Molecular Mechanisms of Resilience

Summary and Comment |
September 10, 2007

Molecular Mechanisms of Resilience

  1. Peter Roy-Byrne, MD

Animal studies of learned helplessness suggest a novel pharmacologic approach to depression.

  1. Peter Roy-Byrne, MD

In animals, repeated inescapable stress induces learned helplessness, which has long served as an experimental model of depression. It is poorly appreciated that after exposure to inescapable stress, some animals regain the ability to actively cope when given a chance to escape, while others remain helpless. In an elegant series of animal studies, researchers used inescapable stress to examine the molecular mechanisms behind resilience.

In initial studies, mice had dramatically divergent responses once they could escape footshocks: Some remained persistently helpless while others showed resilience by eventually resuming their attempts to escape. On autopsy, all stressed animals had high levels of ΔFosB expressed in the ventrolateral periaqueductal gray (vlPAG), which corresponds to the lateral margins of the serotonin-rich dorsal raphe. Higher levels occurred in animals with greater resilience. ΔFosB appeared in neurons positive for substance P, bound directly to the promoter region of the substance P gene, and, in stress-exposed rats, reduced substance P expression in the nucleus accumbens. Blockade of substance P with a selective antagonist promoted resilience, similar to the effect of antidepressants. Viral-mediated overexpression of ΔFosB in the vlPAG also produced resilience.


These experiments show that inescapable stress causes neuroplastic changes in neuronal networks mediating defensive responses, changes that correspond to the learned helplessness state. Production of ΔFosB desensitizes these helplessness-related circuits, counteracting the tendency to give up and producing a more resilient behavioral response. Because the mice were of the same inbred strain, their differences in resilience are due not to genetic effects, but rather to epigenetic, environmental, or random effects. Also, the findings are consistent with evidence that substance P antagonists have antidepressant properties. This protein could constitute a target for future drug development.


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