ABSTRACT
Although the phenomenon of memory formation and recall associated with the use of psychotropic drugs has been extensively studied, mechanisms underlying memories for natural reward have not been clarified. Herein, we test the hypothesis that glutamatergic receptors in the dentate gyrus play a role in memories associated with sucrose. We used pellet self-administration protocol to generate memories in two-port nose-poke discrimination task using male Wistar rats. During non-rewarded probe trial, the conditioned animals readily discriminated the active port versus inactive port and showed massive increase in mRNA expression of AMPA receptor subunit genes (gria2, gria3) as well as c-Fos protein in the DG. Access to sweet pellet further enhanced c-Fos expression in the DG. However, animals pre-treated with AMPA receptor antagonist CNQX (intra-DG), on exposure to operant chamber (no pellet), showed decreased discrimination as well as c-Fos expression. We suggest that AMPA receptors in DG mediate recall and consolidation of memories associated with sucrose consumption. CNQX pre-treated animals, if presented with sweet pellet on nose poke, exhibited high discrimination index coupled with increased c-Fos expression. In these CNQX treated rats, the DI was again decreased following administration of NMDA receptor antagonist AP5. We suggest that, although AMPA receptors are blocked, the access to sweet pellet may induce surge of glutamate in the DG, which in turn may reinstate memories via activation of erstwhile silent synapses in NMDA dependant manner.
Subject(s)
Dentate Gyrus , Receptors, AMPA , Receptors, N-Methyl-D-Aspartate , Sucrose , Animals , Male , Rats , 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology , Conditioning, Operant/drug effects , Conditioning, Operant/physiology , Dentate Gyrus/drug effects , Dentate Gyrus/metabolism , Discrimination Learning/drug effects , Discrimination Learning/physiology , Discrimination, Psychological/drug effects , Discrimination, Psychological/physiology , Excitatory Amino Acid Antagonists/pharmacology , Memory/physiology , Memory/drug effects , Proto-Oncogene Proteins c-fos/metabolism , Rats, Wistar , Receptors, AMPA/metabolism , Receptors, AMPA/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , RNA, Messenger/metabolism , Self Administration , Sucrose/administration & dosageABSTRACT
Neuroadaptations 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 the Bdnf promoters showed concomitant increase. Stereotactic administration of Tet1 siRNA in the DG before and after conditioning inhibited reward memory formation and recall, respectively. Administration of Tet1 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 the Bdnf 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.
