Molecular, cellular, and circuit basis of depression susceptibility and resilience

Prolonged stressful events are an important risk factor for major depressive disorder. However, there are dramatic individual variations in response to stress: a relatively small proportion of people (10%-20%) experiencing prolonged stress develop stress-related disorders, such as depression (susceptibility to stress), whereas most stress-exposed individuals maintain normal psychological functioning (resilience to stress). An accumulating body of studies investigating the neural basis of susceptibility vs resilience to depression is revealing the genetic, epigenetic, immune, and neurophysiological mechanisms that underlie stress susceptibility as well as the active mechanisms that underlie resilience. In this chapter, we discuss, mainly based on our own work, key pathological mechanisms of susceptibility that are identified as potential therapeutic targets for depression treatment. We also review novel mechanisms that promote natural resilience as an alternative strategy to achieve treatment efficacy. These studies are opening new avenues to develop conceptually novel therapeutic strategies for depression treatment.