Mutants at large: ethology meets transgenic technology!

Abstract

Knocking out single genes in the mouse genome has become the gold standard of molecular investigation of the mechanisms of brain function. The effect of these mutations is analyzed by sophisticated behavioral paradigms in the laboratory. The question has been raised, however, whether such paradigms are relevant from biological or evolutionary viewpoints. The artificial laboratory environment might induce abnormal behavioral responses that, some argue, reflect more the impoverished test situation than the biological mechanisms underlying natural behavior or brain function. Probing the brain with the wrong tools could give us false results.Lipp and coworkers [1xLong-term monitoring of hippocampus-dependent behavior in naturalistic settings: Mutant mice lacking neurotrophin receptor TrkB in the forebrain show spatial learning but impaired behavioral flexibility. Vyssotski, A.L. et al. Hippocampus. 2002; 12: 27–38Crossref | PubMed | Scopus (37)See all References[1] report a new and alternative study, which might address the above concern. They were interested in whether forebrain-selective genetic disruption of the tyrosine kinase B (trkB) receptor leads to abnormal learning performance in mice in a naturalistic setting. By releasing homozygous-null mutant, heterozygous-null mutant and wild-type mice tagged with radiotransponders into a large (10×10 m) outdoor pen, they were able to monitor what their subjects were doing, and where, for three weeks. They equipped the pen with eight feeder units placed at the perimeter. The units delivered food only at the first visit made by each mouse every day, thus forcing the mice to remember which unit they have visited on any particular day – a typical working memory problem. In addition, mice were also required to show behavioral flexibility: once in every three days they were offered bowls of unlimited amount of food inside a shelter positioned in the middle of the pen. An optimal foraging strategy, therefore, was to patrol the feeder units for two days and then to stay in the shelter on every third day. Surprisingly, all mice, including the homozygous-null mutant animals, learned to patrol the feeders, and within seven days made almost no errors – that is, they visited each feeder only once, a result that suggested unaltered spatial working memory in the mutants. Interestingly, however, on the shelter-feeding days, mutant mice continued to patrol the feeders, whereas wild-type control mice quickly abandoned this temporarily incorrect strategy and learned to feed inside the shelter. Heterozygous animals exhibited an intermediate performance level. Apparently, the mutants were unable to switch to the new foraging strategy – that is, they showed inflexibility in their behavior. Thus, the authors argue that they were able to dissociate spatial learning from behavioral flexibility – cognitive demands that could not be separated before in classical laboratory tests of learning and memory. Although some questions on potential confounding factors associated with social interaction or olfactory cues remain unanswered, this pilot work could pave the way for novel approaches that will better utilize the rich behavioral repertoire of the mouse in our investigation of the genetics of brain function, and also better model human CNS disorders. After all, humans also do not spend their lives in cells with food and water available ad libitum.