Prefrontal regulation of safety learning during ethologically relevant thermal threat.

Learning and adaptation during sources of threat and safety are critical mechanisms for survival. The prelimbic (PL) and infralimbic (IL) subregions of the medial prefrontal cortex (mPFC) have been broadly implicated in the processing of threat and safety. However, how these regions regulate threat and safety during naturalistic conditions involving thermal challenge still remains elusive. To examine this issue, we developed a novel paradigm in which adult mice learned that a particular zone that was identified with visuospatial cues was associated with either a noxious cold temperature ("threat zone") or a pleasant warm temperature ("safety zone"). This led to the rapid development of avoidance behavior when the zone was paired with cold threat or approach behavior when the zone was paired with warm safety. During a long-term test without further thermal reinforcement, mice continued to exhibit robust avoidance or approach to the zone of interest, indicating that enduring spatial-based memories were formed to represent the thermal threat and thermal safety zones. Optogenetic experiments revealed that neural activity in PL and IL was not essential for establishing the memory for the threat zone. However, PL and IL activity bidirectionally regulated memory formation for the safety zone. While IL activity promoted safety memory during normal conditions, PL activity suppressed safety memory especially after a stress pre-treatment. Therefore, a working model is proposed in which balanced activity between PL and IL is favorable for safety memory formation, whereas unbalanced activity between these brain regions is detrimental for safety memory after stress. Significance Statement This study provides new insights on the role of prefrontal cortical processing for threat and safety learning during thermal challenge. For this, a novel behavioral paradigm was implemented in which laboratory mice learned that a particular spatial zone was associated with either a noxious cold temperature ("thermal threat") or a pleasant warm temperature ("thermal safety"). Manipulations of neuronal activity revealed that the prelimbic and infralimbic subregions of the medial prefrontal cortex bidirectionally regulated memory formation for the thermal safety zone, but not for the thermal threat zone. In addition, the influence of these cortical regions during safety memory formation was altered when mice underwent a stress treatment to produce a disease-like state.