LA JOLLA, CA - A team led by biologists at The Scripps Research Institute has solved the long-standing scientific mystery of how mice first know to nurse or suckle.
This basic mammalian instinct, which could be a key to understanding instinctive behavior more generally, was thought to be triggered by a specific odor (pheromone) that all mouse mothers emit. But, as described online ahead of print by the journal Current Biology on October 4, 2012, the trigger in mice turns out to be a more complicated blend of nature and nurture: a signature mix of odors, unique for each mother, which her offspring learn.
"We set out to find a pheromone trigger, but were excited to find this alternative mechanism," said team leader Lisa Stowers, an associate professor at Scripps Research who was the senior investigator for the new study. "Compared to a pheromonal system, this mechanism would have been easier for animals to evolve."
Looking for the 'On Switch'
Suckling is the defining behavior in mammals, whose very name refers to the milk-making mammary glands of the breast. Most mammals are born knowing how to find their mother's nipples and drink, and would quickly perish if they didn't--making suckling an example of an instinctive or "innate" behavior hard-wired into the brain. "So far, little is known about how innate behaviors are coded in the brain, what triggers them and what represses them," said Stowers.
A first step in studying an innate behavior is to look for its initial trigger or "on switch," yet that can be like searching for a proverbial needle in a haystack. Even a very young animal is exposed to a vast complexity of sights, sounds, smells and other factors. Many of these may seem to be triggers for an innate behavior, but that may be only because the animal has learned to associate them with the behavior. Finding the essential trigger for the very first instance of an innate behavior--before it has ever been experienced or taught--is a painstaking process of elimination requiring an array of sophisticated laboratory methods.
Scientists had found evidence that the trigger for initial suckling in mice is mediated by the main olfactory epithelium (MOE)--the principal smell organ, located within the nasal passages. Without the MOE, newborn mice fail to suckle and die of dehydration. In the new study, Stowers and her colleagues, including postdoctoral researcher Darren W. Logan, who performed most of the experiments, set out to find the special MOE-sensed odor that triggers initial suckling.
Process of Elimination
Stowers's initial hypothesis was that the trigger was a pheromone, a chemical that is emitted by one animal and straightforwardly triggers a behavior or other response in another. In separate research, her laboratory had found several pheromones that activate other innate behaviors in mice. Moreover, an independent group of scientists had found that a specific, MOE-sensed pheromone in mother's milk serves as the trigger for initial suckling in the European Rabbit. Stowers and her colleagues expected to confirm that a similar chemical does the trick in mice.
The researchers began by subtracting certain maternal fluids from the environment of newborn mice, hoping thereby to see a delay or elimination of their first suckling, which would indicate that the subtracted fluid had contained the pheromonal trigger. The scientists eliminated maternal milk and saliva from the newborns' environment and still observed suckling behavior. That left the amniotic fluid of the womb as the source of the suckling trigger. Next the scientists fractionated the amniotic fluid, separating its chemicals into different molecular weight ranges, with the expectation that they would find the trigger in one of these smaller mixes and eventually isolate a single pheromone.
"It soon became clear that the trigger is not a classic pheromone," Stowers said. No single fractionated part of the amniotic fluid could trigger suckling on its own. Even more strikingly, when the researchers added other chemicals such as vanillin to samples of amniotic fluid, the altered amniotic fluid no longer triggered suckling in newborns--whereas a typical pheromone would still have worked under such circumstances. After further tests, Stowers and her colleagues were forced to conclude that there is no single chemical trigger that works for all newborn mice.
Instead, the results indicated that the trigger for the first suckling in newborn mice is a blend of chemicals that is specific for each mouse mother. The brain of a mouse does not recognize this maternal "signature blend" automatically with neural circuits that are fully programmed by the mouse genome. It must learn the signature blend before it is able to suckle. In a narrow time window after birth, a re-exposure to this maternal odor mix triggers suckling. Thus, a behavior that appears completely innate is triggered by a mechanism that is partly learned.
The results suggest to Stowers and her colleagues that other seemingly innate behaviors in mammals may have learned triggers that make use of the versatile MOE. "This mechanism that we found is really just a twist on what the main olfactory system already does, which is to learn to recognize odors to guide an animal's behavior," Stowers said.
Stowers and her colleagues now hope to characterize the special, just-after-birth window of time within which the odor mix of a mother mouse triggers suckling in her newborns. "When we have a full understanding of the trigger mechanism, we'll use it to stimulate the relevant MOE sensory neurons in the lab," Stowers said. "We'll explore the connections those neurons make in the brain, and thus we'll be able to study how these circuits bring about this fundamental behavior."
The other contributors to the paper, "Learned recognition of maternal signature odors mediates the first suckling episode in mice," were Lisa J. Brunet and John Ngai from the University of California, Berkeley, William R. Webb of the Center for Mass Spectrometry at Scripps Research, and Tyler Cutforth of the University of California, Irvine. Darren W. Logan is now a Group Leader at the Wellcome Trust Sanger Institute in Cambridgeshire, UK.
The research was supported by NIH-NIDCD (R01 DC009413, R01 DC006885), the Skaggs Foundation at Scripps Research, and a grant from the Wellcome Trust (#098051).
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. Over the past decades, Scripps Research has developed a lengthy track record of major contributions to science and health, including laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. The institute employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including three Nobel laureates--work toward their next discoveries. The institute's graduate program, which awards Ph.D. degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.