Expression of ΔFosB as a Therapy for Blast-Induced PTSD

 描述（由申请人提供）： 爆炸相关创伤性脑损伤（TBI）与伊拉克和阿富汗战区士兵的神经精神损伤（包括创伤后应激障碍[PTSD]和重度抑郁症）的发展有关。爆炸相关TBI的治疗目前仅限于咨询和姑息治疗。我们在大鼠模型中探索了模拟轻度TBI（mTBI）的74.5 kPa冲击波暴露的影响。暴露于爆炸的大鼠表现出多种PTSD样行为特征，包括焦虑增加、声音惊吓增强、对捕食者气味的反应改变以及线索恐惧反应改变。 先前的研究表明，转录因子ΔFosB的表达在应激和抑郁中受到调节，这种调节似乎可以促进恢复力和抗抑郁反应。证据支持ΔFosB表达减少与抑郁症之间的联系。此外，研究表明，在丘脑核（NAc）中的ΔFosB诱导是对压力情况的弹性或易感性的关键分子决定因素，并且是抗抑郁作用所必需的。我们 也获得了初步证据，即低于正常水平的ΔFosB存在于爆炸暴露大鼠的NAc中，这些大鼠发展为PTSD样表型。本文提出的研究的总体目标是测试ΔFosB的从头表达是否可以在我们的冲击波诱导的mTBI的大鼠模型中在冲击波暴露后逆转已建立的PTSD相关性状。在实验上，我们建议使用重组AAV颗粒将ΔFosB转基因植入爆炸暴露动物的NAc中，并测试这种治疗是否改善与爆炸诱导的PTSD表型相关的抑郁和焦虑样行为。 总的来说，拟议的研究将探索从头ΔFosB表达治疗爆炸诱导的PTSD的潜在治疗益处。这些研究可能会发现新的治疗方案，用于治疗受这种毁灭性疾病影响的现役军人和退伍军人。

 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 ΔFosB is regulated in stress and depression, and such regulation appears to promote resilience and antidepressant responses. Evidence supports a link between decreased ΔFosB expression and depression. Furthermore, studies have indicated that ΔFosB 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 ΔFosB 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 ΔFosB can reverse established PTSD-related traits after blast exposure in our rat model of blast- induced mTBI. Experimentally we propose to transduce the ΔFosB 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 ΔFosB 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.