# Histone Deacetylase Regulation of Cognitive Outcomes after Mild TBI

> **NIH VA I21** · JOHN D DINGELL VA MEDICAL CENTER · 2020 · —

## Abstract

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 Veter...

## Key facts

- **NIH application ID:** 9837348
- **Project number:** 5I21RX002900-02
- **Recipient organization:** JOHN D DINGELL VA MEDICAL CENTER
- **Principal Investigator:** ALANA C. CONTI
- **Activity code:** I21 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-11-01 → 2020-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9837348

## Citation

> US National Institutes of Health, RePORTER application 9837348, Histone Deacetylase Regulation of Cognitive Outcomes after Mild TBI (5I21RX002900-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9837348. Licensed CC0.

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