In the United States, upwards of 3 million traumatic brain injuries (TBI) occur every year with an estimated 80% categorized as ?mild?. While specific populations are at a higher risk of receiving head trauma (e.g. 330,000 service men and women have been diagnosed with a head injury since the start of the Operation Enduring Freedom and Operation Iraqi Freedom wars), the Centers for Disease Control report that 40% of TBIs occur due to falls, making TBI a national concern. Although physical symptoms of mild TBI (mTBI) typically resolve within a week of injury, deficits, such as cognitive dysfunction, have been observed chronically or may reoccur years after a mTBI. The exact mechanism(s) behind this persistent cognitive dysfunction are unknown, but there is support for histone deacetylases (HDACs) playing a key role. HDACs are epigenetic modulators that can control behavior in response to chronic stimuli by modulating DNA accessibility. Specific Class IIa HDACs, HDAC4 and 5, which translocate to and from the nucleus upon phosphorylation, have been implicated in memory and interact with several post-synaptic signaling molecules. These HDACs have specific roles in the structural synaptic plasticity that is germane to learning and memory. The preliminary data presented in the current application demonstrate increased hippocampal levels of the Class IIa HDAC, HDAC4, in the chronic post-TBI period ([14 and 30 days]) using a model of closed-skull mTBI. Together these data warrant further investigation of Class IIa HDACs in the progression of cognitive dysfunction following mTBI. The central hypothesis of this application is that mTBI increases Class IIa (HDAC4/5) expression activity which dysregulates synaptic structure that, when mitigated, will reverse long-term cognitive impairments associated with mTBI. This hypothesis will be tested using these Aims: [(1) Quantify cell type-specific alterations in longitudinal HDAC4/5 expression activity and associated changes in synaptic structure in the memory circuit using novel neuroimaging modalities in a mouse model of closed-skull mTBI.] The technical innovations include the analysis of HDAC expression activity using a novel, substrate-based positron emission tomography (PET) radio-ligand, 6-(tri-fluoroacetamido)-1-hexanoicanilide (18F-TFAHA) for repeated in vivo measures. We anticipate persistent increases in hippocampal Class IIa HDAC expression activity, as measured by PET-CT imaging that will accompany simplification of morphological features in hippocampal neurons. (2) Quantify the efficacy of Class IIa HDAC-selective inhibition in mitigating mTBI-induced cognitive dysfunction. We anticipate that the normalization of HDAC4/5 expression with MC1568 will mitigate cognitive deficits as observed with hippocampal-based fear extinction learning post-mTBI. The proposed studies within this application are translationally-relevant and are designed to provide new biomarkers and therapeutic targets for use in Veterans that have sustained mild TBI and suffer chronically with cognitive dysfunction.

Public Health Relevance

Mild traumatic brain injury (mTBI) affects millions of Americans every year, but active duty and reserve service members are at an increased risk of sustaining a TBI compared to civilians due to combat-related activities. Although symptoms of mTBI are usually short-lived, mTBI can lead to chronic behavioral deficits, such as cognitive dysfunction, particularly that related to the fear learning associated with posttraumatic stress disorder, of which the underlying pathology is not well understood. Thus, the proposed studies aim to utilize highly- translational neuroimaging techniques to longitudinally quantify subcellular, epigenetic regulation following mTBI within regions of the brain that regulate cognition and fear learning. Studies will also evaluate the efficacy of targeting the mTBI-induced epigenetic regulation for rehabilitation of learning and memory, thereby reducing the burden of TBI-related cognitive deficits and improving quality of life for Veterans suffering from TBI.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (I21)
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Rehabilitation Research and Development SPiRE Program (RRDS)
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John D Dingell VA Medical Center
United States
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