Acute Social Stress Engages Synergistic Activity of Stress Mediators in the VTA to Promote Pavlovian Reward Learning

Abstract

Stressful events rapidly trigger activity-dependent synaptic plasticity in certain brain areas, driving the formation of aversive memories. However, it remains unclear how stressful experience affects plasticity mechanisms to regulate learning of appetitive events, such as intake of addictive drugs or palatable foods. Using rats, we show that two acute stress mediators, corticotropin-releasing factor (CRF) and norepinephrine (NE), enhance plasticity of NMDA receptor-mediated glutamatergic transmission in the ventral tegmental area (VTA) through their differential effects on inositol 1,4,5-triphosphate (IP₃)-dependent Ca²⁺ signaling. In line with this, acute social defeat stress engages convergent CRF and NE signaling in the VTA to enhance learning of cocaine-paired cues. Furthermore, defeat stress enables learning of a food-paired cue with no delay between the cue onset and food delivery. We propose that acute stress mediators synergistically regulate IP₃-Ca²⁺ signaling in the VTA to promote appetitive Pavlovian conditioning, likely enabling learning of cues with no predictive value.