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 pretreatment. 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.

The infralimbic and prelimbic cortical areas bidirectionally regulate safety learning during normal and stress conditions.

Safety learning is a critical function for behavioral adaptation, environmental fitness, and mental health. Animal models have implicated the prelimbic (PL) and infralimbic (IL) subregions of the medial prefrontal cortex (mPFC) in safety learning. However, whether these regions differentially contribute to safety learning and how their contributions become affected by stress still remain poorly understood. In this study, we evaluated these issues using a novel semi-naturalistic mouse model for threat and safety learning. As mice navigated within a test arena, they learned that specific zones were associated with either noxious cold temperatures ("threat") or pleasant warm temperatures ("safety"). Optogenetic-mediated inhibition revealed critical roles for the IL and PL regions for selectively controlling safety learning during these naturalistic conditions. This form of safety learning was also highly susceptible to stress pre-exposure, and while IL inhibition mimicked the deficits produced by stress, PL inhibition fully rescued safety learning in stress-exposed mice. Collectively, these findings indicate that IL and PL bidirectionally regulate safety learning during naturalistic situations, with the IL region promoting this function and the PL region suppressing it, especially after stress. A model of balanced IL and PL activity is proposed as a fundamental mechanism for controlling safety learning.