Elsevier

Neuroscience

Volume 163, Issue 1, 29 September 2009, Pages 1-8
Neuroscience

Behavioural Neuroscience
Research Paper
Histone deactylase inhibition combined with behavioral therapy enhances learning and memory following traumatic brain injury

https://doi.org/10.1016/j.neuroscience.2009.06.028Get rights and content

Abstract

Traumatic brain injury (TBI) induces a number of pathological events ranging from neuronal degeneration and tissue loss to impaired neuronal plasticity and neurochemical dysregulation. In rodents, exposure of brain-injured animals to environmental enrichment has been shown to be an effective means of enhancing learning and memory post-injury. Recently, it has been discovered that environmental enrichment may enhance neuronal plasticity through epigenetic changes that involve enhanced histone acetylation, a property that can be mimicked by the use of histone deactylase (HDAC) inhibitors. We therefore evaluated the consequences of the HDAC inhibitor sodium butyrate on the learning and memory of brain-injured mice. In contrast to a previous report using a mouse neurodegeneration model, sodium butyrate (1.2 g/kg daily for four weeks) did not improve learning and memory when tested after the completion of the drug treatment paradigm. In addition, sodium butyrate administration during the reported period of neurodegeneration (days 0–5) also offered no benefit. However, when administered concurrently with training in the Morris water maze task (beginning on day 14 post-injury), sodium butyrate improved learning and memory in brain-injured mice. Interestingly, when these mice were subsequently tested in an associative fear conditioning task, an improvement was observed. Taken together, our findings indicate that HDAC inhibition may mimic some of the cognitive improvements seen following enriched environment exposure, and that the improvement is observed when the treatment is carried out current with behavioral testing.

Section snippets

Animals

All manipulations of animals conformed with the guidelines outlined by the National Institutes of Health in Guide for the Care and Use of Laboratory Animals. Male C57 mice (∼25 g) were purchased from Charles River Laboratories (Wilmington, MA, USA). Mice were group housed and maintained on a 12-h light/dark cycle with ad libitum access to food and water.

Controlled cortical impact injury and drug administration

Animals were initially anesthetized with 5% isoflurane and 2:1 mixture of N2O/O2. While being maintained under anesthesia (2% isoflurane and

Sodium butyrate increases hippocampal histone acetylation

In order to examine if the HDAC inhibitor sodium butyrate can effectively increase hippocampal histone acetylation, mice (n=4/condition) were injected i.p. with (1.2 g/kg) of sodium butyrate or an equal volume of vehicle. This dose has been previously used to examine the effect of this compound on memory formation (Fischer et al., 2007). Thirty minutes following injection, hippocampal tissues were dissected and processed for Western analysis. Fig. 1 shows pictures of representative Western

Discussion

Memory functions, especially hippocampus-dependent learning and memory, are often impaired after TBI. These dysfunctions are thought to be due, in part, to both neuronal death and impaired plasticity of the surviving neurons (Lyeth et al 1990, Zhang et al 2005). Epigenetic changes, such as histone acetylation and methylation, regulate chromatin remodeling and are therefore important contributors to the gene regulation involved in neural development and plasticity. When acetylated, histones

Acknowledgments

The authors would like to thank Jing Zhao, Hyung Jin Ahn, and Min Zhang for technical assistance in performing the cortical impact injury and behavioral studies. This work was supported, in part, by grants from the NIH (NS049160, NS053588, MH072933).

References (28)

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