Harvard Medicine

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(Can’t Get No) Olfaction

Sure, she’s pretty. But how does she smell?

© Dennis Kunkel Microscopy, Inc.<br/>Visuals Unlimited/Corbis Hey, Miss! You, with the googly red eyes! Wanna dance? Wouldn’t it be nice if you could manipulate another’s mood with a waft of your own perfume, turning a stranger from standoffish to sweet? Sirens since Cleopatra have tried, with mixed results. Yet the fly and mouse manage handily. The question is, How?

Ask Edward Kravitz, the George Packer Berry Professor of Neurobiology at HMS, who investigates how innate behaviors such as mating, fighting, foraging, fending off suitors, and evading predators get wired into the brain’s neural network. In the fruit fly, Drosophila melanogaster, as in humans, the sense of smell plays a key role in regulating behavior. Creatures communicate and influence one another’s actions through chemicals called pheromones, which members of a species secrete onto their bodies or into the environment. Neurohormones produced by brain cells, including serotonin and dopamine, also serve important roles in directing behavior.

To study how genes that dictate pheromone production orchestrate complex rituals of courtship and aggression, Kravitz and colleagues tinker with fly DNA using standard techniques—and then watch what happens. Altering a gene called fruitless, which is found in about 2,000 neurons in fly brains, makes males fight like females and females like males—and increases homosexual courtship behavior dramatically. Just three of these neurons also contain the neurohormone octopamine. When the researchers either altered fruitless or lowered octopamine levels, male flies began courting in the midst of battle.

“We can change the mix of pheromones on females to that of males, to prompt females to fight like males,” Kravitz notes. “We can even explore how a male might respond when confronted by a female that smells or behaves like a male.”

The Kravitz lab has generated thousands of fly genotypes, each with different mutations. “One by one, we can ask what each neuron does,” Kravitz says. Tweaking a few serotonin-producing neurons ratchets up aggression, for example, and manipulating a hundred provokes bizarre, seemingly unrelated behaviors.

Can novel experiences override fly routines engraved in DNA millions of years ago? What happens when an amorous fly receives an unexpected whack upside the head from his ladylove? For those curious about the unfolding fruit-fly drama, answers are expected later this year.

Sharing a fascination for how the brain translates pheromones and other olfactory signals into specific behaviors is Sandeep Robert “Bob” Datta, who joined the HMS neurobiology department last year as an assistant professor. Before beginning his work with Drosophila, Datta mastered laser microscopy in the laboratory of HMS Professor of Neurobiology Bernardo Sabatini. Using optical methods he devised himself, he studied neural circuits along which pheromones in flies generate innate sexual behaviors.

Datta has since used his novel laser tool to trace pheromone signals from any of 50 different neuron populations in the fly’s nose-equivalent, the antennae, to the fly brain’s smell center, the olfactory bulb, then onward and upward into the cerebral cortex, which orchestrates behavior. When odor receptors on a group of neurons detect a potential mate, they propel signals along their axons to the olfactory bulb. The axons converge within a single ball-like structure, the glomerulus, which serves as a way station for sensory information.

Datta found he could trace signals from a single glomerulus into the cortex and link them to a specific behavior. By tinkering with fly genes, he could prompt particular groups of olfactory neurons to turn fluorescent green upon exposure to laser light.

“As one would expect, patterns of branching neurons differ in female and male flies, reflecting sex-specific behaviors,” Datta notes. In males, he found, a certain pathway prevented male–male courtship. In females, that pathway proved critical to their receptivity to males’ advances.

Scientists with whom Datta has shared his techniques have begun exploring not just smell, but also taste, hearing, and vision in the fly. These days, Datta does his own neural tracing in mice, whose nervous systems more closely mirror those of humans, asking such questions as: Why is a lemon’s scent behavior-neutral for mice, while fox odor compels them to scamper? Can we map the neural pathway for fear? Can we modify it genetically?

Such questions could one day illuminate our understanding of phobias and post-traumatic stress disorder, Datta notes. For now, he says, “I want to crawl through the brain—the amygdala, the hypothalamus—to see where the information goes.”

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