Functional knockout of forebrain protein 14-3-3 disrupts conditioned taste aversion learning

Abstract

Protein 14-3-3 isoforms are key to many cellular processes and are ubiquitous throughout the brain. 14-3-3 is a regulator of ser/thr phospho-signaling by binding and sequestering phosphorylated substrates including kinases, histone deactylases, and transcription factors. The role of protein 14-3-3 in conditioned taste aversion learning (CTA) has not previously been examined. We parameterized CTA learning in difopein- YFP transgenic mice, which have widespread by expression of the artificial peptide difopein in the forebrain, including the basolateral amygdala and insular cortex, resulting in functional knock-out (FKO) of all 14-3-3 isoforms . We found that a single pairing of saccharin or NaCl (CS) and LiCl injection (US) was not sufficient to induce CTA in FKO mice. Multiples pairings of CS and US did lead to CTA acquisition in the FKO mice; however, the CTA rapidly extinguished within 30 minutes to 24 hours after acquisition. Additionally, we found that 14-3-3 FKO mice have an attenuated visceral neuraxis response to LiCl as measured by c-Fos induction. The deficit in FKO was not due to an inability to discriminate or avoid tastants, because they showed normal unconditioned taste preferences for both palatable (saccharin, maltodextrin , low concentration NaCl) and unpalatable tastants (quinine, HCl, and high concentration NaCl) and they were able to reduce intake of a maltodextrin solution adulterated with quinine. The FKO did not have a global deficit in ingestive learning, because they were able to form a conditioned flavor-nutrient preference. Thus, FKO of forebrain 14-3-3 appears to disrupt CTA learning leading to forgetting, rapid extinction, or failure to reconsolidate. This further implicates ser/thr phospho-signaling pathways in the regulation of long-term CTA learning.