00221309.1937.9918010#.UlO-VBCF04g)
operant and classical conditioning are similar and how they differ. It
wasn't until I had started my [PhD on this
topic](http://brembs.net/dissertation/), that I had found these gems in
the dusty bound volumes of our library. Many of the arguments and
questions raised in this soon 80 year-old exchange became the basis for
my research program in the following now almost 20 years. When I
embarked on this project, six decades had already passed with
significant progress, but without answers to these fundamental
questions.

The first major breakthrough from my perspective came with our discovery
that operant and classical processes can be [genetically
separated](http://brembs.net/rut-pkc), using the right behavioral
experiments. The experimental separation of 'Skinnerian' and 'Pavlovian'
components had not been possible before. These results showed that what
made these processes different was not *how* the animal was learning
(i.e., operantly or classically), but *what* it learned (i.e., about
external stimuli, e.g. Pavlov's bell, or about their own behavior, e.g.
pressing the lever in a [Skinner
box](http://brembs.net/operant/skinnerbox.html)). Thus, in order to
avoid confusion between the procedures (operant vs. classical) and the
mechanisms, we had to come up with descriptive terms for the learning
mechanisms. After much discussion and back-and-forth, we arrived at
'world-learning' for the mechanism that detects and processes
relationships in the external world and at 'self-learning' for the
mechanism that detects and processes the consequences of an animal's own
behavior.

The main reason why traditional experiments failed to uncover this
distinction appears to be that the depressed lever in a Skinner box
constitutes an external stimulus that signals food for the animal, just
as Pavlov's bell does for his dogs. Much like Pavlov's dogs would bark
at the bell when hungry, rats in a Skinner box use whatever means they
have to press the lever -- the specific behavior for pressing the lever
is not relevant and hence not learned. Skinner himself noted that "The
lever cannot be removed" as a technical problem in studying the
processes involved in his type of conditioning. In our experiments, we
were able to overcome this problem and find the genetically separable
mechanisms, which later were shown by other groups to be evolutionarily
conserved.

We have since found out that the [two learning mechanisms
interact](http://brembs.net/learning/drosophila/habit/) in order to
establish adaptive behavioral choice and allow the animal to always
establish the right equilibrium between efficiency and flexibility while
it is balancing the need to explore new resources with the need to
exploit the resource at hand.

Now, after all these years, it is the greatest honor to be invited to
give the keynote address to an entire session just on this research
topic. Granted, this is not a major conference with thousands of
attendees -- it is a small meeting with only a few dozen people.
Nevertheless, after almost two generations of researchers came and went,
these people are the remaining experts for a field long abandoned by
many colleagues as an unsolvable problem. If you find this long-standing
and challenging research topic as exciting as we do, I invite you to
join us in Winter Park, Colorado this coming February 8-12, 2014.

**[Information from the
organizer:]{style="text-decoration: underline;"}**

The *Winter Conference on Animal Learning and Behavior* will convene in
Winter Park, Colorado from Saturday evening, February 8, with departure
Wednesday morning, February 12, 2014. If you are interested in attending
WCALB 2014, please send your small *refundable* deposit by [October 21,
2013]{style="text-decoration: underline;"} so we know how many
condominiums to reserve. See "**\*DEPOSITS\***" section below.

**\*KEYNOTE ADDRESS\***

"Pavlovian and Skinnerian Processes are Genetically Separable"

Björn Brembs, Universität Regensburg

*Abstract*--The commonalities and differences between operant and
classical conditioning have been debated ever since Skinner and Konorski
embarked on their epic exchange about "two types of conditioned reflex
and a pseudo type" in the 1930s. New techniques that surmount
experimental design problems identified in early research allow for a
much improved separation of the two types of conditioning. These
technical advances, combined with modern genetic manipulations, provide
evidence that Pavlovian and Skinnerian processes separate not between
the learning procedure (operant vs. classical), but between learning
content (self vs. non-self). The picture emerging today reinforces
Skinner's early insight that operant conditioning is a composite
situation, comprised of a 'Pavlovian' component (learning about stimuli
-- 'world-learning') and a 'Skinnerian' component (learning about the
consequences of actions -- 'self-learning'). A research program that
distinguished these processes genetically is described.

 

Björn Brembs is Professor of Neurogenetics at Universität Regensburg. He
obtained his doctorate in genetics and neurobiology from Universität
Würzburg and has done post-doctoral research at the University of Texas
Houston Health Science Center.Thematically, Dr. Brembs' research
concerns the general organization of behavior with regards to reward and
punishment with the objective of better understanding how brains
accomplish adaptive behavioral choice.

** \*FOCUS SESSION\***

"Operant and Classical Learning: Comparisons and Interactions"

Allen Neuringer, Peter Killeen, Jeremie Jozefowiez (Université Lille
Nord de France), Michael Commons, Karen Pryor and Stanley Weiss have
already joined the Focus Session. The format is presentations (up to
25-minutes) with extended discussion among participants in a Research
Seminar Session. Additional qualified participants can be added. Let me
(sweiss@american.edu) know if you would like to join this session.

**\*MEETING, WINTER PARK AND ACCOMMODATIONS\***

The Winter Conference is a friendly and informal meeting that provides
an opportunity to combine intensive, scientifically rigorous discussions
--- related to animal conditioning, behavior and learning --- with
skiing at one of Colorado's premier ski areas, Winter Park. See website
(https://www.american.edu/cas/psychology/wcalb/index.cfm) for breadth of
WCALB paper sessions that reflect participants' research interests. All
participants are invited to make a presentation and suggest topics.
Graduate students are welcome and can present with their advisor's
endorsement.

There is downhill skiing for all skill levels, up to black diamond, as
well as excellent cross-country skiing in the Arapaho National Forest,
Devil's Thumb and Snow Mountain Ranch. The majestic snow-covered Rockies
in winter are breathtaking.

The all inclusive cost for registration, four days in a shared Snowblaze
condominium, an opening buffet reception and dinner at a fine Winter
Park restaurant is *only* \$375/person or \$750/couple (couples have
their own room, usually with private bath, in a condo). The Snowblaze is
located in Winter Park near restaurants and shops. It has an excellent
health club with sauna, steam room, hot tub, pool, weight room and
handball courts. All units have complete kitchens.

If available, a *family* can have an entire 2-bedroom condominium unit
for \$1,125 plus \$115 for each person over three. The 2-bedroom units
each sleep up to six people if a convertible sofa in the living room is
used. All family members are invited to the opening buffet reception,
Conference dinner and sessions.

** \*DEPOSITS\***

We will be in the Colorado Rockies just a week before the prime ski
season starts. Therefore, condominiums must be reserved early. If you
think you would like to attend WCALB 2014, please let me
(sweiss@american.edu) know ASAP by e-mail and send your \*refundable\*
(until November 30) deposit (\$50 per person, \$100 per couple, \$200
per family) by **[October 21,
2013]{style="text-decoration: underline;"}**. This will help insure a
place for you in our limited number of reserved condominiums. Make
checks out to Stanley Weiss, WCALB with "WCALB 2014″ in the lower left
corner. [Final payment is due November 30,
2013]{style="text-decoration: underline;"}.

Please send your payment to:

 

Stanley Weiss, Convener  
Winter Conference on Animal Learning & Behavior  
Department of Psychology  
AmericanUniversity  
Washington, DC 20016

 

**We will do our best to include late registrants in the Conference**,
but often they have had to pay substantially more for their
accommodations because our reserved condominiums were full.Therefore, if
you are interested in attending the Conference *let me know soon* and
send your refundable (until November 30) deposit. A CALL for
presentations will go out to registered participants in early
December.If you have any questions or suggestions, contact me at
sweiss@american.edu.

I hope to see you in Winter Park!

Stan

 

Stanley J. Weiss  
Professor of Experimental Psychology Emeritus  
American University  
Washington, D. C. 20016  
Phone: 301-656-3454  
Fax: 202-885-1023  
e-mail:sweiss@american.edu

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

[B. F. Skinner (1935). Two Types of Conditioned Reflex and a Pseudo Type
[The Journal of General Psychology, 12]{style="font-style: italic;"}
(1), 66-77 DOI:
[10.1080/00221309.1935.9920088](https://dx.doi.org/10.1080/00221309.1935.9920088){rev="review"}]{.Z3988
title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+General+Psychology&rft_id=info%3Adoi%2F10.1080%2F00221309.1935.9920088&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Two+Types+of+Conditioned+Reflex+and+a+Pseudo+Type&rft.issn=&rft.date=1935&rft.volume=12&rft.issue=1&rft.spage=66&rft.epage=77&rft.artnum=http%3A%2F%2Fwww.tandfonline.com%2Fdoi%2Fabs%2F10.1080%2F00221309.1935.9920088%23.UlO1WhCF04h&rft.au=B.+F.+Skinner&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CPsychology%2CNeuroscience%2CBehavioral+Biology%2C+%2C+Learning%2C+Quantitative+Psychology%2C+Behavioral+Neuroscience"}  
[J. Konorski, & S. Miller (1937). On Two Types of Conditioned Reflex
[The Journal of General Psychology, 16]{style="font-style: italic;"}
(1), 264-272 DOI:
[10.1080/00221309.1937.9917950](https://dx.doi.org/10.1080/00221309.1937.9917950){rev="review"}]{.Z3988
title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+General+Psychology&rft_id=info%3Adoi%2F10.1080%2F00221309.1937.9917950&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=On+Two+Types+of+Conditioned+Reflex&rft.issn=&rft.date=1937&rft.volume=16&rft.issue=1&rft.spage=264&rft.epage=272&rft.artnum=http%3A%2F%2Fwww.tandfonline.com%2Fdoi%2Fabs%2F10.1080%2F00221309.1937.9917950%23.UlO-VhCF04g&rft.au=J.+Konorski&rft.au=S.+Miller&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CPsychology%2CNeuroscience%2CBehavioral+Biology%2C+%2C+Behavioral+Neuroscience%2C+Learning%2C+Quantitative+Psychology"}  
[B. F. Skinner (1937). Two Types of Conditioned Reflex: A Reply to
Konorski and Miller [The Journal of General Psychology,
16]{style="font-style: italic;"} (1), 272-279 DOI:
[10.1080/00221309.1937.9917951](https://dx.doi.org/10.1080/00221309.1937.9917951){rev="review"}]{.Z3988
title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+General+Psychology&rft_id=info%3Adoi%2F10.1080%2F00221309.1937.9917951&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Two+Types+of+Conditioned+Reflex%3A+A+Reply+to+Konorski+and+Miller&rft.issn=&rft.date=1937&rft.volume=16&rft.issue=1&rft.spage=272&rft.epage=279&rft.artnum=http%3A%2F%2Fwww.tandfonline.com%2Fdoi%2Fabs%2F10.1080%2F00221309.1937.9917951%23.UlO-8RCF04g&rft.au=B.+F.+Skinner&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CPsychology%2CNeuroscience%2CBehavioral+Biology%2C+%2C+Behavioral+Neuroscience%2C+Learning%2C+Quantitative+Psychology"}  
[J. Konorski, & S. Miller (1937). Further Remarks on two Types of
Conditioned Reflex [The Journal of General Psychology,
17]{style="font-style: italic;"} (1), 405-407 DOI:
[10.1080/00221309.1937.9918010](https://dx.doi.org/10.1080/00221309.1937.9918010){rev="review"}]{.Z3988
title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+General+Psychology&rft_id=info%3Adoi%2F10.1080%2F00221309.1937.9918010&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Further+Remarks+on+two+Types+of+Conditioned+Reflex&rft.issn=&rft.date=1937&rft.volume=17&rft.issue=1&rft.spage=405&rft.epage=407&rft.artnum=http%3A%2F%2Fwww.tandfonline.com%2Fdoi%2Fabs%2F10.1080%2F00221309.1937.9918010%23.UlO-VBCF04g&rft.au=J.+Konorski&rft.au=S.+Miller&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CPsychology%2CNeuroscience%2CBehavioral+Biology%2C+%2C+Behavioral+Neuroscience%2C+Learning%2C+Quantitative+Psychology"}


This year’s Winter Conference on Animal Learning and Behavior (WCALB) will be on one of my oldest and most central research projects, the commonalities and differences between operant and classical conditioning.

Almost 80 years on, progress on operant and classical conditioning

[*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'm using 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 post is from [April 29,
2011](http://blogarchive.brembs.net/news735.html):*]{style="font-size: 12px;"}

<div>

</div>

<div>

<div>

</div>

<div>

Only very few laboratories in the world perform [operant
conditioning](http://brembs.net/learning/operant.html){target="_blank"
rel="external"} of [spinal
reflexes](https://en.wikipedia.org/wiki/Stretch_reflex){target="_blank"
rel="external"}. In fact, a [quick PubMed
search](https://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=%28%28%28operant%5BTitle%2FAbstract%5D%29+AND+conditioning%5BTitle%2FAbstract%5D%29+AND+reflex%5BTitle%2FAbstract%5D%29+AND+stretch%5BTitle%2FAbstract%5D&save_search=true){target="_blank"}
reveals there is only a single lab which has published in this field in
the last decade, the lab of [Jonathan
Wolpaw](https://www.wadsworth.org/resnres/bios/wolpaw.htm){target="_blank"}.
Jonathan's review "What Can the Spinal Cord Teach Us about Learning and
Memory?" in [*The
Neuroscientist*](https://dx.doi.org/10.1177/1073858410368314) shows what
neuroscience is missing out on by not investing more in this fascinating
field.[Operant
conditioning](http://brembs.net/learning/operant.html){target="_blank"
rel="external"} of spinal reflexes is probably the most controlled
[operant
conditioning](http://brembs.net/learning/operant.html){target="_blank"
rel="external"} situation imaginable: reward the animal when it responds
with a reflex magnitude above or below a certain threshold,
respectively. This is done by triggering the reflex with a cuff
electrode around the nerve and then measuring the amplitude of the
reflex with
[electromyography](https://en.wikipedia.org/wiki/Electromyography){target="_blank"}
(EMG):

![hreflex.png](http://blogarchive.brembs.net/e107_images/newspost_images/hreflex.png){decoding="async"}  
The electrical stimulation via the cuff excites the muscle directly (the
M signal in the EMG in the upper left corner) and, with a delay,
indirectly via the H-reflex.

Below is an image of what that setup looks like when it's implanted in a
rat:  
![hreflex_rat.png](http://blogarchive.brembs.net/e107_images/newspost_images/hreflex_rat.png){decoding="async"}  
The rat is running around in its cage and receives a food reward
whenever the H-reflex reaches the required amplitude.

Given that the textbook reflex (i.e., the spinal stretch reflex shown in
the first image above) is monosynaptic, one would expect just this
synapse to be modified after [operant
conditioning](http://brembs.net/learning/operant.html){target="_blank"
rel="external"}. However, this synaptic plasticity only contributes to
one form of this learning, namely up-conditioning. Up-conditioning
refers to the experiment where increased reflex amplitude was rewarded.
In these experiments, the synaptic input from the primary 1a afferents
(blue, in the first figure above) is increased, making the reflex
amplitude larger. In down-conditioning, however, the synaptic input to
the motor neuron is not altered, but the motor neuron itself (green)
reveals an increased firing threshold and reduced [postsynaptic
potentials](https://en.wikipedia.org/wiki/Postsynaptic_potential){target="_blank"},
making the motor neuron less likely to fire (and hence reflex amplitude
smaller). In addition to these different forms of plasticity, correlates
of the memory can be found throughout the spinal cord and even in the
cortex. Some of these correlates appear to be compensatory modifications
to other reflexes, preventing the increased amplitude of the conditioned
reflex from making the animal limp. Again others are required for the
maintenance of the memory, but do not seem to directly contribute to the
memory trace itself. There are many more examples in the paper.

Taken together, the results presented in this review open up more
questions than they answer and demonstrate that this is a promising
research field, with still plenty of low-hanging fruit and a large
variety of basic neuroscientific lessons which are hard, if not
impossible to learn from other models.

What are you waiting for? Go and study [operant
conditioning](http://brembs.net/learning/operant.html){target="_blank"
rel="external"} of these reflexes
already! ![smallgrin.png](http://blogarchive.brembs.net/e107_images/emotes/yellow/smallgrin.png){decoding="async"}

</div>

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

<div>

Wolpaw, J. (2010). What Can the Spinal Cord Teach Us about Learning and
Memory? The Neuroscientist, 16 (5), 532-549 DOI:
[10.1177/1073858410368314](https://dx.doi.org/10.1177/1073858410368314){rev="review"}

</div>

</div>


<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’m using this functionality to re-blog a few posts from the archives during the month of august while I’m away.
</em>

Flashback: What can the spine teach us about learning?

<em>
 In the process of migrating content from the old site to WordPress, I’m also moving some articles from there and re-publishing them here as posts. This one is such a case, originally published on December 7, 2006.
</em>

Brains as output/input systems

[*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>

Messaggi di Rogue Scholar

No need to only send your best work to Science Magazine

Two evolutionary conserved, fundamental learning mechanisms

Almost 80 years on, progress on operant and classical conditioning

Flashback: What can the spine teach us about learning?

Brains as output/input systems

Flashback: The neurobiology of self-learning