Why We Study Invertebrate Brains

As you guys might know by now, I study fruit flies.

When I tell people I study fruit fly brains, the first question I usually get is, “Fruit flies have brains??”

Yes, they have brains. Fairly complex ones actually. I challenge the smartest engineers in the world to build a computer that’s half as smart as a fly brain.

The second question I get is, “Why on earth would you study fruit flies?”

Drosophila_melanogaster_-_side_(aka) (1)

the fruit fly Drosophila melanogaster (credit: A. Karwath via Wikimedia Commons)

I can see why you guys think that we fruit fly neuroscientists are such weirdos. I mean yeah, flies are barely visible to the naked eye, they’re pretty gross when they show up en masse after you’ve forgotten a banana at the bottom of the fruit bowl, and they’re stupid enough to drown in your glass of wine. (I always wonder about the whole wine-drowning thing—like, ok, what was the plan here guys? I like wine too, but I’m not just going to dive into a giant pool of it when I know I can’t swim…)

Even from a neurobiology perspective, there are plenty of reasons why you might think studying flies or other invertebrates, like worms, is stupid. Fly brains look nothing like human brains. Fruit flies have about 100,000 neurons compared to 100 billion in humans. That’s a million times fewer neurons! The most commonly studied worm, Caenorhabditis elegans (abbreviated as C. elegans), gets by with just 302 neurons and barely has a recognizable brain at all.

Simpler can be better

Despite looking very different from ours, invertebrate nervous systems can teach us a lot about our own brains. In fact, their smaller scale actually provides many advantages for understanding how they work.

Worms are often able to accomplish certain tasks with a single neuron, like smelling an odor or moving forward or backward. I’m not talking about a single type of neuron—I mean literally ONE neuron. Yeah, that’s a lot of weight on that poor neuron’s shoulders! The same task might typically be accomplished by one or a few neurons in flies, dozens of neurons in a fish, and hundreds or thousands of neurons in a mammal.

C._elegans

a C. elegans worm expressing a green fluorescent protein, which can be seen through its transparent skin (credit: D. Dickinson via Wikimedia Commons)

Say you’re a neuroscientist who’s interested in how the nervous system accomplishes a particular task. You want to study the neurons that are involved and analyze what kind of information they’re encoding. Well, it’s a lot easier to study just one or a few neurons as opposed to hundreds or thousands of cells. Moreover, when you’re dealing with hundreds of neurons you first need to convince yourself that they’re really even the same type of cell and are doing the same thing. Neurons that look the same on the surface often turn out to be different types of cells with different functions, and sorting that out is a lot simpler when you have just a few neurons instead of hundreds.

A road map for the brain

The smaller scale of invertebrate nervous systems also offers other advantages besides being able to study fewer neurons. Their relative simplicity means that we’re often able to gain a more comprehensive understanding of how they work.

Take tiny C. elegans, with its 302 neurons. You might be wondering how scientists came up with such a precise number. It’s because back in the 1980s, a dedicated team of biologists led by the great Sydney Brenner identified every single neuron in the entire worm.1 Not just that—they gave each neuron a name and identified all the connections (called synapses) that every neuron makes with other neurons. Yes, this was just as painstaking as it sounds, and for this work Brenner won a share of the Nobel Prize in 2002.

This map of all the neurons and connections—the “connectome”—means that we understand the architecture of the C. elegans nervous system far better than that of any other animal. More importantly, the connectome has been invaluable for researchers studying how the worm nervous system actually functions.2 If you’re investigating a particular worm behavior and have identified at least one neuron that’s involved, you can immediately consult a database and identify other neurons that are likely to function in the same circuit (because they’re physically connected). That’s why it’s often possible for worm researchers to characterize an entire neural circuit from beginning to end in a single study, a feat that’s very rare in flies and almost never occurs in rodents.

worm connectome diagram

The C. elegans wiring diagram, depicting all neurons and their connections. Sensory neurons (which directly receive information from the environment) are shown in red; motor neurons (which control muscle movement) are shown in green; interneurons (all other neurons) are shown in blue. In this diagram information generally flows downward. (credit: wormatlas.org)

In his Nobel lecture, Brenner credited C. elegans for his success in mapping the connectome. Referring to this humble worm, he titled his lecture “Nature’s Gift to Science” and declared, “Without doubt the fourth winner of the Nobel prize this year is Caenorhabditis elegans; it deserves all of the honour but, of course, it will not be able to share the monetary award.” (Maybe he could buy his worms some super-premium bacteria to eat?)

Indeed, the choice of C. elegans as a model organism was essential for Brenner’s project. Extremely high-magnification pictures are required in order to identify individual cells and their connections, so mapping an entire nervous system was only possible in an animal as tiny as C. elegans. Its small number of neurons also made it feasible to define all the connections between neurons without requiring immense computing power (as would be needed if there were, say, a million neurons to consider). Nearly thirty years after the C. elegans connectome was published in 1986, even with all the improvements in technology, accomplishing a similar task today for a mammalian nervous system still seems far-fetched.

Practical considerations

Of course, there are also all the practical advantages that studying invertebrates affords. Invertebrates like flies and worms grow up quickly, breed easily, and are cheap to acquire and maintain as compared to mammals. They also don’t take up as much space, which is a bigger deal than it might seem. (Limited space has led to all kinds of turf wars in my lab—it’s not uncommon to return from vacation and find that other people have taken over some of your lab bench or shelves. They’ve also probably eaten all the chocolate stashed in your drawer, but that’s a different problem.)

fly stocks

My fly city consisting of 200+ stocks (don’t mind the stray razor blade)

Currently I have about 250 fruit fly stocks, each representing a different, genetically modified type of the same species. Each stock consists of a family of 10-100 flies, and each family has its own small vial to call home. All the flies live in a little city taking up about 1-2 feet of space right next to my desk. The flies die naturally once they get old and new generations take over; all I need to do is give them clean new vials and fresh food once a month. Maintaining worms like C. elegans is likewise a simple and low-cost endeavor.

In contrast, if I worked on mice or rats, just one cage would take up about the same amount of space as my entire fly city! (Don’t even get me started with monkeys.) And rodents cost a lot more to feed and house, so even with unlimited space, keeping too many animals just isn’t practical. They also take longer to breed (2-3 months for mice, as opposed to 10 days for flies and 3-4 days for worms), so creating new strains is significantly more time-consuming.

The reason it’s important to be able to have a gazillion flies isn’t just so they can keep me company when I’m lonely (though that’s an added benefit). Rather, it allows us to do certain kinds of experiments that require screening through large numbers of animals. For example, there are ways that you can disrupt the function of random genes or neurons, generating a collection of thousands of flies that each have an abnormality in a particular gene or set of neurons. Then you can go through these flies and identify ones that show defects in the behavior you’re interested in, which tells you which genes or neurons are involved in that behavior.

These sorts of screening experiments in flies and worms have not only allowed scientists to identify countless genes and neurons involved in all kinds of behaviors, but have also helped generate powerful genetic tools for studying the brain.3 Screening isn’t easy; it often feels like looking for a needle in a haystack. But it would be impossible if you didn’t have the money or space to get the haystack in the first place.

Conclusion: Fruit flies rock. Worms are cool too.

Hopefully by now I’ve convinced you that invertebrates like fruit flies and worms are really powerful model organisms for studying the brain and behavior. Compared to mammals, they’re easier and cheaper to work with, they offer an extensive array of tools for probing brain function, and their relative simplicity makes them more tractable for those of us who want to understand how neural circuits work in obsessively fine detail.

Obviously there are certain topics for which mammals are more appropriate subjects of study. And of course it’s nice to show that findings from invertebrate studies do have some relevance to mammalian brains; I’ll discuss this more specifically in a future post (this one’s already too long!). In the meantime I hope I’ve at least marginally improved your opinion of lowly flies and worms, which exemplify (in Sydney Brenner’s words) “how the great diversity of the living world can both inspire and serve innovation in biological research”.

 

Notes:

1. White JG, Southgate E, Thomson JN, Brenner S. The structure of the nervous system of the nematode Caenorhabditis elegans. Philos Trans R Soc Lond B Biol Sci 314(1165):1-340 (1986).

2. Here’s a nice article about the impact that the connectome has had on C. elegans research, along with its limitations: The Connectome Debate: Is Mapping the Mind of a Worm Worth It? (Sci. Am., 2012).

3. For example, a project at the Howard Hughes Medical Institute at Janelia recently generated and characterized thousands of fly strains that genetically target specific neurons in the brain. This is a powerful set of tools because now we can do whatever we want to a particular neuron without affecting other cells in the brain, such as inspecting its anatomy, recording its activity, or artificially silencing or activating it.


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