Histone acetylation increase rescues a weak remote fear memory in rats

Abstract

According to multiple studies, inhibitors of histone deacetylases (HDACs) hinder the activity of HDACs, thus enhancing histone acetylation [1, 2]. This process can promote long-term memory and potentiation [3, 4], and even alleviate memory deficits [5]. Our recent findings demonstrate that sodium butyrate (an HDAC inhibitor) improves rat’s recent fear memory and serves as a cognitive enhancer. The aim of this study was to investigate the potential of HDAC inhibitor sodium butyrate to improve the weakening of remote fear memory in rats. The experiment was conducted on both male and female Wistar and Long Evans rats. The animals were routinely handled for a week prior to the start of the experiment. They underwent contextual fear conditioning, where the unconditioned stimulus (US) — an electrical shock to the foot — was connected with a conditioned stimulus (CS), a particular context. The duration of their freezing behavior was assessed during the test session T0. At 24 hours after conditioning (test session T1), the animals that were conditioned froze when in the conditioning environment, providing evidence of successful learning. Subsequently, their freezing responses were measured during retrieval sessions six months after conditioning (test session T2). Following T2, the control groups were administered sham injections of saline, while the experimental groups were given injections of sodium butyrate. Freezing duration was then evaluated in all groups during a subsequent trial (T3) 24 hours later. After completing the training, all groups of rats displayed a longer duration of freezing, indicating the formation of context fear memory during the test session T1 compared to the test session T0. After six months (test session T2), all groups demonstrated a significant decrease in the duration of freezing compared to the T1 test session. The experimental groups were intraperitoneally injected with sodium butyrate immediately after T2, while the control groups received a vehicle injection of sterile saline. 24 hours after the third test session, results showed that rats treated with sodium butyrate had significantly higher freezing responses to the context compared to those receiving vehicle treatment. Additionally, the sodium butyrate-treated groups in the third test session exhibited similar levels of freezing as seen in the first test session. Male and female groups injected with sodium butyrate showed similar levels of freezing and did not display any differences throughout all test sessions. Thus, retrieving weakened remote contextual fear memory followed by immediate administration of the HDAC inhibitor sodium butyrate resulted in a significant improvement of memory. Our findings demonstrate that the reactivated remote fear memory was enhanced when exposed to the HDAC inhibitor sodium butyrate. This aligns with previous studies suggesting the role of HDAC inhibitors in facilitating contextual fear.