Whole-brain cFos mapping reveals the paraventricular thalamus as a key node for stress-enhanced fear learning.

Introduction: Fear learning is critical for organisms to respond appropriately to potentially harmful stimuli. In cases of post-traumatic stress disorder (PTSD), potent or persistent trauma can facilitate future aversive learning, leading to maladaptive fear responses in generally safe contexts. Despite this knowledge, the neural circuit mechanisms that underlie stress-enhanced fear learning (SEFL) remain poorly understood. Methods: We utilized brain clearing and light sheet imaging, mapping whole-brain expression of the immediate early gene cFos in mice to identify brain regions engaged by SEFL. Next, we used chemogenetics to test the causal contribution of a candidate target region, the paraventricular thalamus (PVT), to sensitized fear learning. Results: SEFL was associated with reduced activity throughout the brain, most prominently within higher order thalamic nuclei. Despite the overall reduction, cFos expression in the PVT positively correlated with a principal-component-derived predictor of subsequent sensitized fear expression. Furthermore, chemogenetic inhibition of the PVT 30 days after stress exposure prevented the acquisition of SEFL and restored freezing to control levels. Discussion: Our results provide a comprehensive whole-brain SEFL-induced cFos map. Furthermore, we reveal a novel function for one identified brain region, the PVT, in sensitized fear learning.