Drug Discovery Opinion

Emotionally resilient people adapt to adversity and bounce back after stressful events; less resilient individuals find it difficult to cope with setbacks and may decline into depression or post-traumatic stress disorder (PTSD). Mice, like humans, vary widely in their reaction to stressful situations and a study led by researchers at Mount Sinai School of Medicine which was funded by the National Institute of Health’s National Institute of Mental Health (NIMH) has now uncovered a mechanism that helps to explain differences in resilience.

Mice experience stress when confronted by an aggressive, larger mouse and about two thirds of animals that repeatedly undergo this ‘social defeat’ have altered behaviours including long-lasting social avoidance and anxiety-like symptoms. The other third of the ‘defeated’ mice showed relatively few behavioural effects and these resilient animals were found to have higher levels of the transcription factor ΔFosB in the nucleus accumbens, an important brain reward-associated region or “pleasure centre”. Social behaviour in ‘defeated’ mice can be normalised by chronic antidepressant treatment and the action of fluoxetine was found to require induction of ΔFosB in the nucleus accumbens. Post-mortem examination shows that ΔFosB is also depleted in the brains of people who suffered from depression, suggesting that induction of this protein is a positive adaptation that provides resilience to stress.

ΔFosB is also known to be involved in regulating responses to both drugs of abuse and natural rewards such as food, sex and exercise, although the cell populations involved in these responses differ somewhat from those involved in protection from stress. The team suggest that concentrations of ΔFosB in the nucleus accumbens are important in setting the level of an individual’s reward-seeking motivation and that reduced concentrations of the protein are linked to the impaired motivation and ability to experience pleasure seen in many people with depression. The team now hope to discover small molecules that will augment the actions of ΔFosB and lead to resilience-boosting treatments for depression.

The study is published in the journal Nature Neuroscience.

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