HDAC inhibition facilitates the switch between memory systems in young but not aged mice.
Chromatin modifications, especially histone acetylation, are critically involved in gene regulation required for long-term memory processes. Increasing histone acetylation via administration of histone deacetylase inhibitors before or after a learning experience enhances memory consolidation for hippocampus-dependent tasks and rescues age-related memory impairments. Whether acutely and locally enhancing histone acetylation during early consolidation processes can operate as a switch between multiple memory systems is less clear. This study examined the short- and long-term behavioral consequences of acute intra-CA1 administration of the histone deacetylase inhibitor Trichostatin A (TSA) on cue versus place learning strategy selection after a cue-guided water maze task and competition testing performed 1 or 24 h later in mice. Here, we show that intra-CA1 TSA infusion administrated immediately post-training biased young mice away from striatum-dependent cue strategy toward hippocampus-dependent place strategy under training condition that normally promotes cue strategy in vehicle controls. However, concomitant infusions of TSA with either PKA inhibitor, Rp-cAMPS, into CA1 or cAMP analog, 8Br-cAMP, into dorsal striatum failed to bias young mice to place strategy use. Behavioral and immunohistochemical analyses further indicated that post-training TSA infusion in aged mice rescued aging-associated deregulation of H4 acetylation in the CA1 but failed to reverse phosphorylated CREB deficits and to produce strategy bias on the 24 h probe test. These findings suggest that post-training intra-CA1 TSA infusion promotes dynamic shift from striatum toward the hippocampal system in young but not aged animals, and support the possibility of a role for CREB in the TSA-mediated switch between these two memory systems.
Université de Bordeaux, Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5287, 33405 Talence, France.
Malorie
M
Dagnas
Jean-Louis
JL
Guillou
Thomas
T
Prévôt
Nicole
N
Mons
D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003463:Cues; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D018782:Maze Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology
D017362:Cyclic AMP Response Element-Binding Protein; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047428:Protein Kinase Inhibitors; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; C012589:trichostatin A; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases