Mice brains on stress

Blogging on Peer-Reviewed ResearchIn February 2006, a research team at University of Texas and Tufts University published a piece in Science on how experience could modify the structures in the brain that affect the production of dopamine through brain-derived neurotrophic factor (BDNF) (abstract here). The research team used ‘social defeat’ to explore ‘the neurobiological mechanisms through which psychosocial experience alters the activity of the mesolimbic dopamine pathway’; in other words, the malleable system that can induce structural changes in the brains of mice in response to persistent patterns of social interaction.The abstract, while a little thick, suggests all sorts of intriguing possibilities:

Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway–specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.  


The mice were subjected to systematic aggression and then exposed to their aggressor while protected, with a new aggressor each day for ten days. After the period, experimental mice avoided contact with a new mouse, whereas control mice interacted with a new mouse when placed in a cage together. ‘When tested again 4 weeks after the 10 days of repeated psychosocial stress, mice with a history of social defeat still displayed dramatic social avoidance’ (Berton et al. 2006:864). The team then tested whether the subject mice responded to treatment with anti-depressants as a way of seeing if the mechanism in mice was at all similar to stress-related changes in humans.

Sure, that’s not new, but what’s especially intriguing about this research is that the team looked specifically at the mechanism in the brain that was being tripped by the repeated aggression. As Daniel and others on this blog have discussed, it’s not just that we find experience causes changes in behaviour patterns — that’s pretty old news — but that brain research now lets us think about the neurophysiological channels that might be ‘enculturable’ in this fashion (and which ones might not be, as well).

The research team, in this case, knocked out the gene that produces BDNF, a neurotrophic protein that helps to regulate the mesolimbic dopamine pathway. Social defeat had produced very high levels of BDNF in the subject mice, and the team hypothesized that this was the mechanism (at least part of it) for conditioning the aversive response in the mice subjected to aggression. The BDNF deletion did the trick; the behaviour of BDNF-deprived mice subjected to the pattern of aggression was the same as the controls who experienced no aggression. They were immune to the long-term effects of repeated bad experience with strange mice.

The article is very comprehensive, including a fascinating (although challenging to the non-specialist) discussion of the gene regulating effects of the social aggression intervention. What I found particularly intriguing was the sheer number of genes in various key sites being affected by the experimental protocol; that is, trauma was affecting the experience of a large number of genes at key sites, and the gene expression pattern persisted after the trauma stopped.

The researchers specifically discuss the implications of their research for the treatment of post-traumatic stress disorder (PTSD), in particular the need for chronic rather than acute or short-term treatment with anti-depressants in order to interfere with the BDNF-mediated cascade that affects dopamine production. While the implications for PTSD are certainly important, I was also struck by the range of socio-cultural phenomena that might also be affected by a mechanism like this: military training, law enforcement, patterns of aggressive social interaction in a host of places. Because of my own research obsessions…. errr… ‘interests,’ I also thought that there might be much less severe effects (but something similar) in young people trained to be aggressive with each other on a regular basis, through things like agonistic games or violent sports. Although the ‘manipulation’ of the subject might be much less severe than aggression followed by long-term sensory contact with your aggressor, the ‘manipulation’ period could be much longer. I was also intrigued by the implications for de-mobilization of soldiers, as this has been a constant source of trouble for the military, especially after low-intensity conflicts (like the Iraq situation, where fighting and interacting with civilians are intermingled to such a high degree).

References

Berton, Olivier, Colleen A. McClung, Ralph J. DiLeone, Vaishnav Krishnan, William Renthal, Scott J. Russo, Danielle Graham, Nadia M. Tsankova, Carlos A. Bolanos, Maribel Rios, Lisa M. Monteggia, David W. Self, and Eric J. Nestler. 2006. Essential Role of BDNF in the Mesolimbic Dopamine Pathway in Social Defeat Stress. Science 311 (5762): 864-868. (abstract)

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