TET1-induced DNA demethylation in dentate gyrus is important for reward conditioning and reinforcement

AbstractNeuroadaptations in neurocircuitry of reward memories govern the persistent and compulsive behaviors. The study of the role of hippocampus in processing of reward memory and its retrieval is critical to our understanding of addiction and relapse. The aim of this study is to probe the epigenetic mechanisms underlying reward memory in the frame of dentate gyrus (DG). To that end, the rats conditioned to the food baited arm of a Y-maze and subjected to memory probe trial. The hippocampus of conditioned rats displayed higher mRNA levels of Ten-eleven translocase 1 (Tet1) and brain-derived neurotrophic factor (Bdnf) after memory probe trial. The DNA hydroxymethylation and TET1 occupancy at theBdnf promoters showed concomitant increase. Stereotactic administration ofTet1 siRNA in the DG before and after conditioning inhibited reward memory formation and recall, respectively. Administration ofTet1 siRNA impaired the reward memory recall that was reinstated following administration of exogenous BDNF peptide or after wash-off period of 8  days. Infusion of a MEK/ERK inhibitor, U0126 in the DG inhibited reward memory retrieval. The TET1-induced DNA demethylation at theBdnf promoters raised BDNF levels in the hippocampus, thereby setting the stage for reward memory retrieval. The study underscores the causative role of TET1 in the DG for reward memory formation and recall.

Source: Molecular Neurobiology - August 25, 2022 Category: Neurology Source Type: research