Ventral tegmental area glutamate neurons mediate the nonassociative consequences of traumatic stress

Exposure to trauma is a risk factor for the development of a number of mood disorders, and may enhance vulnerability to future adverse life events. Recent data implicate ventral tegmental area (VTA) glutamate neuronal activity as functionally important for signaling aversive or threating stimuli. However, it is unknown whether VTA glutamate neurons regulate transsituational outcomes that result from stress and whether these neurons are sensitive to stressor controllability. This work established an operant mouse paradigm to examine the impact of stressor controllability on VTA glutamate neuron function and stressor outcome. Uncontrollable (inescapable) stress, but not physically identical controllable (escapable) stress, produced social avoidance in male mice. Cell-type-specific calcium recordings showed that both controllable and uncontrollable stressors increased VTA glutamate neuronal activity. Chemogenetic reduction of VTA glutamate neuron activity prevented the behavioral sequelae of uncontrollable stress. Our results provide causal evidence that mice can be used to model stressor controllability and that VTA glutamate neurons may contribute to transsituational stressor outcomes, such as social avoidance and exaggerated fear that are observed within trauma-related disorders.