Expression of ΔFosB as a Therapy for Blast-Induced PTSD

 描述(由申请人提供)： 与爆炸相关的创伤性脑损伤(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)和严重抑郁症)的发展有关。爆炸性脑外伤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脑损伤(MTBI)的74.5 kpa冲击波暴露的影响。爆炸暴露的大鼠表现出各种类似创伤后应激障碍的行为特征，包括焦虑增加，声音惊吓增强，对捕食者气味的反应改变，以及提示的恐惧反应改变。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，这种调节似乎促进了弹性和抗抑郁反应。有证据支持ΔFosB表达减少与抑郁症之间的联系。此外，研究表明，伏隔核中ΔFosB的诱导是决定对应激状态的韧性或敏感性的关键分子决定因素，是抗抑郁作用所必需的。我们 也获得了初步证据表明，在发生创伤后应激障碍样表型的冲击波暴露大鼠的NAC中存在低于正常水平的ΔFosB。本文提出的研究的总体目标是测试ΔFosB的从头表达是否能够逆转我们的冲击伤诱导的大鼠创伤后创伤后应激障碍相关特征。在实验方面，我们建议使用重组Δ颗粒将AAVFosB转基因基因导入爆炸性创伤后应激障碍动物的NAC中，并测试这种治疗是否改善与爆炸性创伤后应激障碍表型相关的抑郁和焦虑样行为。总之，拟议的研究将探索从头ΔFosB表达在治疗原始细胞诱导的创伤后应激障碍中的潜在治疗益处。这些研究可能会发现治疗受这种毁灭性疾病影响的现役军人和退伍军人的新的治疗方案。

 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.