HDAC INHIBITOR EFFECTS ON ADULT NEUROGENESIS POST-TBI

We are interested in the effects of TBI on neural stem cell (NSC) behavior in the adult brain. TBI stimulates increased proliferation of progenitor cells in niches known to harbor NSCs in the adult. Whether these cells replace neurons lost to TBI or are capable of restoring lost function has not been determined. Indeed it remains unclear if TBI-induced stem cell activation has beneficial or adverse effects on recovery. Disconcertingly, epilepsy is a common co-morbidity of TBI and is postulated to result from aberrant TBI-induced neurogenesis, highlighting possible adverse side-effects of neurogenesis. Further complicating the issue is our poor understanding of the mechanisms that regulate normal and pathogenic NSC behavior.The purpose of this project is to expand our basic knowledge of the effects of TBI on NSCs through the careful characterization of the cellular and molecular effects of controlled cortical impact (CCI) on NSCs in the subventricular zone (SVZ) of adult mice. We will focus on the role of epigenetic mechanisms in this process by examining the effects of histone deactylase (HDAC) inhibition and histone demethylase (HDM) knockdown on adult NSC biology and neuroregenerative responses. Post-translational modifications of histones by HDACs and/or HDMs can lead to transcriptional activation/suppression.The activities of histone modifying enzymes are functionally linked in the adult brain and TBI induces changes in histone acetylation and histone methylation in adult rats. Pre-clinical treatment models demonstrate HDAC inhibitors (HDACi) exert neuroprotective effects and stimulate neurogenesis in TBI and ischemia, restore learning and memory in TBI and neurodegenerative mice, enhance neuronal differentiation and synaptic plasticity and exert antidepressant-like effects. However these same HDACi have also been reported to both prevent or induce neuronal apoptosis in culture, a contradiction that is likely the result of differences in neuronal cell type, the culture conditions employed and the type of HDACi molecule tested.The aims of this project are: (1) to characterize the effects of controlled cortical impact on the proliferation, cell fate and gene expression of NSCs in the SVZ of adult mice; and (2) to determine the effects small molecule HDAC inhibitors or shRNA-mediated HDM knockdown on adult NSC biology; and 3) to identify HDAC/HDM-mediated responses that have therapeutic potential in the treatment of TBI. By focusing on the regulatory role of histone acetylation/methylation in NSC biology, we aim to demonstrate that epigenetic therapies can be used to modulate NSC proliferation and neurogenesis to improve outcomes in the treatment of TBI.