Transcriptomic Architecture of Weak Versus Strong Contextual Fear Extinction Learning Uncovers Extinction-Suppressive Role of TIA1.

BACKGROUND: Extinction, the capacity for an individual to inhibit or diminish fear memories, is a critical aspect of fear processing. In humans, weak extinction learning is often observed in anxiety and fear-related disorders such as posttraumatic stress disorder. However, the mechanisms behind regulating extinction and determining individual variability in extinction learning remain poorly understood. METHODS: To investigate the molecular basis of interindividual and sex-related differences in the ability to extinguish fear, extinction learning was analyzed in inbred wild-type male and female mice. Contextual fear conditioning and extinction were combined with profiling of the hippocampal transcriptomes associated with weak and strong extinction learning and genetic manipulations to extend our transcriptomic findings. RESULTS: We identified significant sex-dependent and -independent differences in hippocampal gene expression between weak and strong extinction learner animals. Very high transcriptomic overlap between weak learner males and females was especially surprising, showing upregulation of multiple genes associated with neurotoxic insult and cellular stress, including a gene encoding a major stress regulator, a prion-like TIA1. Overexpression of Tia1 in the dorsal hippocampus caused sex-independent dysregulation of microglia and diminished fear extinction learning in animals of both sexes. CONCLUSIONS: We demonstrated the brain-based transcriptomic architecture associated with weak versus strong fear extinction learning in male and female mammalian subjects and identified the sex-independent extinction-suppressive role of hippocampal TIA1 upregulation. Our results should help to develop a better understanding of the mechanisms that underlie individual and sex-dependent differences in extinction and could inform novel therapeutic targets for pharmacological extinction augmentation strategies in fear-related disorders.