Transient receptor potential ankyrin 1 ion channels may control stress adaptation and conditioned fear responses in male mice following footshock

INTRODUCTION: Stress maladaptation and dysregulated conditioned fear are hallmarks of trauma- and stressor-related disorders. The centrally projecting Edinger-Westphal nucleus (EWcp) is involved in stress adaptation. As the urocortin 1/cocaine- and amphetamine-regulated transcript (UCN1/CART)-positive neurons of mouse and human EWcp express transient receptor potential ankyrin 1 (TRPA1) mRNA, which reacts to stress, we hypothesized their role in stress adaptation and conditioned fear responses. METHODS: Male Trpa1 wild-type (WT) and knockout (KO) mice underwent footshock-induced fear conditioning. Behavioural analyses included evaluating freezing/jumping responses and extinction to trauma-related context/cues, and a social interaction test (SIT). Plasma corticosterone (CORT), changes in EWcp/TRPA1/UCN1/CART neurons (RNAscope combined with immunohistochemistry), glial markers and tumor necrosis factor-α (TNF-α) immunoreactivity in the EWcp, hippocampus, central amygdala and medial prefrontal cortex (mPFC) were assessed. RESULTS: Stress increased freezing in both genotypes with significantly higher jumping rate in KOs during conditioned fear. Both shocked groups displayed reduced social interest, with higher freezing in KOs than WTs. Fear extinction developed upon repeated introduction to trauma context/cues but was delayed in KOs. Additionally, relapse occurred in KOs only, accompanied by lower CORT levels. In WTs, stress downregulated Trpa1 and increased Ucn1 mRNA expression with enhanced astrocyte responses (except mPFC). In KOs, trauma elevated Cart mRNA and CART peptide levels with higher microglia scores and increased TNF-α immunoreactivity (except EWcp). CONCLUSION: In the EWcp, TRPA1 may modulate trauma-induced neuropeptide cocktail composition. Through influencing astrocyte-microglia interaction, TRPA1 may regulate neuroinflammation in stress-responsive brain areas. Moreover, TRPA1 may diminish fear generalization and promote durable fear extinction.