(1) PURPOSE - The purpose of the project is to evaluate putative neurotrophic factor mechanisms and related treatments in blast induced traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) using rodent models. The three goals of this project are to: 1) measure the effects of blast induced TBI on cognition and on fear conditioning;2) understand the effects of blast induced TBI on brain derived neurotrophic factor (BDNF) protein levels and on neurodegeneration in prefrontal cortex, hippocampus and amydala;and 3) pilot a novel treatment approach to enhance cognition and BDNF levels in these models. We hypothesize that TBI impairs both spatial learning and fear extinction by reducing plasticity and BDNF. We hypothesize that pharmacological approaches which enhance BDNF levels will attenuate TBI induced learning impairments. The epigenetic regulation of BDNF, using a histone deacetylase (HDAC) inhibitor, is hypothesized to enhance learning. (2) BACKGROUND- (a) Scientific Rationale- TBI and PTSD have become the signature war zone injuries in Operation Enduring Freedom and Operation Iraqi Freedom. Too little is known about the pathophysiology of these co-occurring conditions. The mechanisms of TBI and associated PTSD involve alterations in neurotrophic factors such as BDNF. BDNF promotes the survival of existing neurons and produces synaptic remodeling via its enhancement of axonal and dendritic sprouting. Preliminary research suggests that neural BDNF levels are reduced in TBI conditions. An important mechanism for mediating changes in behavior and neural function is through the regulation of chromatin structure via post-translational modifications of histones. Histone deacetylase (HDAC) inhibitors are promising candidates for the pharmacological treatment in neuropsychiatric conditions. HDAC inhibitors have been shown to increase learning via enhanced neuroplasticity and BDNF activity. (b) How this Research will Advance Knowledge in Rehabilitation Research - By increasing our understanding of the mechanisms and sequelae of brain injury caused by blast pressure waves in animal models, we can pre-clinically screen candidate pharmacological approaches. (c) Significance of the Research and How it Relates to RR&D Priority Areas -The research relates to the RR&D Priority Area of Traumatic Brain Injury. Developing a standardized mouse model for a pressure wave brain injury and PTSD is of critical importance for the development of effective treatments. (d) Direct Benefits and Quality of Services - This study will investigate the effects of blast damage and PTSD that have been sustained by many Veterans. It is important to test treatments in animal models before exposing humans to such interventions. (3) EXPECTED OUTCOMES OR PRODUCTS - The first outcome of this study is to demonstrate that this animal model of blast induced TBI in mice alters learning and associative fear conditioning. The second outcome is to show that blast induced TBI and stress alters BDNF protein levels in prefrontal cortex, hippocampus and amydala. The third outcome demonstrates that a HDAC inhibitor, with a form available for human use, enhances TBI induced learning and extinction of fear via BDNF enhancement. (4) METHODS AND RESEARCH PLAN - Male C57BL/6 mice are proposed for use because of their demonstrated utility in TBI and PTSD models. The shockwave blast injury (SWBI) model uses an on-site electrohydraulic shockwave apparatus with characteristics that simulate features of a blast. Different SWBI cohorts are separately assessed for cognition and fear conditioning. Prior to each day of the cognitive conditioning and fear extinction learning, sodium butyrate is administered to examine effects. After behavioral testing, brains are harvested from mice to measure neural plasticity marker BDNF in sections using quantitative IHC with alternate sections undergo Nissl staining to examine brain tissue loss.
The significance of this pre-clinical research is that it can inform pharmacotherapy and behavioral interventions and can guide the design of clinical interventions. In this study, we purposefully test an available medication (sodium butyrate related to the clinical pharmaceutical Buphenyl) so that a more rapid translation into the clinical setting is possible. Relevance to Veterans Health: The research relates to the RR&D Priority Area of Traumatic Brain Injury. Developing a standardized mouse model for a pressure wave brain injury and PTSD is of critical importance for the development of effective treatments. This study will investigate the blast damage, cognitive deficits, and conditioned fear responses that have been sustained by many Veterans. For the purposes of safety and efficacy, it is critical to first test novel treatments for such injuries in animal models before exposing humans to such interventions.
|Heinrichs, Stephen C; Leite-Morris, Kimberly A; Guy, Marsha D et al. (2013) Dendritic structural plasticity in the basolateral amygdala after fear conditioning and its extinction in mice. Behav Brain Res 248:80-4|