Björn Brembs

In a discussion about what decisions are, [John
Krakauer](https://en.wikipedia.org/wiki/John_Krakauer) emphatically
pronounced that "decisions happen for reasons", in answering 'no' to my
question if it wasn't a decision with which foot to start walking from a
stand-still.

A [recent article](https://www.nature.com/articles/s41586-024-07890-3)
from the laboratory of Carolina Rezaval in Birmingham studied a
decision-making process in male *Drosophila* fruit flies where the
reasons for each decision seemed apparent. When a male fly was presented
with a looming stimulus (which mimics a threat from a nearing predator)
while in the early stages of courtship, it stops courting and either
freezes or tries to escape. In later stages of courtship, however, the
same threat stimulus is no longer able to interrupt courtship and elicit
escape. While it is less clear if the male fruit fly is able to
articulate them, the reasons for him to behave in that way seem obvious:
in the early stages of courtship, the male escapes as it is still not
clear if the courtship attempts will be successful. In a later stage,
once sufficient information has accumulated about the receptivity of the
female and/or copulation is close, it's worth trading some safety for
the prospects of getting one's genes into the next generation. In
biology, such reasons are commonly called "ultimate causations" of the
behavior, while the neurobiology by which they are implemented are the
"proximate causations". The recent article concerned the proximate
causations of these decisions in *Drosophila*.

In the early stages of courtship, the authors found, a class of visual
neurons in the fly's optic lobe called LC16 detect and respond to the
threat stimulus. Via several other neurons, these LC16 neurons connect
to P1 neurons in the fly brain, which collect multimodal information
(e.g., female sensory cues) and can mediate courtship behavior. If LC16
neurons are activated by a threat stimulus, downstream neurons release
serotonin, which inhibits the P1 neurons, halting courtship. This
inhibition between different behavior circuits is a common theme
observed in many other preparations, preventing two behaviors occurring
at the same time. In this case, LC16 neurons mediate escape behavior and
inhibit other behaviors, such as courtship, which could interfere with
the escape.

The fact that LC16 no longer inhibits courtship at later stages implies
that there is more to this story than the simple inhibition known from
so many other experiments with different animals. In the course of
courtship, as the duo gets closer to copulation, a population of
dopamine neurons in the male slowly ramp up their activity. These
dopamine neurons make direct synaptic connections with LC16 neurons and
inhibit them. In other words, the lack of escape is not due to a failure
of LC16 to inhibit courtship, but due to a failure of LC16 to respond to
threat stimuli.

Taken together, much like what was known from other preparations, there
is a mutual inhibition between circuits mediating different behaviors:
escape behavior circuits inhibit courtship circuits and courtship
circuits inhibit escape circuits. Until now, such mutual inhibition was
mainly studied in central-pattern-generator driven behaviors such as
swimming/feeding in molluscs (cited by the authors). In these cases, the
inhibition was identified very close to the motor side of the circuits.
In the case of male *Drosophila*, the relation of the neuronal processes
appears much closer to sensory input: Both LC16 and P1, while not being
sensory neurons, respond to sensory stimuli: LC16 to visual threat and
P1 to female sensory cues. Their inhibition can be interpreted as a lack
of sensation. The authors themselves do not seem to have made up their
minds about this. While they start their article by emphasizing the
animals' "decisions that require balancing opportunities and risks",
title and abstract of their work invoke more attention-like processes by
using words such as "love-blind". Which is it, decision or attention?

Is the decision to court or to escape really a decision, where the
"risks and opportunities" are weighed and then one of the two options is
chosen, or is this just an example of sensory competition, where
eventually one "blinds" the other, such that the losing stimulus is
simply not perceived? If only one of the two options is perceived, it
can no longer be a decision, can it? As neither LC16 nor P1 are directly
involved in sensing the stimuli, it is fair to assume that both the
looming stimulus and the female sensory cues are processed appropriately
even if any of the two classes of neurons are inhibited. However, if the
perceived looming stimulus is not longer assessed as a threat, or the
female sensory cues no longer perceived as sexually attractive, aren't
the animals then just simply responding to the single remaining
stimulus, without needing any reasons? As an aside: if so, what are the
'losing' stimuli perceived as?

The flies cannot tell us what they perceive and how, but this is not the
first time an animal's behavior that outwardly looks, sounds and smells
like a decision, loses these properties upon neuronal inspection.
Leeches commonly respond with local bending of their body wall to
mechanosensory stimulation such as light touches. Increase the intensity
of the touch a little, and the animal will start crawling away from it,
and with further increases, the animal will start swimming to escape.
However, when the animal is feeding, not even the strongest
mechanosensory stimuli can get the animal to do swim or crawl away. The
reasons for this decision are clear: if the leech has itself attached to
the animal it is sucking blood from then this animal is likely moving
around in the pond or stream where the leech lives. Given the common
environments for this leech species with plenty of vegetation in the
water, the moving animal will likely touch an number of obstacles and
chances are that these obstacles will also touch the leech. If it were
to start crawling away or even swim away in that phase, it would not be
able to obtain a sufficient blood meal for survival and procreation. So
the leech will literally hold on for dear life until it has had a
sufficient meal.

Decades of research have provided a pretty good understanding of the
circuitry for the processing of mechanosensory stimuli in the leech. Way
back in [2009, Gaudry and
Kristan](https://www.nature.com/articles/nn.2400) reported on the
neuronal mechanisms underlying the decision of feeding leeches to ignore
mechanosensory stimuli. Analogously to the male flies where a
sufficiently progressed courtship inhibits the transmission of threat
stimuli, feeding in the leech also leads to the release of a biogenic
amine, in this case serotonin. Serotonin then inhibits transmitter
release from the mechanosensory neurons. Conceptually very similar to
the male flies, the sensory stimuli are still perceived by the relevant
sensory neurons, but the transmission of the signal is blocked via
central processes. In male flies, dopaminergic neurons active during
courtship inhibit threat transmission during courtship, in the leech,
serotonergic neurons active during feeding inhibit mechanosensory
transmission during feeding. In the case of the leech, the authors take
an unambiguous position: Title, abstract and text all call the
inhibition of responses to mechanosensory stimulation during feeding a
'choice' or 'decision'.

In both flies and leeches, their behaviors were tied closely to sensory
stimuli: looming stimuli, female cues, blood, touch. It is precisely
because of these stimulus situations, that we can articulate the reasons
for the decisions the animals make. The animals' decision appear very
"reasonable" for the human observer. However, the two examples above are
just two of a growing list of examples where this very intuitive sense
of the behavior being a "decision" starts to disappear with our
understanding of how the neurons are doing it. If one of the two stimuli
the animal has to decide about gets shut out so that only one remains,
where is the decision?

A classic example of a decision in humans is "red or white wine?" If
human nervous systems would mediate such a decision analogously to flies
and leeches, the decision would be that between, say, an empty glass and
a glass filled with wine -- very different from how we envisage and
experience such decisions. But then again, the decisions studied in the
examples above are life-and death decisions for the animals. Everybody
knows that decisions about loved-ones are clouded by our love -- the
world "love-blindness" exists for a reason. Everybody has experienced
products in a grocery store becoming much more attractive when we are
hungry. It is conceivable that our minds similarly bend our sensory
experiences when in a life-threatening situation. If the animal examples
were anything to go by, decisions with reasons would more like reactions
to stimuli and less like actual decisions?

One can think of two arguments why studying the neurobiology of
decisions without reasons may actually be a more fruitful endeavor for
understanding decision-making, one conceptual and one practical.

Conceptually, as long as we haven't understood the whole process, we can
never be sure how much choice any human or animal ever has in a given
situation. We simply cannot know how coercive, ahem, compelling the
reasons for the decision actually are. Practically, it is also not the
most efficient way to just study one decision after another until one
happens to stumble upon one where the 'reasons' aren't really just
competing stimuli eliciting responses where, ultimately, one wins in a
very deterministic way. And even if one finds such a lucky situation, as
is seems to be the
[case](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256560)
with
[photopreference](https://royalsocietypublishing.org/doi/full/10.1098/rsob.160229?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org)
in flies, even then the practical problem remains, that without complete
knowledge of sensory processing, it is exceedingly difficult to know if
one's manipulations are actually affecting the decision-making process
itself or just some aspect of sensory processing.

A decision involves that there actually are at least two real options.
In the animal examples above, it looks, to the observer of the behavior,
like there were two such options, but once the neuronal mechanisms
mediating the 'choice' have become clear, one of the options was gone.
This is not the case when studying decisions that have no reasons at
all. Under such circumstances, the decision is always 50-50. The outcome
is, if the experiment is properly designed, unpredictable and happens
exclusively in the animal and cannot be dictated by external stimuli.
There are many such examples: isolated buccal ganglia of the sea slug
*Aplysia* produce different motor programs in a petri dish, without any
sensory organs. Analogously, [isolated leech nervous systems start and
stop producing swimming motor
programs](https://www.youtube.com/watch?v=-DmH3NxnUvM) in the dish.
[Tethered fruit flies produce different flight maneuvers even if flying
stationarily](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0000443)
inside the center of a ping-pong ball. In these cases, there are no
obvious, outwardly discernible 'reasons' for the animals/nervous systems
to pick one behavior over another. The reasons for the decision come
solely from within the animal itself. Conceptually, these situations
appear much closer to what we call "decisions" and practically, they
avoid the sensory confounds altogether.

These two kinds of decisions have traditionally been referred to as
"picking" and "choosing" in a [1977 seminal
paper](https://www.jstor.org/stable/40971175) by Ullmann-Margalit and
Morgenbesser.

So what really is a decision and how do we study them in neuroscience?
Picking or Choosing?

In human psychology, there is a
[distinction](https://archive.charlespence.net/papers/2016_Animal_Decisions.pdf)
between "judgments" and "decisions" (i.e., the judgment and
decision-making, JDM, framework):

> 'Judgments' refer to how individuals acquire and process information
> to arrive at an understanding of the situation or state of the world.
> 'Decisions' refer to the processes by which individuals use judgments
> to arrive at a course of action. In other words, individuals can vary
> in two main ways: how they 'see' the world, and what they decide to do
> about it.

It appears that the leech and fly work cited above merely concerns the
"judgment" aspect of JDM, leaving the decision-making untouched. In this
JDM framework, does it not seem wise for neuroscience experiments to
circumvent the practical problems of judgments by studying decisions
that happen in the absence or at least with equivalence of sensory
stimuli?


In a discussion about what decisions are, John Krakauer emphatically pronounced that “decisions happen for reasons”, in answering ‘no’ to my question if it wasn’t a decision with which foot to start walking from a stand-still. A recent article from the laboratory of Carolina Rezaval in Birmingham studied a decision-making process in male

 Drosophila

fruit flies where the reasons for each decision seemed apparent.

What is a decision?

Last week, [Elizabeth
Pennisi](https://news.sciencemag.org/author/elizabeth-pennisi) asked me
to comment on the [recent paper from Schreiweis *et
al.*](https://www.pnas.org/cgi/doi/10.1073/pnas.1414542111) entitled
"Humanized FoxP2 accelerates learning by enhancing transitions from
declarative to procedural performance". Since I don't know how much, if
anything, of my answers to her questions will end up in [her
article](https://news.sciencemag.org/biology/2014/09/human-speech-gene-can-speed-learning-mice),
I thought I might expand my answer into a post about this very
interesting work.

As the title implies, Schreiweis *et al.* have tested transgenic mice in
which the mouse version of the [language-related gene
FoxP2](https://en.wikipedia.org/wiki/FOXP2) was replaced with the human
version. They found that the timing of when repeated behaviors become
stereotypic is altered, such that the behaviors become stereotypic
earlier in the humanized mice than in the unaltered animals.

Importantly, this was only observed in tasks where two learning systems
were engaged simultaneously. In the literature, there are several
accounts of how to label these learning systems. In vertebrate learning
they are often referred to as procedural vs. declarative (also in
Schreiweis *et al*.), in animal navigation many authors refer to them by
allocentric vs. egocentric, and in *Drosophila* fruit flies we have
coined the terms world- vs. self-learning. The gist behind these word
pairs is that brains as different as those from insects and mammals seem
to adhere to a common functional organization that makes a very
fundamental distinction between self and non-self on various levels. Of
relevance to the current research is that external cues are treated by
different brain regions and learning of relationships among external
cues is mediated by different molecular processes than the internal
processes controlling behavior. Hence our distinction between [world-
and self-learning](http://blogarchive.brembs.net/comment-n794.html).

In situations where both world- and self-learning can occur
simultaneously, world-learning commonly dominates in the first phases of
training, while self-learning kicks in later. There is converging
evidence from vertebrates and invertebrates suggesting that this
staggering is probably accomplished by inhibitory connections from
circuits engaged in world-learning slowing down the circuits involved in
self-learning. Thus, it is this negotiation between self- and
world-learning which provides us with time to practice our skills before
they become automatic. One may also say that this negotiation is the
reason why it takes time (and how much time it takes) to form habits.
I've written a [longer
account](http://blogarchive.brembs.net/comment-n802.html) of this
negotiation on occasion of the poster publication of some of the
Schreiweis *et al.* work in 2011.

The recently published work by Schreiweis *et al*.  now contains both
molecular genetic and physiological results in addition to the
behavioral data. It adds weight to the so-called 'motor-learning
hypothesis' that came up some time around 2006/7 or thereabout. This
hypothesis posits that FoxP2 is mainly involved in the motor, or speech
component of language, i.e., learning to control the muscles in the
lips, tongue, voice chords, etc. in order to articulate syllables and
words.The movements of these organs have to become stereotypic in order
to reliably produce understandable language and the main experimental
paradigms for this stereotypization of behavior (independent of
language) have been procedural learning and habit formation. This work
provides further evidence that indeed FoxP2 is an important component of
the learning process that leads to automatic, stereotypic behavior.

In particular, it suggests that FoxP2 is involved in the control of the
process of stereotypization, i.e., at what point the behavior shifts
from being flexible, to becoming more rigid. Until this work, the
evidence from vertebrates and invertebrates has pointed to FoxP genes to
be involved in the automatization of behavior. Now, this evidence is
extended to also -- at least in mammals -- include the negotiation
process, which I don't think anybody had on the radar thus far.

One of the most interesting mechanistic questions that derive from the
fact that these mice only showed an effect on the negotiation between
the two learning systems (and not on the individual systems when
isolated), is how this negotiation takes place. Again, converging
evidence from invertebrates and vertebrates points towards inhibitory
connections from the world-learning processes keeping a break on the
self-learning processes. Is FoxP directly affecting these inhibitory
connections, or is it just subtly increasing the relative strength of
the procedural/self mechanism, such that it cannot be detected in
individual experiments where the components have been isolated, but only
in experiments where the negotiation actually takes place? The
physiological results by Schreiweis et al. point towards the latter:
induction of [long term
depression](https://en.wikipedia.org/wiki/Long-term_depression) (LTD) in
the dorsolateral, but not the dorsomedial striatum is enhanced in the
humanized mice -- and the dorsolateral striatum is the region thought to
be involved in self-learning, while some world-learning processes have
been localized to the dorsomedial striatum.

::: {#attachment_648 .wp-caption .aligncenter style="width: 530px"}
[![The mice with the humanized version of FoxP2 form habits earlier and
this might be due to earlier formation of LTD in the dorsomedial
striatum.](https://bjoern.brembs.net/wp/wp-content/uploads/2014/09/humfoxp-1024x339.png){.size-large
.wp-image-648 fetchpriority="high" decoding="async"
aria-describedby="caption-attachment-648" width="520" height="172"
srcset="https://bjoern.brembs.net/wp/wp-content/uploads/2014/09/humfoxp-1024x339.png 1024w, https://bjoern.brembs.net/wp/wp-content/uploads/2014/09/humfoxp-300x99.png 300w, https://bjoern.brembs.net/wp/wp-content/uploads/2014/09/humfoxp.png 1805w"
sizes="(max-width: 520px) 100vw, 520px"}](https://bjoern.brembs.net/wp/wp-content/uploads/2014/09/humfoxp.png)

Mice with the humanized version of FoxP2 form habits earlier and this
might be due to earlier formation of LTD in the dorsolateral striatum.
(Fig. S7 in Schreiweis *et al*.)
:::

The generation of these humanized mice was a particularly cool aspect of
the work. Compared to other, more common transgenic manipulations (e.g.
knock-outs), this humanization of FoxP2 is a rather sophisticated and
subtle alteration with rather nuanced but nevertheless very exciting
consequences. Many of the more drastic FoxP manipulations are homozygous
lethal and since there is evidence for positive selection of the human
variant, it was very straightforward to try and see what the human
variant would do in an organism that doesn't normally express this
version. Moreover, such a subtle alteration may uncover more subtle
roles of FoxP than the cruder manipulations have been able to. In fact,
the most specific behavioral consequences of any gene manipulation have
commonly been the most subtle of genetic manipulations. Therefore, the
scientific value of this manipulation extends far beyond the fact that
it mimics the human gene.

One needs to keep in mind, though, that it was only the structure of the
protein that was humanized, the regulatory region of the gene was not
altered, i.e., the putative expression pattern of the humanized FoxP2
gene is still that of the mouse version (and I don't know how different
the human regulatory region is from the mouse one -- in fact, I'm not
sure if we have full knowledge about the regulatory region of FoxP2,
yet).

Thus, it is quite amazing that these mice showed any difference at all
to WT mice, subtle as these differences may be perceived to be.

On a wider perspective, this work adds to our growing understanding of
the relation between learning and language acquisition. Schreiweis *et
al*.'s results fall very nicely within a string of recent work
suggesting that a major component of language acquisition is based on a
form of learning called [operant
conditioning](http://blogarchive.brembs.net/comment-n734.html). The
debate about the relevance of this form of learning for language is at
the core of the idea history of neuroscience and psychology. In 1957, BF
Skinner published "[Verbal
Behavior](https://en.wikipedia.org/wiki/Verbal_Behavior)" in which he
made the sweeping claim that language was essentially acquired via
operant learning.

Two years later, Noam Chomsky took Skinner to task in what would become
one of the cornerstones in the fall of behaviorism and the rise of
cognitive neuroscience and with it, of course, Chomsky's rise to fame as
one of the US' leading intellectuals.

If one can summarize Chomsky's massive (32 pages) [book
review](https://www.chomsky.info/articles/1967----.htm) in a single
sentence, it might be: "it may look like operant learning, but you don't
have any evidence". Instead, Chomsky went on to famously propose that we
all have inborn language acquisition devices as well as 'universal
grammar'. Of course, Chomsky also did not provide any evidence,
either.In the absence of any evidence on either side, Chomsky's
outstanding rhetorical skills prevailed and changed nearly all of
psychology and neuroscience for the coming 5 decades until this day (I'm
simplifying and exaggerating somewhat, for the sake of brevity and
argument).

In the last few years, evidence has accumulated not only that the
concept of universal grammar likely is untenable, but also that indeed
operant learning (and especially the form of operant learning called
motor learning) is an important if not crucial component of language
acquisition, in particular the speech component of language. For
instance, [*FoxP* manipulations in
flies](https://bjoern.brembs.net/2014/06/the-drosophila-foxp-gene-is-necessary-for-operant-self-learning/)
specifically affect operant self-learning, but not other forms of
learning. Thus, the currently available evidence points towards an
ancestral FoxP function in self-learning, a function that is not only
conserved in humans, but one that has been further honed by evolution to
allow for the acquisition of language.This work by Schreiweis *et al*.
falls neatly within this last string of publications tilting the outcome
of this long-standing debate more and more in Skinner's favor.

As we don't know the exact mechanism by which the negotiation between
self- and world-learning processes takes place, one can only speculate
what advantage the current human version of the FoxP2 gene might have
conferred. One interesting aspect here might be that it may have been
critical for the evolution of language to speed up the stereotypization
of certain orofacial movements during the first attempts to articulate.

A further, even more tentative speculation might be that this speeding
up was adaptive, because it allowed more effective communication between
parents and their infants, at an earlier time point in the development
of the child, when it was beneficial for the vulnerable infant to convey
its status in a more nuanced way than just crying to its caregivers. In
this way, children which were able to speak earlier may have had a
survival advantage over those that spoke later.But then again, at this
time point, such speculations are merely just so stories.

On a personal note, being so used to data mostly falsifying my
hypotheses over the last 20 years, it makes me quite nervous that now in
this particular research field, everything seems to fit so well
together. If something fits so well to one's ideas, one should be
especially cautious and (beware of confirmation bias!), think hard to
make doubly sure that the next experiments are designed such that they
can easily yield results that contradict the current hypothesis, more so
than usual.

And on a side note, it is quite an irony that [three years
ago](https://bjoern.brembs.net/2014/06/why-use-fruit-flies-to-study-a-gene-involved-in-language/)
a reviewer (for the same journal that now published his work, PNAS)
heavily criticized our essentially analogous conclusions. Now, three
years later, PNAS is finally ready to publish work that supports the
motor hypothesis.

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

[Schreiweis, C., Bornschein, U., Burguiere, E., Kerimoglu, C.,
Schreiter, S., Dannemann, M., Goyal, S., Rea, E., French, C., Puliyadi,
R., Groszer, M., Fisher, S., Mundry, R., Winter, C., Hevers, W., Paabo,
S., Enard, W., & Graybiel, A. (2014). Humanized Foxp2 accelerates
learning by enhancing transitions from declarative to procedural
performance [Proceedings of the National Academy of
Sciences]{style="font-style: italic;"} DOI:
[10.1073/pnas.1414542111](https://dx.doi.org/10.1073/pnas.1414542111){rev="review"}]{.Z3988
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Last week, Elizabeth Pennisi asked me to comment on the recent paper from Schreiweis

 et al.

entitled “Humanized FoxP2 accelerates learning by enhancing transitions from declarative to procedural performance”. Since I don’t know how much, if anything, of my answers to her questions will end up in her article, I thought I might expand my answer into a post about this very interesting work.

Humanized FoxP2 and the timing of habits

[[![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

 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.

No need to only send your best work to Science Magazine

[[![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;"}Rejection
is one of the unpleasant but inevitable components of life. There are
positive components to rejection: they build character, they force you
to deal with negativity and sometimes they force you to change your life
to avoid future rejections. In science, if your submitted manuscript is
rejected by the journal you submitted it to, Calcagno *et al.* reported
that the way the authors change the manuscript has an [effect on future
citations](https://www.sciencemag.org/content/338/6110/1065) this
manuscript receives. The effect is on the order of [\~0.1
citations](https://caseybergman.wordpress.com/2012/10/), tiny.

So much about the benefits. How about the costs? On the whole,
peer-review costs an estimated 2.2 billion € (US\$ \~2.8b) annually
([Research Information Network,
2008](https://www.frontiersin.org/Human_Neuroscience/10.3389/fnhum.2013.00291/full#B105)),
so re-review costs money. How much, I don't think anybody knows.
However, revise, resubmit and re-review costs time as well. Time in
which the article might have been cited. [Çağan H.
Şekercioğlu](https://bioweb.biology.utah.edu/sekercioglu/) has now
provided us with a rough estimate of the [citation cost of the
rejection-resubmission
cycle](https://www.sciencedirect.com/science/article/pii/S0960982213009263)
(toll access). The gist of his analysis:

> On average, each resubmitted paper accumulated 47.4 fewer citations by
> being published later, with an overall opportunity cost of 190 lost
> citations.

Compared to these costs, the estimated benefit of \~0.1 citations
appears laughable. It is quite likely that [Casey
Bergman](https://caseybergman.wordpress.com/2012/10/) is correct in his
assessment of the reason why Calcagno *et al*. was published in
*Science*:

> Nature and Science have a vested interest in making the case that it
> is in the best interest of scientists to submit their most important
> work to (their) highly selective journals and risk having it be
> rejected.  This gives Nature and Science first crack at selecting the
> [(what authors think is their)]{style="color: #ff0000;"} best science
> and serves to maintain their hegemony in the scientific publishing
> marketplace.

Çağan's analysis shows quite unequivocally: the citation costs clearly
outweigh the potential benefits of the rejection-resubmission cycle. I
wonder if he submitted it to Nature and Science as well, before
publishing it with Current Biology and how much that might have cost
him?

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

[Çağan H. Şekercioğlu (2013). Citation opportunity cost of the high
impact factor obsession [Current Biology,
23]{style="font-style: italic;"} (17) DOI:
[10.1016/j.cub.2013.07.065](https://dx.doi.org/10.1016/j.cub.2013.07.065){rev="review"}]{.Z3988
title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Current+Biology&rft_id=info%3Adoi%2F10.1016%2Fj.cub.2013.07.065&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Citation+opportunity+cost+of+the+high+impact+factor+obsession&rft.issn=&rft.date=2013&rft.volume=23&rft.issue=17&rft.spage=0&rft.epage=0&rft.artnum=http%3A%2F%2Fwww.sciencedirect.com%2Fscience%2Farticle%2Fpii%2FS0960982213009263&rft.au=%C3%87a%C4%9Fan+H.+%C5%9Eekercio%C4%9Flu&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CResearch+%2F+Scholarship%2CEcology%2C+Evolutionary+Biology%2C%2C+Library+Science%2C+Career%2C+Policy%2C+Publishing%2C+Science+Communication"}


Rejection is one of the unpleasant but inevitable components of life. There are positive components to rejection: they build character, they force you to deal with negativity and sometimes they force you to change your life to avoid future rejections.

The cost of the rejection-resubmission cycle

[[![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;"}Until
1986, it was thought that so-called [optomotor
responses](https://en.wikipedia.org/wiki/Optomotor_response){target="_blank"},
i.e., the tendency of all animals and humans to follow moving visual
stimuli with their eyes or their bodies, were a prerequisite for gaze or
trajectory stabilization: whenever the scenery in your gaze moves, you
adjust gaze or body orientation to compensate for the shift. The main
concept was that these behaviors were responses to external stimuli,
e.g., shift to the left elicits a counter movement to compensate for the
shift. Without such simple input-output processes, it was thought, it
would be impossible to maintain course or gaze. However, in 1986, [Wolf
and
Heisenberg](https://www.nature.com/nature/journal/v323/n6084/abs/323154a0.html){target="_blank"}
reported on experiments in *Drosophila* fruit flies with drastically
reduced optic lobes, the primary visual processing centers of insects.
These flies with the double mutation *rol* (reduced optic lobes) *sol*
(small optic lobes, see figure 1) were incapable of performing optomotor
responses to rotating stimuli, but nevertheless fixated a stripe in
their frontal visual field if they were allowed to control the position
of that stripe with turning maneuvers that were simultaneously recorded.
In other words, the flies could not see in which direction the stripe
was moving, but nevertheless managed to move the stripe in a way that
fixated it preferentially in front of the flies. Further experiments
showed that the only way the flies could possibly accomplish this feat
is by 'trying out' which turning maneuver led to the stripe staying in
the frontal part of their visual field -- an operant (or, as one would
also say today, goal-directed) behavior. For more details on this and
two related classic experiments from the Heisenberg lab see "[The
Importance of Being
Active](https://bjoern.brembs.net/downloads/?download=16 "The importance of being active")".

::: {#attachment_133 .wp-caption .alignright style="width: 160px"}
[![rolsol](https://bjoern.brembs.net/wp/wp-content/uploads/2013/05/rolsol-150x150.jpg){.size-thumbnail
.wp-image-133 decoding="async" aria-describedby="caption-attachment-133"
width="150"
height="150"}](https://bjoern.brembs.net/wp/wp-content/uploads/2013/05/rolsol.jpg)

Fig. 1: Side by side comparison of the brains of wild type (WT) and rol
sol double mutant flies (click to enlarge).
:::

Now [Bahl *et
al.*](https://www.nature.com/neuro/journal/v16/n6/full/nn.3386.html){target="_blank"}
in the lab of [Alexander
Borst](https://www.neuro.mpg.de/borst){target="_blank"}
[(](https://www.neuro.mpg.de/borst){target="_blank"}a [graduate student
of
Heisenberg](https://neurotree.org/neurotree/tree.php?pid=8061){target="_blank"}'s
from 1982-84) have not only replicated this seminal study, they have
done so in an impressively sophisticated and meticulous manner, avoiding
many if not all of the methodical problems of the original experiments
and adding exciting new findings to our body of knowledge along the way.
Their fabulous publication constitutes a shining example of the power of
combining today's genetic technology with state-of-the-art behavioral
physiology and computational modeling. Technically, it doesn't get any
better than that in our field today. A major procedural concern with the
1986 Wolf & Heisenberg paper had always been that none of the potential
side-effects of the drastic double mutation *rol sol* were known.
Granted, the optic lobes were vanishingly tiny in these mutants (see
figure 1) and almost any visual capability seemed like a surprise, but
which other processes were affected and in what way was completely
unknown. Rather than almost ablating the entire optic lobes of the
flies, Bahl *et al.'*s genetic manipulations specifically affected only
two sets of interneurons, T4/5, in the flies' visual system which the
[Borst lab had previously
reported](https://dx.doi.org/10.1007/s00359-012-0716-3){target="_blank"}
as abolishing all optomotor responses. Not only was it known that these
highly specific manipulations abolished optomotor responses, it was also
known why this happened: these neurons are a crucial component of the
fly's visual motion detector. Thus, these flies were exclusively
motion-blind and all other faculties were unaltered. Amazingly, despite
this highly specific manipulation, these flies behaved exactly like the
*rol sol* flies: they did not respond to moving visual cues, but when
allowed to control a black stripe with turning maneuvers, they kept the
stripe in their frontal visual field. The authors not only replicated
this aspect of the flies' behavior, they also did so using walking
flies, while the original study had examined flying flies, thus
extending and generalizing the findings of Wolf and Heisenberg.
Moreover, the authors found out, by careful and detailed dissection of
the flies' behavior, that optomotor responses improve fixation by
increasing the tendency of the fly to move the stripe to the front of
its visual field. For more details see the original publication or an
[excellent news-type article by Masson &
Goffard](https://dx.doi.org/10.1038/nn.3411){target="_blank"}. This
news-article also emphasizes, btw, the relevance of fly work for our
general understanding of gaze stabilization even in vertebrate systems.

::: {#attachment_134 .wp-caption .alignleft style="width: 160px"}
[![Fig. 2: "Inverting goggles" experiment. Whenever the tethered fly
attempts a turning maneuver, the fly\'s visual panorama is rotated in
the same direction. In the depicted example, a right turning maneuver
leads to a rotation of the panorama to the right. In this situation, any
attempts of the fly to follow the stripe will lead to a catastrophic
feedback of increasing speed of the stripe and yaw torque of the fly in
the same direction. Nevertheless, flies learn to generate turning
maneuvers in the opposite direction in order to establish a zero net
rotation of the stripe (optomotor balance). Fly drawing courtesy of
Reinhard
Wolf.](https://bjoern.brembs.net/wp/wp-content/uploads/2013/05/inversegoggles-150x150.jpg){.size-thumbnail
.wp-image-134 decoding="async" aria-describedby="caption-attachment-134"
width="150"
height="150"}](https://bjoern.brembs.net/wp/wp-content/uploads/2013/05/inversegoggles.jpg)

Fig. 2: "Inverting goggles" experiment. Whenever the fly attempts a
turning maneuver, the fly's visual panorama is rotated in the same
direction. Fly drawing by R. Wolf.
:::

Very much like Wolf & Heisenberg in 1986, Bahl *et al.* come to the
conclusion that there is, in addition to the well-studied optomotor
system, a less well-studied position system that acts in parallel during
object fixation/course control. Specifically, and this is where they
differ markedly from Wolf & Heisenberg, the authors assume that both
systems operate according to more or less fixed input-output rules,
i.e., "turn left on stimuli moving to the left" or "turn right if the
bar is on the right". However, the single most critical condition in the
experiments by Wolf & Heisenberg was the one where a right turn of the
fly led to a rotation of the visual field to the right, instead of to
the left (the '[inverting
goggles](https://www.grand-illusions.com/acatalog/Reversing_Goggles.html){target="_blank"}'
experiment, see figure 2). The *rol sol* flies showed no difference in
stripe fixation between both conditions, whereas control flies took much
longer to fixate the stripe under 'inverting goggles' conditions. This
decisive experiment showed that "turn right when the stripe is on the
right" (i.e., the conclusion Bahr *et al.* arrive at) cannot explain
fixation in these motion blind flies. Had the *rol sol* flies performed
this function exclusively, they would not have been able to fixate the
stripe. The same then also holds for the flies from Bahr *et al.*: if
their flies also fixate the stripe equally well in the regular as well
as the inverted situation, their entire explanation for their results
falls apart. Regrettably, Bahl *et al.* did not perform this very
crucial, essential experiment, not in their flies, nor in the computer
model they derived from their data. Hopefully, their next publication
will contain these exciting experiments.

**UPDATE**: I have visited Axel Borst's lab yesterday and they are
working on the inverting goggles experiment. For now, the flies have
trouble stopping the stripe from rotating at all, so there may be some
technical problems using walking flies instead of flying flies for this
kind of experiment, or simply the right parameters have not been found,
yet. Either way, as I speculated, they are working on it!

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

[Bahl, A., Ammer, G., Schilling, T., & Borst, A. (2013). Object tracking
in motion-blind flies [Nature Neuroscience,
16]{style="font-style: italic;"} (6), 730-738 DOI:
[10.1038/nn.3386](https://dx.doi.org/10.1038/nn.3386){rev="review"}]{.Z3988
title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature+Neuroscience&rft_id=info%3Adoi%2F10.1038%2Fnn.3386&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Object+tracking+in+motion-blind+flies&rft.issn=1097-6256&rft.date=2013&rft.volume=16&rft.issue=6&rft.spage=730&rft.epage=738&rft.artnum=http%3A%2F%2Fwww.nature.com%2Fdoifinder%2F10.1038%2Fnn.3386&rft.au=Bahl%2C+A.&rft.au=Ammer%2C+G.&rft.au=Schilling%2C+T.&rft.au=Borst%2C+A.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CNeuroscience%2CBehavioral+Biology%2C+Ecology%2C+Evolutionary+Biology%2C+Genetics%2C+Zoology%2C+Behavioral+Biology%2C+Computational+Biology%2C+Genetics+%2C+Zoology%2C+Behavioral+Neuroscience%2C+Computational+Neuroscience"}  
[Wolf, R., & Heisenberg, M. (1986). Visual orientation in motion-blind
flies is an operant behaviour [Nature, 323]{style="font-style: italic;"}
(6084), 154-156 DOI:
[10.1038/323154a0](https://dx.doi.org/10.1038/323154a0){rev="review"}]{.Z3988
title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature&rft_id=info%3Adoi%2F10.1038%2F323154a0&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Visual+orientation+in+motion-blind+flies+is+an+operant+behaviour&rft.issn=0028-0836&rft.date=1986&rft.volume=323&rft.issue=6084&rft.spage=154&rft.epage=156&rft.artnum=http%3A%2F%2Fwww.nature.com%2Fdoifinder%2F10.1038%2F323154a0&rft.au=Wolf%2C+R.&rft.au=Heisenberg%2C+M.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CNeuroscience%2CBehavioral+Biology%2C+Genetics%2C+Zoology%2C+Behavioral+Neuroscience%2C+neurogenetics"}


Until 1986, it was thought that so-called optomotor responses, i.e., the tendency of all animals and humans to follow moving visual stimuli with their eyes or their bodies, were a prerequisite for gaze or trajectory stabilization: whenever the scenery in your gaze moves, you adjust gaze or body orientation to compensate for the shift.

Messages de Rogue Scholar

What is a decision?

Humanized FoxP2 and the timing of habits

No need to only send your best work to Science Magazine

The cost of the rejection-resubmission cycle

Dissecting a fly’s course control system