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.