Stress History Modulates CRF Neurons to Establish Resilience

Cumulative stress is a major risk factor for developing major depressive disorder (MDD), yet not everyone experiencing chronic stress develops MDD. In those who do not, it is unclear at what point, or by what mechanism, a trajectory of stable resiliency emerges.

Utilizing a 10-day repeated social defeat stress model (RSDS) for MDD, we observed that a critical period between 7 and 10 daily defeats marks the phenotypical divergence of resilient from susceptible mice. Using cell-type selective electrophysiology, chemogenetics, optogenetics, fiber photometry and RNA quantification was employed to investigate the nature of stress effects on neuroadaptation in the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) required to determine resilience.

In response to ongoing stress, corticotropin-releasing factor (CRF ⁺ , but not CRF ^- ) neurons of the (BNSTov) displayed a sustained increased firing rate in resilient, but not susceptible mice. This neurophysiological adaptation was self-sustaining, but only after 7 critical stress exposures, indicating that the process of developing resilience is dependent on stress history.

Our study reveals a novel process by which individuals might persist in the face of adversity by way of stress-provoked activation, not inhibition of a key CRF limbic region that establishes a pathway to resilience.