The Lonely Mouse
(January 16th, 2015) Danish researchers found that single-housed lab mice show signs of depression. This might affect their use in clinical studies and could help explain why so many candidate drugs fail in humans. Did we underestimate the complexity of this model organism?
Usually, laboratory mice do not have an eventful life. They live in tiny cages, furnished with standardised fitments, stacked on endless shelves. These poor creatures have no names or identity; they rarely see daylight. But they provide a vital service to science as the most important animal model. That’s why people do care about them. People like Jann Hau, who’s a leading researcher in animal science and welfare, at the University of Copenhagen, Denmark. The professor of Comparative Medicine heads a small group continuously striving to improve the work with and the life for laboratory animals. In a recent study, Otto Kalliokoski, a member of Hau’s group, and colleagues made an astonishing finding: “Single housing affects serotonergic signalling integrity” in male mice – or in other words, these lonely mice were closer to depression than their group-housed mates.
Kalliokoski, a biotechnology engineer, originally from Sweden, explains why it is worth studying single-housed mice: “We were doing a study, in which we used special metabolism cages. If you want to study the metabolism of a mouse, then you control what they drink and what they eat, but you also have to collect what comes out. These cages do it automatically but are also more uncomfortable for mice,” he explains. The question was, does the cage itself affect the metabolism of the mice – do the mice become stressed or depressed when they are in the cage? “We looked at stress-sensitive parameters and realised that the metabolism cages are not good for mice. We also had a control group of single-housed mice, which behaved differently from our regular, group-housed mice,” he explains. “The single-housed mice came from group-housing and behaved normally in the beginning, but after three weeks’ time, their response differed significantly from the group-housed mice.”
Kalliokoski and Co. compared the so-called 8-OH-DPAT challenge response. 8-OH-DPAT is a selective serotonergic agonist activating a subset of serotonin receptors (5-HT1A) and is used extensively for the study of depression in mice. Besides regulating mood, serotonin signalling also influences body temperature. When mice are given 5-HT1A agonists, they respond with hypothermia. How this is done, still eludes scientists. Also, the response to the 8-OH-DPAT challenge depends on the number and activity of serotonin receptors; more receptor activity means a bigger drop in body temperature.
Kalliokoski explains: “There are different opinions on how to interpret this. One is that the lack of social contact leads to less serotonin in the brain and thereby to less stimulation of serotonin receptors. These get up-regulated or sensitised, which we can demonstrate by challenging them: The mice who have been sitting alone in their cages have a greater response to the 8-OH-DPAT injections. This mechanism is suggested to be the same in humans when they are depressed.” But he warns: "In mice, you are not supposed to talk about depression because mice cannot get depressed, by definition. In a human context, depressions are defined as ‘having suicidal thoughts’ but mice do not interview well. Therefore, we use wordings like ‘depressive state’."
Why did the scientists only study male mice? Because single-housing them is much more common. “Male mice tend to fight and there is so much literature saying that male mice are fine when you single-house them”, Kalliokoski says. “Back in the 1990s, people did some behavioural tests and looked at acute stress parameters but our study has a different nature because we measured long term stress." This is one issue, the scientist want to bring to wider attention with their publication. They also want to stress that mice always seem to choose social interaction over being alone. This is surprising, since mice are not known to be a social species in nature. Otto Kalliokoski speculates that the artificial situation in a laboratory creates this conversion because mice do not have the stimulant of roaming freely anymore and the social interactions make up for what they lose in freedom to move.
So, what does it all mean for researchers, working with mice? "If I absolutely have to single-house a mouse, there might be something I can do to compensate for what it loses in social interaction. This could be, for example, a more stimulating environment", Kalliokoski tells us.
Even in the wider perspective, the Lonely Mouse Study has important lessons. Mice are also used in drug discovery and it’s a well-known problem that translating findings from a little mouse to a big human being isn’t as straight-forward as we’d like it to be. In some areas, more than 90% of candidate drugs fail in clinical studies. Otto Kalliokoski explains that it is not primarily the difference in complexity between mice and humans that causes these failures. "Most failures have been found to be because the experiments were not done in a purposeful way. We argue, of course, that stress is one big contributing factor because it has such major influence on the physiology", he tells. But, in retrospect, it is very hard to prove that the mice were stressed in a study. He is sure, "you will get different results for anti-depressant drugs when you test them on single-housed or group housed mice".
Sometimes, one paper can make a difference, for researchers and lab animals. And there is still so much more to be discovered. In the end, researchers will not only improve their lab pet’s welfare but also the quality of their own research results.
Photos (2): K. Lauschke