Histone deactylase inhibition combined with behavioral therapy enhances learning and memory following traumatic brain injury.
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.
Dash
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PK
Department of Neurobiology and Anatomy, The University of Texas Medical School, Houston, TX 77225, USA. p.dash@uth.tmc.edu
Orsi
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SA
Moore
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D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001521:Behavior Therapy / Q000379:methods*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D002087:Butyrates / Q000494:pharmacology / Q000627:therapeutic use*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004780:Environment, Controlled; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007859:Learning Disabilities / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics; D010812:Physical Stimulation
D002087:Butyrates; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1