On the one hand, this is a strange tale of mutant, bisexual, necrophiliac flies, and you've got to love it for the titillating nature of the experiments. But on the other, much more interesting hand, it's a story about drilling down deeply into the causes of a complex behavior, and tracing it to a single gene product — and it also reveals much about the way the chemicals sloshing about in the brain can modulate responses to stimuli. Work by Grosjean and others on a simple Drosophila mutant, genderblind, which causes flies to be indiscriminate about gender in their courtship, opens up a window into how sexual responses are shaped and specified.
Think about human sexual responses. Some of us, when we see an attractive woman, are at least mildly aroused; others are have their sexual interest picqued when they see an attractive man; still others might feel sexual urges when they see a shoe, or a plush animal, or a pot of baked beans. No matter what the stimulus, these are all biological responses, with something in the environment matching some trigger in our brains and initiating a cascade of neural, neurochemical, and hormonal activity that leads to sexual behaviors. The question we want to address is what every step in the biology is doing; unfortunately, human behaviors are both too complex and not amenable to ethical experimentation, so we turn instead to simpler organisms that allow us to find simpler causes and carry out thorough experiments to probe the behavior.
Like flies. A fly's desires are relatively straightforward: they want to mate with a member of the same species and of the opposite sex. Males tend to be the initiators, and they approach other flies, and test sex and species by tasting — they secrete specific pheromones from their cuticles — and by singing species-specific courtship songs. Females strike males or run away if they don't want to mate, so interaction between the potential partners is also important. Male flies secrete several substances that proclaim their maleness, 7-tricosene and cis-vaccenyl acetate, which other males find distasteful and discourage them from attempting to mate.
Well, wildtype males find it discouraging; there are a lot of fly mutants that modify this behavior. There are mutations that cause a female pattern of brain organization to develop in a male body, and vice versa, and which cause males to wait for other males to start courting them, or that create females that try to initiate sex with other females. The mutant of interest here, genderblind, creates an unusual pattern of behavior illustrated in the test below.
Here's the test. Put an experimental male fly in a petri dish (the fly in the center above) with a choice of two potential mates, a male on the left and a female on the right. Courtship is, of course, a matter of two interacting flies, so to simplify things, the potential mates have been decapitated to make them unresponsive (they're still alive, but they aren't going to be doing much, like rejecting potential suitors). Then watch and see what the fly does.
A wildtype (WT) male fly pretty much completely ignores the decapitated male fly, but spends 60% of his time (the black bar) trying to court the decapitated female fly; perhaps he thinks she's playing hard to get. A genderblind male fly (gb[KG07905]), on the other hand, splits his time between the decapitated male and female flies (gray bars), spending even more time in frustrated attempts to coax a response out of either one.
Genderblind flies are perfectly normal in other ways. If their partners are not headless, they can successfully court and mate female flies. They also aren't indiscriminately trying to mate with anything that moves; they retain species specificity and are indistinguishable from wildtype flies in the frequency of attempted matings with other species of flies, showing diminished attempts with increasing species disparity.
What all this means is that these are truly bisexual flies — they have normal sexual responses except that these male flies don't find other male flies unattractive. Some change has simply stripped away some attribute of their brain that inhibits wildtype flies from same-sex courtship, while leaving other proclivities and preferences intact. Now, because it is in that easily manipulable experimental animal, the fly, investigators can also trace the change back to a single gene…and this is where it gets really interesting. How can a gene's activity be translated into a behavior?
Genderblind is a gene for a glial amino acid transporter. That is, it makes a protein that is inserted into the cell membrane of glia, not neurons, and is responsible for secreting amino acids (in particular, glutamate) from the glia into the extracellular spaces of the brain. The micrographs of the fly brain below were made with a fluorescent marker for genderblind that is pseudocolored magenta. In addition, all neurons are green with green fluorescent protein (GFP) in (a), all glia are GFP-green in (b), and a subset of neurons that use glutamate are GFP-green in (c). If a cell has both the GFP marker and the genderblind marker, it will appear white in the photograph. Notice where genderblind colocalizes: not with the neurons, but with the glia in the brain.
Genderblind (genderblind) protein is
expressed in central glia surrounding
glutamatergic neurons. (a-c) Single ï¬uorescence
confocal microscopy sections from male adult
brains, stained with antibodies to genderblind
(magenta) and CD8 (green). Colocalization is
represented by white color. For each image, the
transgenic transmembrane protein CD8::GFP was
expressed in a speciï¬c tissue-type using the Gal4/
UAS system. CD8 expression was driven with the
neuronal driver Elav-Gal4 (a), Repo-Gal4 (which is
expressed in a subset of glia, b) or the weak
glutamatergic neuron driver OK371-Gal4 (c).
Selected brain structures are indicated in each
panel. AL, antennal lobe; CA, calyx; CC, central
complex; MB, mushroom body; SOG,
subesophageal ganglion (see also Supplementary
Fig. 3). Scale bars represent 25 µm.
Maybe you're still baffled. How does glutamate from glia translate into bisexuality in flies? Another part of the story is that the normal fly brain is awash in an environment containing glutamate, which is also a neurotransmitter. All the glutamate desensitizes the glutamate receptors on neurons so that they are less attentive to incoming signals — it's basically jamming synapses with a lot of background noise. In the genderblind mutant, ambient glutamate concentrations are cut in half, so it's as if the nervous system is a little quieter, receptors are not desensitized as much, so neurons are suddenly more sensitive to stimuli. These glia are affecting neuronal activity indirectly.
Fitting this model are some other observations: the genderblind flies overreact to other chemosensory stimuli. Olfactory traps that use scent to lure flies are much more effective on genderblind vs. wildtype flies, suggesting that sensory processing in these flies is a bit more responsive in general.
In other clever experiments, they used a temperature-inducible RNAi to selectively block synthesis of the protein by simply dialing up the temperature on the incubator, the bisexual behavior could be switched on just by warming them up. Bisexual flies could also be switched to wildtype heterosexuality by giving them apple juice doped with γ-DGG, a glutamate-receptor antagonist, that also desensitized receptors. Within hours, they can turn bisexuality off and on in Drosophila — and the cool part is that this doesn't involve manipulation of specific, individual neurons, but is done by modifying a diffuse chemical balance in the brain, a balance maintained by populations of glia.
Here's the proposed model. The authors suggest that there is a general response to chemosensory stimuli that is selectively switched off in wildtype flies by desensitization of glutamate receptors to specifically male signals — so flies have a general courtship urge that is modified by a sex-specific downregulation.
In addition to demonstrating a behavioral role for genderblind, our
results also suggest a physiological model for Drosophila sexual preference that parallels a model recently proposed for mice. In this model, wild-type ï¬ies are 'pre-wired' for both heterosexual
and homosexual behavior, but genderblind-based transporters suppress the glutamatergic circuits that promote homosexual behavior. In
gb mutants, the repression of homosexual behavior does not occur and
ï¬ies become bisexual. Heterosexual courtship is not altered in gb
mutants, indicating that circuits driving heterosexual courtship are
not regulated by genderblind. This could be because circuits promoting
heterosexual courtship are not glutamatergic, or because they are
perfused by a different ambient extracellular glutamate pool than the
one that is regulated by genderblind-based transporters.
Humans are definitely messier and less well-defined, so don't even think that you might be able to get that hot same-sex person to be receptive to your signals with a few chemicals in their apple juice — it's just not going to work in exactly the same way. The general concept, however, is intriguing: the work is saying that the extracellular chemical environment of your nervous system has an extremely important role in modulating significant behavioral properties.
Grosjean Y, Grillet M, Augustin H, Ferveur J-F, Featherstone DE (2007) A glial amino-acid transporter controls synapse strength and homosexual courtship in Drosophila. Nat Neurosci.Dec 9; [Epub ahead of print].
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Reminds me of when Beavis and Butthead half remembered a joke about how the hottest girls are the ones without heads.
As always, PZ, your bio posts are wonderfully clear, illuminating, and helpful. This explains the results of the paper much more clearly than anything else I've read.
fascinating
I knew it. We're all closet bisexuals.
It sound like there's a mechanism to toggle attraction to males (i.e., mucking about with the glutamate concentrations) but that there is no way of shutting off attraction to females (short of, I suppose, adding so much glutamate that the insect would be unresponsive to everything). Do female fruit flies use a different mechanism to mediate attraction, or do they also have an attraction to male fruit flies which is dependent on an underlying baseline attraction to other females?
Wait, so did the bisexual fruit flies go for the pot of sexy baked beans, too?
There are so many dirty jokes waiting to be made about this. And I'm sure I'll go there soon enough. But for now, I actually have a sincere question.
This study shows that the genetically genderblind flies will court either male or female flies. My question: Are there any studies about whether the genderblind flies will accept attempts to mate with them from other genderblind members of the same sex?
In other words, do the genderblind flies ever actually engage in same-sex sexual behavior? Or is it all just unsuccessful mating attempts?
No: "they retain species specificity".
A few years back, a colleague of mine accidentally discovered a way to turn male Drosophila gay!
Here's the Paper
Interestingly, this was caused by overexpression of another transporter -- the white gene.
You should have seen the all-male fly orgies! (I wonder if the movie is on the web somewhere?)
Wonderfully insightful as usual.
Perhaps one day, we can find the faulty mechanism that exists between the extracellular matrix and the neural and glial surface membranes in the brains of presidential candidates.
Are you sure the species-specifity remained intact? None of the flies tried to mate, say, a box turtle?
Thanks, PZ. Enlightening as always. Nothing like the gritty genetic determinism of behavior to put a little spring in my step.
Hmm... and because bisexuality is linked with a better sense of smell, in some situations you might find this mutation selected for (when the advantage of greater sensitivity outweighed the expenditure of energy attempting to mate with the wrong sex) and so find a natural level of the characteristic in the population, yeah?
I suppose it would be an environment where food is available but hard to find, and predators using scent traps are rare. Unless the mutant being discussed here is entirely artificial.
Thank you for the explanation, PZ. I'd read a description of the experiment before somewhere else, but found it more confusing (and inaccurate as well) than helpful.
Speaking in general . . . all the research on sexual orientation that I've found so far focuses on male behavior and male homosexuality, not on females. Call me curious (or cynical), but has there been any work at all done on female homosexuality, or even on lesbianism in humans? And why is male sexual behavior more "interesting"?
The pictures in that article were pretty steamy themselves.
That last bit is amusing somehow.
PS: Greta Christina, does this answer your question about successful same-sex matings? I guess it depends on how you define success!
Really, really good post. This is the sort of thing that got me reading Pharyngula regularly even before its ScienceBlog incarnation. Liberal and Atheist I can get elsewhere (not that I disapprove) but you're one of the best science writers going on the web.
Great post, as always!
I worry about studies like these, with people superimposing the findings onto human behavior. While it's nice to have strong evidence that non-heterosexuality is at least partially genetic (shocking: people aren't just making it up!), human bisexuality certainly has nothing to do with an inability to tell men and women apart. Human sexuality, like all of human behavior, is mind-bogglingly complex. The media has a nasty tendency to painfully simplify these sorts of findings.
Thanks for putting the article into very accurate, very understandable terms.
"Their courtship displays included touching partners with forelegs, unilateral wing extensions, genitalia licking, and curling of the abdomens to achieve genital-genital contact."
Sounds like Saturday night to me...
And Sarah, while I agree that this finding doesn't necessarily translate to human behavior, I don't think it's completely irrelevant to it either. If nothing else, it shows that same-sex sexual orientation and behavior *can* be biologically determined. Which is an important message, both for the homophobic right wing and for the queer-theory constructionist crowd.
I just feel the need to point out that Freud thought we started out with a sort of "polymorphous perversity", and we narrowed our sexual interests down as we got older. Not necessarily applicable to humans here, but interesting nonetheless.
That's an interesting comment. I assumed the flies were able to tell male and female, just that they were attracted to both? As in in those flies the "male scent" did not "deter" them?
Someone asked about "success" there are other animals, especially birds where the gay couples willingly go through the entire mating act much like heterosexual mating. Gay/bisexual male bison deliberately stand for and even help the mounting male achieve full penetration etc. They likes it!
Another superb piece. This topic has materialised over at the Richard Dawkins forums, so I've linked to this blog entry from there for everyone's convenience (hope you don't mind the hits you'll be receiving as a result!) and also linked to the scala natura fallacy entry because there's apposite material on insect neurodevelopment in that post too.
On the subject of this latest development in fruit fly research, I'm tempted to say that once again, observational reality and rigorous deductive work make a mockery of doctrine. I can imagine, with a truly shameful level of schadenfreude glee, the apoplectic fits bisexual fruit flies will be sending though the fundie crowd. :)
@13 (Maureen)
You may be interested in an article by Chivers,Rieger, Latty and Bailey (2004). They published work showing a fundamental difference in human sexual arousal between males and females. Basically, it shows that females are more bisexual than males even taking sexual orientation into consideration.
Reference
Chivers, M.L., Reiger, G., Latty, E., Bailey, M.J. (2004). A sex difference in the specificity of sexual arousal. Psychological Science, 15(11), 736-744.
Stupid question: Why are the female flies denoted with the symbol for Mercury instead of Venus?
Interesting story. Which Drosophila species is this paper on? I assume D. melanogaster but I didn't see it mentioned anywhere, which makes the interspecific comparison chart difficult to interpret.
I had to take a cold shower even before I finished reading the article.
Excellent writing.
In the case of a life-form where the male makes the moves, it's certainly easier and more "interesting" to study the males doing something (including going after incorrect targets) than to sit around waiting for or figuring out how to arrange for the females to react! Of course that's not really a good enough reason not to investigate the female side at all. It just takes a better calibre of researcher and/or more luck in finding an observable difference to study.
It ought to be for their antennae! :-D
However, remember that the experimental male subjects are going after both male and female objects - but still attracted more to their own species than to other related species. So it's quite reasonable to denote the object of their attentions as a mixed male and female, ie mercury.
Great post--thanks, PZ.
"In the case of a life-form where the male makes the moves, it's certainly easier and more 'interesting' to study the males doing something (including going after incorrect targets) than to sit around waiting for or figuring out how to arrange for the females to react!"
Too true.
I remember in the early '90s, a researcher was coming out with reports of male homosexual behavior in sheep (Rocky Mountain Bighorn Sheep, if I recall correctly). He was asked why they only observed male homosexual behavior, and he said (paraphrasing here), "It would be too hard to observe lesbianism in female sheep, since the way female sheep initiate sex is to just stand there."
Every lesbian I knew had the same reaction:
"I've been to that bar."
It actually became a catch-phrase. Whenever we were talking about lesbians who were sexually shy or unassertive, we'd use the phrase "lesbian sheep."
I think the problem is that females may be just as important in the courtship game, but their tools tend to be subtler -- they aren't passive sheep, but they also have something of an upper hand in the courtship rituals; they are to be courted.
And really, look at the action in a non-lesbian bar. By that stereotype of women as sheep, what you'd expect is that all the ladies would be sitting there, and the males would be flitting from woman to woman, doing their cute little mating calls, until someone said yes. But we don't. I've been there. The males are looking for those little, subtle signals of agreeability, a smile or a glance, that gives them a kind of go-ahead to say hello and begin the dance.
(Except that there are some males who try the brute force ask-every-woman approach, of course -- but they're going to get rejected by the majority.)
Re #21 -- Tony Jeremiah, thank you for the paper. I just downloaded a PDF of it and will read it tomorrow when I'm more awake.
#28 -- LOL!
Even so, if the book Biological Exuberance and this BBC article on topi antelope are any guide, there are species in which females do actively seek out sex, rather than passively waiting. Then again, I suppose topi antelope would not be easy to study in a laboratory setting . . .
I think girls want their part of the action too, sometimes...
Here are some references explaining the effect of mutations in the gene fruitless. In brief, there are splicing mutations that can actually induce courtship behavior in female flies. Which end up courting other female flies.
Humans always try to think of themselves as uber-complicated beings, but here are some sobering reports about the power of simple genetic mutations on very complex behaviors. They are surely food for thought.
"human bisexuality certainly has nothing to do with an inability to tell men and women apart."
are you sure about that?
do you think humans dont determine mates, at least in part, by how they smell?
there was an experiment i recall seeing where they took a bunch of guys of various physiques and had them sleep in their shirts for..i dont remember how long, then they baged the shirts and had a woman smell them and arange them on which she thought would be the most attractive, and she, and others as well who did the experiement, aranged them with the buff physique at the top and the rounder physique at the bottom, basically how you would expect them to arrange them if they were looking at them.
our arousal we get from a person comes a lot from our receptiveness to their pheromones, not to mention how they look. thats perhaps at the lowest level of attraction, good thing about humans is that we arent dependant solely on evolution, we can overcome biology and prefer people for other reasons. more..higher level reasons, such as their personality or such, but for initiating sexuality...its usualy biological, for maintaining it...thats another story.
human personality is very complex this is true, its a unique blend of psychology and biology.
i just hope that this data doesnt lead to some misguided fool trying to "cure" people of homosexuality or bisexuality with a drug, or of people refering to such things as a mutation (in the usual ignorant misuse of the word, they dont mind their brains or hetrosexuality as being mutations) or worse a birth defect.
No: "they retain species specificity".
I wouldn't be too worried about a cure. Most likely you'd have straight people making their kids straight, gay people making their kids gay, and bisexual people making their kids bisexual. In fact as a bisexual myself I'd want to have bisexuals if possible. Even though there's discrimination I consider it a gift. I can decide whether to have a relationship with a person based on their personality without letting gender get in the way. But to each their own and I think it will be very little time maybe not any time at all between when parents can choose genes for their children and adults can change their genes. Gene therapy (or protein therapy) could even become inexpensive and changing your sexual orientation could become like dying your hair. Rarely is anyone ever prejudiced against somebody for their hair color, so it might actually be good for tolerance. I think with a more tolerant society more people will choose bisexuality. There's nothing wrong with heterosexuality or homosexuality it's just why limit your options if you don't have to?
As for not being able to tell men and women apart of course we can at a conscious level just like we can tell races apart, but that doesn't mean racial recognition is inborn. There's the concept of gender that children learn. But attraction takes place at the subconscious level. People don't think "I'd like to be attracted to that person" and then they're attracted. Attraction is uncontrollable.
Something else I thought of. Would the genderblind gene blind any flie to gender or just flies that would have otherwise been heterosexual? I think they should do another experiment. This time modifying the white gene as one poster mentioned, making the flies gay, then feeding them spiked juice to see if it makes them try to mate with both males and females.
Also even if this makes bisexuals smelling work better as far as noticing that something smells doesn't not being able to tell the difference between male and female pheromones mean that there is a decrease in ability to distinguish between different kinds of smells or is it just for the pheromones? Regardless I'd be interested to see scientific studies into the olfactory function of bisexual males.