Safety Signals Mitigate the Consequences of Uncontrollable Stress Via a Circuit Involving the Sensory Insular Cortex and Bed Nucleus of the Stria Terminalis

Background: Safety signals exert a powerful buffering effect when provided during exposure to uncontrollable stressors. We evaluated the role of the sensory insular cortex (Si) and the extend amygdala in this "safety signal effect." Methods: Rats were implanted with microinjection cannula, exposed to inescapable tailshocks either with or without a safety signal, and later tested for anxiety-like behavior or neuronal Fos expression. Results: Exposure to the uncontrollable stressor reduced later social exploration but not when safety signals were present. Temporary inhibition of Si during stressor exposure but not during later behavioral testing blocked the safety signal effect on social exploration. The stressor induced Fos in all regions of the amygdala, but safety signals significantly reduced the number of Fos immunoreactive cells in the basolateral amygdala and ventrolateral region of the bed nucleus of the stria terminalis (BNSTlv). Inhibition of BNSTlv neuronal activity during uncontrollable stressor exposure prevented the later reduction in social exploration. Finally, safety signals reduced the time spent freezing during uncontrollable stress. Conclusions: These data suggest that safety signals inhibit the neural fear or anxiety response that normally occurs during uncontrollable stressors and that inhibition of the BNSTlv is sufficient to prevent later anxiety. These data lend support to a growing body of evidence that chronic fear is mediated in the basolateral amygdala and BNSTlv and that environmental factors that modulate fear during stress will alter the long-term consequences of the stressor.