Divergent projections of the paraventricular nucleus of the thalamus mediate the selection of reactive and proactive defensive behaviors

Abstract

The appropriate selection of reactive and proactive defensive behaviors amid fearful situations is essential for survival. Studies in both rodents and primates have shown that reactive defensive responses depend on the activity of the central nucleus of the amygdala (CeA) whereas proactive ones primarily rely on the nucleus accumbens (NAc). However, the mechanisms underlying flexible switching between CeA-driven (reactive) and NAc-driven (proactive) defensive responses, remain unknown. Here, using a behavioral task in which mice must trade a reactive defensive strategy (i.e. freezing) for an instrumental one (i.e. active avoidance) to avoid punishment, we discovered that the paraventricular nucleus of the thalamus (PVT) mediates the selection of defensive behaviors through its interaction with the CeA and the NAc. In vivo calcium imaging using fiber photometry showed that unlike the PVT–CeA pathway which drives conditioned freezing responses, the PVT–NAc pathway is inhibited during freezing and instead signals active avoidance events. In addition, optogenetic manipulations of these circuits revealed that activity in the PVT–CeA or PVT–NAc pathway biases behavior toward the selection of reactive or proactive defensive responses, respectively. Our collective findings provide direct evidence that the PVT, a structure increasingly considered as a potential site for guiding behavioral decisions amid motivational conflicts, mediates flexible switching between opposing defensive behaviors.