JOURNAL CLUB: Flies, glia and sexual preference
Noah Gray
Wednesday, 09 January 2008 21:43 UTC
Strange grouping, you say? Well then, try reading a new paper in Nature Neuroscience by Featherstone and colleagues. While studying a glial glutamate transporter in Drosophila, the authors stumbled upon a bizarre courtship behavior in male flies. A mutation in this transporter caused male flies to court other males with an equal probability to females. Thus, in the spirit of clever names for proteins expressed in this model organism, the mutation was aptly named genderblind.
In the described behavioral experiments, mutant males exhibited mating behaviors when in the presence of other males in a dose-dependent fashion; more mutant transporter caused more abnormal courtship. However, genderblind did not demonstrate these aberrant behaviors if sex pheromones, even male ones, were absent. In a mutant male lacking the chemical 7-tricosene, genderblind was uninterested in courtship. However, if 7-tricosene was applied to the body of the pheromone-challenged males, courtship resumed. This was especially odd since 7-tricosene was previously thought to strongly inhibit male-male courtship, an unproductive behavior for obvious Darwinian reasons. Therefore, the conclusion was that although the signal from the pheromone was detected, the processing was disrupted, causing improper circuits be activated and the wrong behavioral patterns to be initiated.
The mechanism underlying all of this altered processing falls back to the glial transporter. This protein should regulate extracellular glutamate concentration; any changes in its activity would affect synaptic transmission significantly (many studies have demonstrated the powerful role of glia in the tripartite synapse over the past few years). This assumes that the altered processing observed in genderblind is due to synaptic communication changes and not due to developmentally-induced re-wiring. To rule out the latter, the authors used genetic tricks to express genderblind in adults, after normal development of the circuits, and then induced the expression of the mutant. These flies still exhibited the same male-male courtship preferences. There are still many loose ends, not least of which is the question of which circuits actually process the pheromone signals and then translate (transmit?) the information to other (the same?) circuits governing motor programs essential for courtship behavior. Although we don’t know the answer, glia obviously play an important role in this process.
This paper, interesting from a number of angles, attempts to hype the results in a way that suggests homosexuality can be turned on or off, at least in flies, simply by using a pharmacological inhibitor of the genderblind transporter. This implies that homosexuality may be simply a result of abnormal signal processing in the appropriate circuits. This vast oversimplification is discussed in a commentary accompanying the article. Unfortunately, I’m sure that many will not read, nor even see, the thought-provoking issues raised by the commentator. This is apparent from many comments listed in two blog conversations (here and here) at the NY Times regarding these findings. This article obviously provides more than just interesting science, but also speaks to the interface between science and the public as well.
Discussion Points
1. How could changing the glutamate content in the extracellular space contribute to the altered processing by the appropriate (but unknown) circuits?
2. How do these Drosophila courtship behaviors relate to mammalian courtship rituals and what does the current research say about those behaviors?
3. What other data would you need to see for the authors to convince you of their conclusions?
4. What are the next experiments that you would do in order to advance our knowledge of pheromone processing?
Updated 12 February 2008 17:49 UTC
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Replies
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Thanks, Noah, for linking to Levine’s excellent commentary. I think it’s unfortunate that interesting science can get buried by provocative sound bites.
I find it very interesting that females were not used as experimental subjects in this paper. I’m curious how the expression of genderblind compares in glia from wild-type male and female Drosophila. I’m also curious whether disrupting genderblind affects male-typical behaviors other than mate preference, like aggression.
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“Unfortunately, I’m sure that many will not read, nor even see, the thought-provoking issues raised by the commentator.”
Part of the reason I support the idea of discussing science online in this manner (JC, BPR3 etc) is that these otherwise hidden elements often become more accessible to the general public (both scientist and non-scientist) via search engines. The movement of professional scientific discussion onto the internet might not necessarily enhance the knowledge within the professional scientific community per se, but it could well serve to provide the non-scientific community with broader access to the views and opinions of those professionals – unfiltered by the lens of a media that, for obvious reasons, prefers to focus on the sensationalist aspects of scientific discovery.
It’s probably the next best thing in the absence of ScienceFactCheck.Org.
BTW a good example of this is the recent hoo-hah regarding alien contact and SETI, and the pro-science bloggers’ rapid response to it.
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There are some great questions raised in this blog. As senior author on the paper, perhaps I could give my opinions? I’d love to hear whether people think I’m full of B.S. or not. Science advances through critical discussion.
1. Regarding our use of the term ‘homosexual’: Our use of the term ‘homosexual’ in describing our results was in no way intended as ‘hype’. In fact, we authors of the genderblind paper are of the opinion that fly behavioral science —particularly sex behavior studies—has suffered greatly from sloppy use of language and unwarranted extrapolation. Those who read our paper will see that we treat the genderblind mutant phenotype mainly as a sensory stimuli interpretation problem. In this case, the sensory stimuli happen to carry information critical for mate choice. Contrary to statements in the Levine News & Views article, we state clearly, and show in a figure, that genderblind mutants are bisexual. That’s why we named the gene ‘gendereblind’, after all!
So why did we use the term ‘homosexual’? We used the terms ‘homosexual’ and ‘heterosexual’ to refer to courtship directed at the same sex (homo+sexual) and courtship directed at a different sex (hetero+sexual), respectively. This distinction was critical, because the genderblind mutation ONLY affected homosexual courtship. Heterosexual courtship and sex was not affected. (A lot of these data are in supplemental figures, and honestly I now regret putting those data there, because people seem to keep overlooking them. But Nature Neuroscience has its article length limits…)
The original title of the article was “A glial amino acid transporter controls synapse strength and homosexual courtship in Drosophila”. The editors removed the word ‘homosexual’. Personally, I think the title is now misleading, because it implies that all courtship was affected, which is untrue. Only homosexual courtship was affected. I was baffled by their decision by a long time, but I think I finally figured it out. Please tell me, Noah, whether I am right:
I think the confusion is that societal use of the term ‘homosexual’ implies same sex PREFERENCE. e.g. an increase in same sex mate choice with a simultaneous decrease in different sex mate choice. In that case, yes, our use of the term was misleading. However, common societal use of the term ‘homosexual’ is not strictly in line with the etymology of the word, which literally means same sex. So we were using the term precisely and accurately. Of course, one could argue that societal use of the term is actually the best. But our data as well as recent data from mice, suggest that mate choice is not some sort of ‘compass arrow’ that can only point at one target. In which case societal use of the term becomes fundamentally misleading, and adhering to that sloppy usage potentially derails advances in our understanding of mate choice behavior. Let me make an analogy: mate choice is a lot like food choice. The fact that I like corn dogs doesn’t keep me from liking pizza. They are separate sets of sensory stimuli, to which I can respond independently. If I found a mutant human that didn’t like corn dogs but still liked pizza, I might write a paper with the title: “Mutations in XXX control corn dog preference”. And I don’t think anyone would have a problem. The alternative title “Mutations in XXX control food preference” would still be correct, but less informative and accurate. Unfortunately, this latter sort of title is what we got stuck with.
‘Homosexual’ and ‘heterosexual’ are simply descriptive terms that define particular types of mate choice, same as ‘corn dog’ and ‘pizza’ define particular types of food. One of the important things about our paper is that we showed that homosexual courtship and heterosexual courtship could be manipulated independently. So we had to carefully distinguish the two types of behavior. We did.
2) Noah doubts that fly homosexual (male-male) courtship can be turned on and off using drugs. But our paper shows that we can. In fact, we can turn it on and off within SECONDS using light-gated channels expressed in glutamatergic neurons. This is consistent with current work that we’re doing that shows clearly that GB mediates a form of courtship learning in flies (courtship learning is a form of learning where, basically, flies learn which potential partners are worth pursuing). We hope to submit this stuff for publication soon.
Next, I’ll answer the reader questions, and then take a stab at Noah’s ‘Discussion Points’.
3) Regarding Debra’s question on female behavior: Both males and females express genderblind, throughout development (Augustin et al 2007). Females are generally passive in courtship, except for rejection behaviors. Since females are passive, it makes it sort of hard to put a bunch of females together and see changes in behavior. What we would have needed to do was put a genderblind female in with another female that was willing to do male courtship behavior, to see if the first female rejected advances from another female. A male-acting female could be engineered by expression of male-specific fruitless isoforms, which essentially make the brain ‘male’. But we don’t know if that would also have affected the pheromone blend that they express (the fruitless transcription factor affects many aspects of development). And that might have goofed up the experiment. And that wasn’t our interest anyway. There are other labs that are better than us when it comes to fruitless stuff. We wanted to see whether genderblind regulated synapse strength in a way that was behaviorally meaningful.
4) We agree with the Damien’s enthusiasm for discussing science online. I came across this page by accident, but it’s great. Unfortunately, we authors of the genderblind paper are unanimous in our opinion that it is Joel Levine that is sensationalist, but we encourage readers to read both his essay and our article and make up their own minds. Yes, I am actually asking you to THINK! (This is probably the University professor in me coming out).
OK, so now on to Noah’s discussion points…
1) Readers interested general discussion of how glutamate alters glutamatergic synapse strength should read a recent review I wrote: David E. Featherstone and Scott A. Shippy. (2007) Regulation of synaptic transmission by ambient extracellular glutamate. The Neuroscientist (Oct; doi: 10.1177/1073858407308518) Scott Shippy is a chemist here at UIC that I have been collaborating with in our increasing studies of extracellular glutamate. Trust me when I say that we are getting some amazing insights consistent with things discussed in the review.
2) It think courtship behaviors are likely to differ among species based on ecological and evolutionary considerations. In Drosophila, the rate-limiting factor for male reproduction is access to a receptive female. This means that his best strategy is to ‘try it on’ with many potential partners and gradually winnow down his targets. This will keep male neurophysiology perched at the edge of willingness to court many potential targets. Indeed, as shown in our paper (Grosjean et al), wild-type Drosophila males are initially (before courtship learning kicks in) quite willing to pursue females of related species. And of course, flies rely on somewhat different sensory modalities than other animals (like us) when choosing a mate. It is easy to figure out what sensory modalities are important for human mate selection, because there are lots of people making money off them. Think porn industry, phone sex industry, perfume industry… You can also do thought experiments (Would heterosexual guys go for a woman who smelled like a man? Sounded like a man? Looked like a man? What if I switched something in the heterosexual male’s brain so that every guy ‘looked’ like a woman? Would he court them?)
3) Yea, what other data do we need? We’d love to hear your ideas for future experiments! Or do the experiments yourselves, submit them to Noah for publication in Nature Neuroscience, and save us the work!
4) There’s lots of great work going on in this area, so make sure you read the literature first. Personally, I am fascinated by the sort of question that we tried to get at with our paper: What makes a pheromone (or any sensory ‘package’) actually trigger changes in behavior? Is there a switch in the brain that gets flipped? Is a neural circuit activated? Is a normally suppressed neural circuit unsuppressed? It seems to me that these are the sorts of questions that really get at how we think and behave.
Make sense? Am I full of crap?
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I just noticed that I forgot to answer Debra’s question about other behaviors. Over a year ago, we gave genderblind mutant flies to Yi Rao (Northwestern), who said he wanted to measure aggression in them. I never heard anything from him one way or another. I also sent flies to Paul Shaw (Washington Univ.) a long time ago. He checked them for sleep/circadian disorders, and found nothing obvious. We tried to get learning labs interested in checking out the genderblind mutants at the Cold Spring Harbor fly neuro meeting a couple years ago, but no one was interested because GB isn’t expressed in the mushroom body and there is this erroneous conclusion among many that unless something is, it can’t be involved in fly learning.
(A minor digression, because it’s a pet peeve of mine:
There is also an erroneous conclusion that fly brains only have 10% glia. That’s clearly bogus as well, propagated by glial development people who still haven’t found a transcription factor expressed in all glia and only glia, but who pump each latest gene as the ‘master differentiator’ anyway. Which makes people assume that markers of glial subsets are pan-glial markers. As a result, the numbers of glia are consistently underestimated. And if you are a glial differentiation person (which is most of the Drosophila glial people; almost nobody studies genetics of glial function), you have no interest in correcting this misperception, because that would make your ‘master regulator of glial differentiation’ seem less masterful. Someone needs to make an accurate count by doing 3D confocal reconstructions of fly brains stained with DAPI (to mark all nuclei) and Elav (Which isn’t perfect, especially in embryos, but is about the best pan-neuronal marker we have). Because glia are, by definition, any non-neuronal cell tightly associated with the nervous system, any DAPI speck that is not overlapped with Elav should be glia. Any takers out there? Prove me wrong!)We HAVE found that genderblind mutants, both male and female, over-react to startling stimuli, consistent with the idea that GB acts as sort of a ‘throttle’ on glutamatergic synapse strength. But we haven’t followed up on this much, mainly due to lack of people-power in my lab right now.
And genderblind mutants, both male and female, respond more strongly to food odors, as evidenced by increased capture in ‘olfactory traps’ baited with food medium. This is reported in our paper (Grosjean et al). There’s not much fluff in that paper; you have to read it carefully!
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It would be remarkable if this JC forum can sustain an environment in which the authors of the articles under discussion feel comfortable engaging with the readers and addressing their comments, as David has here.
BTW, the issue of using culturally-sensitive terminology in science is an interesting one that is worthy of discussion. Especially if science is become more accessible to non-scientists. It reminds us that there are subtleties to the science/culture debate than can often be lost in all the fist-shaking about evolution and climate change.
Is there a latin word for “same” that could replace the Greek prefix “Homos”, and thus produce a pure latin word that wouldn’t have the cultural baggage of its predecessor? I’m kidding, of course. Well, sort of.
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Dear All:
I don´t know if Drosophila has tripartite synapses like mammalians. In the mammalian brain a mechanism by which astrocytes promote the integration of information is described in my paper with Furlan in Nature Precedings (please click here)
In order to understand how this mechanism could influence sexual preferences, first it is necessary to define “sexual preference”: in this context, is it understood only as the kind of sexual act practiced by the animal, or there is more – a “psychological” dimension of the behavior? In the first case, the explanation could possibly be found by examining how glial transmission affect the production and/or concentration of some hormones.
Some speculation: if neuropeptides involved in the triggering of this behavior are produced by neurons (not by glial cells), then the explanation does not involve a change in peptide production, but a change in the glial receptors and/or signaling pathways activated by the produced peptides after they are diffused in extracellular space (purinergic transmission).
Best Regards
Alfredo Pereira Jr.
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