Expression of ΔFosB as a Therapy for Blast-Induced PTSD

James J Peters Va Medical Center, Bronx NY

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Abstract

? DESCRIPTION (provided by applicant): Blast-related traumatic brain injury (TBI) is associated with the development of neuropsychiatric injuries (including post-traumatic stress disorder [PTSD] and major depression) among soldiers in the war theaters of Iraq and Afghanistan. Treatment for blast-related TBI is currently limited t counseling and palliative care. We have explored the effects of 74.5-kPa blast exposures that mimic mild TBI (mTBI) in a rat model. Blast- exposed rats exhibit a variety of PTSD-like behavioral traits, including increased anxiety, enhanced acoustic startle, altered responses to a predator scent, and altered cued fear responses. Previous research has demonstrated that expression of the transcription factor ?FosB is regulated in stress and depression, and such regulation appears to promote resilience and antidepressant responses. Evidence supports a link between decreased ?FosB expression and depression. Furthermore, studies have indicated that ?FosB induction in the nucleus accumbens (NAc) is a key molecular determinant of resilience or susceptibility to a stressful situation and is required for antidepressant action. We also have obtained preliminary evidence that below normal levels of ?FosB are present in the NAc of blast-exposed rats that develop a PTSD-like phenotype. The overall goal of the research proposed herein is to test whether de novo expression of ?FosB can reverse established PTSD-related traits after blast exposure in our rat model of blast- induced mTBI. Experimentally we propose to transduce the ?FosB transgene into the NAc of blast-exposed animals using recombinant AAV particles and to test whether this treatment ameliorates the depression- and anxiety-like behaviors associated with the blast-induced PTSD phenotype. Collectively, the proposed studies will explore the potential therapeutic benefits of de novo ?FosB expression for the treatment of blast-induced PTSD. These studies may uncover new therapeutic options for the treatment of active duty military personnel and veterans affected by this devastating condition.