Olfactory input dominates reproductive behavior in mice

New research indicates mouse nose detects most pheromones governing reproduction

Scientists at Harvard University have found strong signs that the pheromones driving reproduction and fertility in mice are detected primarily by the nose — not by the specialized vomeronasal system that many researchers had suspected of receiving and processing the bodily chemicals that govern mating behavior. The unexpected finding may settle an ongoing scientific debate by providing evidence that key reproductive behaviors in mice arise predominantly, if not exclusively, from olfactory input instead of input from the vomeronasal, visual or auditory senses.

The results, from a team led by Harvard biologist Catherine Dulac, appear on the web site of the journal Cell this week, and will be published in the journal’s Nov. 18 issue.

“It’s always interesting when there is a surprise finding,” says Dulac, professor of molecular and cellular biology in Harvard’s Faculty of Arts and Sciences and an investigator with the Howard Hughes Medical Institute. “Most biology textbooks now say that pheromones affecting reproductive behavior in non-human mammals are detected by the vomeronasal organ, while the nose processes all other odors. Our work suggests quite convincingly that the mouse nose processes both pheromones and other scents, and in fact provides much or all of the chemosensory input that drives mating.”

Dulac and her colleagues made pioneering use of a retrograde pseudorabies virus, which is capable of traveling across the synapses separating neurons but does so in a direction opposite to that in which nerve impulses ordinarily travel. By injecting fluorescently marked virus into a mating center in the mouse hypothalamus — a collection of neurons that produce luteinizing hormone-releasing hormone (LHRH), which manages the development and function of mammalian gonads — the scientists could trace backward to find the sensory receptors that first detect pheromones, species- and gender-specific chemical cues that drive animal mating, as well as fighting and territorial behavior.

The researchers expected to find neurons in the vomeronasal organ that receive pheromones and then activate hard-wired brain circuits such as those that express LHRH. Instead, they found that almost all the neurons feeding into the LHRH-making region of the hypothalamus appeared to originate in the nose. The scientists also found that mice with compromised olfactory function show dramatically impaired mating behavior; no reproductive effects were seen in mice lacking vomeronasal signaling.

“Strikingly, our study failed to document any anatomical or functional connectivity between LHRH-expressing neurons and structures of the vomeronasal pathway, thus contradicting the established notion that vomeronasal activity exerts a direct influence on LHRH neuronal activity, and in turn, on the endocrine control of reproduction,” Dulac says. “Although not previously documented, it appears that olfactory activity plays an essential role in eliciting male mating behavior with females.”

Dulac says this finding helps explain a paradox in humans, which lack functional vomeronasal systems. All vomeronasal-related mouse genes are inactive in humans, but this may not matter if pheromones can be sensed by the nose in humans as in mice.

The exact nature of vomeronasal input to the hypothalamus’s reproductive centers remains unclear, although research has shown clearly that some neurons adjacent to the brain’s LHRH-producing cells — cells that may also play a role in reproduction — do receive vomeronasal stimuli. The current finding is consistent with a 2003 model proposed by Dulac and colleagues which held that non-vomeronasal cues may be sufficient to trigger mating, while the vomeronasal system itself functions to ensure that mating is gender-specific.

Dulac’s co-authors on the Cell paper are Hayan Yoon, a graduate student in the Department of Molecular and Cellular Biology at Harvard, and L.W. Enquist of Princeton University’s Department of Molecular Biology. In addition to funding from the Howard Hughes Medical Institute, their research was supported by the National Institutes of Health.