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. In response to ongoing stress, corticotropin-releasing factor (CRF) neurons of the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) display 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.
The Bed Nucleus of the Stria Terminalis (BNST) has been studied extensively for its role in coordinating what appears to be often opposing adaptive behaviors. However, what is missing in the literature is the link between internal affective states and the adaptive stress behaviors they motivate. Previously, we uncovered a stress window during which neuronal activity of Corticotropin-Releasing Factor (CRF) expressing neurons of the oval nucleus of the BNST, (BNSTovCRF) maintains resilient behavior through self-sustained activation1. Here, we explore how BNSTovCRF neurons achieve this through shifting the valence of stress contexts to represent a less aversive experience. Using cell-type-selective optogenetics and transgenic Crf-ChR2 mice, we show that BNSTovCRF induces resiliency through dampening the deleterious effects of social defeat encoding, enhancing the positive salience of both appetitive and aversive stimuli, shifting socio-affective bias, and promoting tolerability of non-social physical stress. Adaptive responses to stress typically emanate as a response to negative internal states by external stimuli; here we show that in resilient mice, stressful environments are less aversive than susceptible mice, suggesting a different motivational capacity to endure stress in this group. Thus, we describe a novel role for BNSTovCRF neurons in resisting the emotional effects of cumulative stress by reducing the internal experience of aversion.
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