Laboratory mice are commonly used in biological and medical research because they are inexpensive and breed quickly. But because they are produced by artificial selection – the process by which humans breed animals over dozens of generations for specific characteristics – this has led their domestication. They pass on specific qualities that make them well-adapted for research under lab conditions; they lose characteristics such as aggression, the desire and ability to escape from danger and anxiety caused by environmental disturbances.

But the artificial selection process also causes the mice to lose the very important trait of being able to survive in the wild. Besides these lost traits, female lab mice also developed the tendency to immediately mate with every male in their vicinity, including siblings and parents. That is, they lost the ability to selectivity choose a mate according to traits that “promise” the offspring better genes and a higher survival rate. At the same time, they evolved the willingness to take care of pups belonging to others.

The strains of lab mice chosen to undergo further artificial selection are those who are not “fussy eaters,” grow faster and reach sexual maturity more quickly relative to wild mice. That is how we ended up with larger, less aggressive mice that reproduce at a younger age and are less particular when it comes to choosing a mate. In other words, these strains are quite different from wild mice with regard to structural, physiological and behavioral features.

Dr. Tali Kimchi of the Weizmann Institute of Science’s neurobiology department understood that these lab mouse strains are not suitable for answering some types of questions. She is studying the neural and genetic roots of social behavior, including reproduction and maternal instinct (for example, a mother’s aggression toward another’s offspring, and the role of pheromones (a secreted or excreted chemical factor that triggers a social response in members of the same species) in mate selection and caring for offspring.

Therefore, Kimchi had to develop a unique mouse strain, restoring those properties removed from the laboratory mouse strains, while retaining the ability to employ genetic engineering tools to create genetically mutant strains that disable the function of a particular gene.

To do this, Kimchi and her research group back-crossed strains of lab mice that had a specific mutation in the gene responsible for detecting pheromone signals with wild-derived (undomesticated) mice for 10 generations. As a result, in these new back-crossed strains, the scientists managed to reinstate traits typical of wild mice which were lost through the domestication process and absent in lab strains, including those relating to behavior, body structure, hormones, various biological processes and genetic functions.

More specifically, they restored, among other things, the ability to react to and escape from danger, spontaneous anxiety-related jumping and freezing behavior, and aggressive attacks toward other females. Another important feature that was restored in the new breed of mice was maternal instinct: “naïve”(not yet mated and maternal) back-crossed wild-derived female mice were less likely to nurture another’s pup. They were also aggressive toward those pups, as well as among themselves – just like wild mice.

The new mouse model Kimchi and her team created has allowed them to explore for the first time the biological roots of aggressive behavior in females, both toward each other and especially toward the pups of others. It also enabled them to locate a particular gene which is responsible for the perception of pheromone signals, and to determine this to be the main cause for rejecting strange pups, as well as the aggressive behavior displayed toward them.

Their findings, recently published in the journal Nature Communications, provide the basis for developing additional mouse strains that will enable a better understanding of the neural and genetic basis of behavior relating to reproduction in females, and the differences between males and females.

Kimchi hopes that further research will lead to a renewed understanding of the biological mechanisms underlying social and reproductive processes that have not been possible to explore in standard lab mice models. It may also lead to a better understanding of the social component of neuropsychiatric diseases, which appears in different ways in men and women. Such knowledge will contribute to improving the development of drugs targeted to the different sexes and will enable an analysis of the effect of certain drugs on women.

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