- Introduction to Clinical Research Training
- Medical Education
- United Kingdom Clinical Scholars Research Training
- Vanderbilt Hall
- Financial Aid
- Office of the Registrar
- Student Services
- Registering for Courses
- Exchange Clerk Program for Visiting Medical Students
- Curriculum Requirements
- Student Handbook
- Being a Student at Harvard Medical School
- History of Harvard Medicine
- 1. The MD Programs at Harvard Medical School
- 2. Academic Information and Policies
- 3. Academic Resources
- 4. Student Conduct and Responsibility
- 5. Combined degree programs
- 6. Financial Obligations
- 7. General Policies
- 8. Housing and Dining Services
- 9. Student Health
- 10. Services and Programs
- Alumni Services
- Campus Planning and Facilities
- Ombuds Office
- Committee on Microbiological Safety
- Human Resources
- HMS Foundation Funds
- Office for Academic and Clinical Affairs
- Joint Committee on the Status of Women
- The Academy
- Global Health Research Core
- Global Clinical Scholars Research Training Program
- HMA Standing Committee on Animals
- Office of Research Compliance
- Global & Community Health
- Harvard Medical School Event Calendar
- Contact @HMS
- Office of Diversity RIA Program
- The Dean's Perspective
- Department of Pathology
- Harvard Mahoney Neuroscience Institute
- OHRA Home
- Office of Research Subject Protection
- Tools and Technology
- Alumni Association
- Cancer Biology & Therapeutics Program
- Celiac Program
- Department of Medicine
- HMS Community Values Initiative
- HMS Information Technology
- HMS TransMed Program
- Introduction to the Practice of American Medicine
- Office of Communications & External Relations
- Office of Global Education
- Shenzhen-HMS Initiative in International Education
- South American Clinical Research Training
- test page
- Safety Quality and Informatics Leadership
- Human Resources
- Jobs @ HMS
- Contact us
- Dental Medicine
- Harvard University
Scents and Sensibilities
December 12, 2012
When birds evolved from their dinosaur ancestors, they grew feathers and learned to fly. When the house mouse Mus musculus evolved, it developed the ability to release, and to love, a pungent and repugnant chemical.
Sometimes evolution stinks.
A team of researchers led by Stephen Liberles, assistant professor of cell biology at HMS, has mapped the evolution of biosynthesis pathways that enable the excretion of trimethylamine, a powerful chemical signal that repels rats—and humans.
Synchronized with the increased production of trimethylamine, Liberles and his group at HMS, along with colleagues at the Scripps Research Institute and Novartis Institutes for BioMedical Research, Neuroscience DA, noted the evolution of new behavioral responses to the odor, namely, the mouse species that emit the highest levels of the once-repellant chemical find the odor highly attractive. The results of this study appeared last month in Current Biology.
The life of a mouse is an odorous affair. Much of the information they have about their world comes from their sense of smell. They use odors to communicate with other members of their own species and to avoid potential predators. In many animals, a simple change in odor production or odor perception can be enough to drive the creation of a new species, Liberles said. In the current study the researchers noted that two complementary changes were necessary for the mice to come to love such a noxious odor. “First you need a change in the biosynthesis pathway for a pheromone or an odor, and along with that you need a change in the neural circuits and neural systems that respond to that pheromone or odor,” he said.
Trimethylamine, which is produced during the decomposition of plant and animal matter, is a signature component of the smell of rotting fish. The gut bacteria that help animals digest food also produce the chemical. In most species, trimethylamine is metabolized in the liver by an enzyme that transforms it into a non-volatile chemical by oxidation, rendering it odorless. Mus musculus has evolved a mechanism that suppresses the production of the oxidizing enzyme.
Mice detect trimethylamine using the trace amine-associated receptor TAAR5, which is exquisitely sensitive to even tiny amounts of the chemical. The researchers measured the concentrations of the chemical in the urine of various species and subspecies of mice using TAAR5 receptors in a reporter-gene assay. They also measured samples using NMR spectroscopy. In addition, the researchers compared the behavioral response to the odor in mice in which the TAAR5 receptor had been disabled, wild-type mice, and rats.
Mus caroli, an Asian rice-field mouse, is closely related to musculus, but it doesn't produce any trimethylamine. None of the samples from Asian species of mice contained detectable amounts of the chemical, but species in the Eurasian clade have several evolutionary intermediaries, the researchers found. These species appear to emit more of the chemical as they draw closer to musculus on the mouse family tree. These findings suggest that this evolutionary development is recent.
In musculus, wild-type mice were attracted to the scent, but mice lacking TAAR5 were not. Trimethylamine is a highly attractive scent to wild-type mice, but TAAR5-knockout mice were not attracted to the scent. This is the first time that a behavioral response has been directly linked to a single specific main olfactory receptor, Liberles said.
“For rats, it’s the most aversive chemical we’ve ever tested,” said Liberles, who has also studied the responses of rodents to odors produced by predators. “Rats hate this scent.”
Rats eat mice, and researchers speculate that the ability to release such a repellant odor might have been part of the selective pressure that allowed this stinky chemical to accrue in a few mice with genetic mutations. When the offspring of these malodorous mice began to prosper in their relatively rat-free territories, the lucky few among their progeny that evolved responses allowing them to become attracted to the once-aversive odor gained an even stronger reproductive advantage, which drove this evolutionary change.
TAARs, a particular kind of olfactory receptor that Liberles first identified in 2006, have previously been associated with instinctive aversive responses, leading Liberles to theorize that they might be wired directly into the avoidance centers of the brain. Finding that they are also at work in detecting attractive stimuli adds an interesting wrinkle to that theory, he said.
“Understanding how the brain encodes likes and dislikes is a basic question in neuroscience,” Liberles said.
The fact that mice have made such a stark transition from aversion to attraction is particularly intriguing. The researchers proposed three possible explanations: that the neural circuits linking TAAR5 to the brain may have been rewired as part of the evolution of the new behavior; that while TAAR5 mediates the attraction response, other receptors that once mediated the aversive response have been lost in the evolutionary process; or that the new behavior is a learned response, overcoming hard-wired instinctive behaviors. Each of these scenarios has possible implications for the treatment of human diseases related to aversion and attraction, including drug addiction.
“We are interested in understanding how the neural system could control this change in behavioral response,” Liberles said.
This work was supported by a grant from the National Institute on Deafness and Other Communicative Disorders (S.D.L., award number R01DC010155).