Research reveals molecular mechanisms involved in stress resilience and susceptibility.
Susceptibility to stress can be an important factor in precipitating depression, a condition that, according to the WHO, currently affects 350 million people worldwide. A study published in Nature found that the protein beta-catenin, which functions in a cell signalling pathway called the canonical wnt pathway by binding to and allowing transcription of target genes in the presence of wnt, appears to play a key role in mediating resilience to stress.
Mice were first exposed to chronic stress, which led to control animals displaying depression-like behaviour. The scientists found that this susceptible-to-stress phenotype could be prevented by overexpressing β-catenin in the nucleus accumbens (NAc), the brain’s reward and motivation area, leading to mice that were more resilient to stress. Similarly, blocking β-catenin signalling in the NAc led to susceptibility to stress after sub-threshold stress exposure.
48 hours after exposure to chronic stress the group found that resilient mice had increased levels of two proteins that operate downstream of β-catenin, and 10 days after stress exposure a protein called Axin2, which is produced when β-catenin signalling is activated, was found to be increased in resilient compared to susceptible mice. This suggests that resilience is associated with increased β-catenin signalling.
The action of β-catenin in the NAc was also shown to be cell-type-specific as overexpression in medium spiny neurons (MSNs) expressing the D2 dopamine receptor subtype produced a pro-resilient response, an effect not seen with overexpression in MSNs expressing the D1 receptor.
β-catenin regulates a wide variety of genes and several of these were found to be up-regulated in resilient vs. susceptible mice. Knockdown (a technique used to reduce expression of a gene) of one of these genes, Dicer1, in the NAc followed by exposure to sub-threshold stress led mice to display depression-like symptoms. While overexpression of β-catenin was able to prevent depression-like symptoms occuring in control animals, whose Dicer1 gene was untouched, overexpression in animals following Dicer1 knockdown was not able to block development of depression-like symptoms following stress.
These findings also extended to humans; post-mortem studies of patients who were suffering from depression when they died revealed that levels of proteins associated with β-catenin signalling were reduced , indicating that β-catenin signalling is also suppressed in human depression.
While more research is needed, this study strongly implicates β-catenin signalling in mediating resilience to stress. The evidence presented also provides a new avenue for future research, for example into why signalling may be up-regulated in some individuals and not others, whether Dicer1 is also affected in human depression and, if so, are there are any mutations associated with this/other genes, and depression.
Original Study: Dias, C., Feng, J., Sun, H., et al. (2014). β-catenin mediates stress resilience through Dicer1/microRNA regulation. Nature. 516; 51–55.
WHO factsheet: http://www.who.int/mediacentre/factsheets/fs369/en/
Image credit: http://goo.gl/c5ZL28
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