The “social” aspect of the bio-psycho-social model is the least investigated by far, especially preclinically, as many (wrongly!) believe that rodents could not possibly be relevant to human social behaviour. MOGILab has conducted some of the first systematic characterizations of the bidirectional relationship between social behaviour and pain, and in many cases translated findings directly from mice to humans, even in the same published paper. These demonstrations have served to remind that the presence of conspecifics in the testing situation can have a robust effect on stress levels and experimental conclusions. The ease with which these findings can be translated from mice to humans is a challenge to assumptions regarding the “unique” social status of our species.
The “Cage Order Effect”
MOGILab’s interest in social impacts on pain stems from a chance finding derived from an analysis of a very large database of baseline tail-withdrawal test measurements made over a long period of time in multiple laboratories. We found that mice tested after other mice in their cage displayed progressively higher pain sensitivity (and higher sensitivity to morphine analgesia) compared to mice tested previously. The simple manipulation of returning mice to a holding cage after testing instead of returning them to their home cage abolished the effect, suggesting that the increase in pain sensitivity was produced by social communication between cagemates.
Emotional Contagion of Pain
We demonstrated that mice tested for pain in dyads rather than in isolation displayed higher levels of pain, but only when the other member of the dyad was a cagemate, not a stranger. Pain could be modulated bidirectionally by visual observation of the other mouse, and pain behaviours were found to be synchronized in time. We attributed these effects to emotional contagion of pain, the lowest form of empathy (see Preston & De Waal, Behav. Brain Sci., 25:1-72, 2002); this was the first demonstration of any form of empathy in a non-human species.
Empathy and Stress
In a paper whose origin was an email conversation between Dr. Mogil and Dr. Robert Sapolsky (even involving a wager, which of course Dr. Sapolsky ended up winning), we investigated the hypothesis that empathy (i.e., emotional contagion of pain) is not observed in stranger dyads because of stress. Reduction of stress—either pharmacologically (using metyrapone, which inhibits the synthesis of corticosterone/cortisol) or psychologically (using an “icebreaker” exercise, involving the videogame RockBandTM)—allowed emotional contagion between strangers to occur. The pharmacological experiment was performed in both mice and humans, with identical results. We note that this study revealed that simple proximity to a stranger does indeed cause increases in corticosterone/cortisol levels in mice and people, a fact that should be taken into account when designing studies in both species.
Effect of Pain and Social Proximity
Having established that social factors affect pain sensitivity, we wished to determine whether pain affects social behaviours. The first question, of course, is that of proximity; without proximity (communications technologies aside) there is no social interaction. In a simple Plexiglas alleyway with “jail cells” at each end, we found that female mice will spend more time in proximity to a jailed cagemate (but not stranger) in pain over one not in pain. Furthermore, the more social contact that occurs between the free and jailed mouse, the less pain behaviour is displayed by the jailed mouse. Dr. Mogil likens this phenomenon to nursing, and it suggests that female mice might be displaying prosociality. In another study of male mice, we found that unfettered proximity to a non-affected, gonadally intact male mouse produced stress-induced analgesia, and that proximity behind a jail-bar barrier produced stress-induced hyperalgesia.
The Tube Co-Occupancy Test
The current ubiquitous assay of social interaction, the three-chamber test, is sub-optimal in a number of ways, including the extremely short (≤15-min) testing period, the incarceration of one of the social partners, and confounds related to location of the stimulus animals. We would also suggest that a preference for strangers over familiars is not at all consistent with human social preferences; humans prefer to interact socially with familiars and maintain closer distances to friends than strangers. MOGILab developed a novel assay of social propinquity (voluntary social proximity) for mice and rats, the tube co-occupancy test (TCOT). We find that siblings and cagemates will spend more time co-occupying a single tube in a novel, high-stress environment, but that after 3 hours strangers “get over it” and will co-occupy as well. Interestingly, we find that the initial sibling>stranger co-occupancy difference can only be found in outbred and wild mice, not inbred mice, suggesting that the latter may be unsuitable for social behaviour research.
Dominance and Pain
Using the TCOT test described above, we showed that stranger mice in which both members of the dyad have neuropathic pain are more likely to co-occupy a tube. In addition, neuropathic pain itself can change pre-existing dominance relationships among male (but not female) mice, such that previously dominant males who now have neuropathic pain lose their dominance status somewhere between 1 week and 1 month post-injury.
We are currently testing large cohorts of mice living together in an Eco-HAB, a housing colony consisting of four chambers connected by four connecting tubes. Mice are RFID-chipped, such that the system can log their position at all times. We are conducting several different experiments looking at the effect of chronic pain on social organization in the Eco-HAB, over the time span of weeks-to-months.