TIP39 modulates effects of novelty‐induced arousal on memory

Tuberoinfundibular peptide of 39 residues (TIP39) is a neuropeptide localized to neural circuits subserving emotional processing. Recent work showed that mice with null mutation for the gene coding TIP39 (TIP39‐KO mice) display increased susceptibility to environmental provocation. Based on this stressor‐dependent phenotype, the neuroanatomical distribution of TIP39, and knowledge that novelty‐induced arousal modulates memory functions via noradrenergic activation, we hypothesized that exposure to a novel environment differently affects memory performance of mice with or without TIP39 signaling, potentially by differences in sensitivity of the noradrenergic system. We tested TIP39‐KO mice and mice with null mutation of its receptor, the parathyroid hormone 2 receptor (PTH2‐R), in tasks of short‐term declarative and social memory (object recognition and social recognition tests, respectively), and of working memory (Y‐maze test) under conditions of novelty‐induced arousal or acclimation to the test conditions. Mice lacking TIP39 signaling showed memory impairment selectively under conditions of novelty‐induced arousal. Acute administration of a PTH2‐R antagonist in wild‐type mice had a similar effect. The restoration of memory functions in TIP39‐KO mice after injection of a β ‐adrenoreceptor‐blocker, propranolol, suggested involvement of the noradrenergic system. Collectively, these results suggest that the TIP39/PTH2‐R system modulates the effects of novelty exposure on memory performance, potentially by acting on noradrenergic signaling.