Systemic or intrahippocampal delivery of histone deacetylase inhibitors facilitates fear extinction

Abstract

Several recent studies have shown that chromatin, the DNA-protein complex that packages genomic DNA, has an important function in learning and memory. Dynamic chromatin modification via histone deacetylase (HDAC) inhibitors and histone acetyltransferases may enhance hippocampal synaptic plasticity and hippocampus-dependent memory. Little is known about the effects of HDAC inhibitors on extinction, a learning process through which the ability of a previously conditioned stimulus, such as a conditioning context, to evoke a conditioned response is diminished. The authors demonstrate that administration of the HDAC inhibitors sodium butyrate (NaB) systemically or trichostatin A (TSA) intrahippocampally prior to a brief (3-min) contextual extinction session causes context-evoked fear to decrease to levels observed with a long (24-min) extinction session. These results suggest that HDAC inhibitors may enhance learning during extinction and are consistent with other studies demonstrating a role for the hippocampus in contextual extinction. Molecular and behavioral mechanisms through which this enhanced extinction effect may occur are discussed.

Figure 1.

Mice re-exposed to the conditioned context for 24 min exhibited less freezing during testing than those re-exposed for 3 min. A) Mice were conditioned on Day 1, re-exposed to the conditioned context on Day 2 for 3 or 24 min, and tested on Day 3. Both groups showed comparable freezing during the acquisition and extinction sessions, but mice that were re-exposed for 3 min had significantly higher freezing during testing than those exposed for 24 min (p<0.05). B) The protocol from A was used with different conditioning chambers and a different tracking system (see Methods for details). Again, mice re-exposed to the conditioned context for 24 min showed less freezing than the mice re-exposed for 3 min (p<0.05). Percent freezing is shown during the acquisition, extinction, and testing periods in 3-min time blocks.

Figure 2.

HDAC inhibition enhances extinction of contextual fear. A) During a 3-min extinction session, mice injected systemically with NaB or Vehicle prior to extinction did not differ, but during testing, mice injected with NaB showed less freezing compared to vehicle-treated mice (p<0.05). B) Mice administered TSA or vehicle via intrahippocampal cannulae prior to the extinction session exhibited enhanced extinction during testing. Mice showed comparable freezing during acquisition and extinction, but TSA treated mice showed significantly lower freezing during testing (p<0.05). Percent freezing is shown during the 3-min extinction session and in 6-min time blocks during testing.