Memory and Mood Enhancing Therapies for Gulf War Illness

描述（由申请人提供）： 虽然海湾战争疾病显示出多种中枢神经系统（CNS）损伤，但认知功能障碍、记忆丧失、抑郁和焦虑是最常见的症状。预防性药物溴化吡啶斯的明（PB）的摄入，长期暴露于杀虫剂（如避蚊胺和氯菊酯），以及第一次波斯湾战争期间与战斗有关的压力被认为是海湾战争疾病的根本原因。与这一假设相一致的是，我们实验室使用大鼠模型进行的研究表明，低剂量的上述化学品（PB、避蚊胺和氯菊酯）和轻度应激的组合暴露28天会导致海马依赖性功能的显著损害，包括新空间学习能力受损、形成新记忆的能力下降以及抑郁和焦虑样行为增加。对海马组织的分析进一步揭示，行为障碍与海马中的神经发生大大下降但大部分神经元细胞层完整有关。考虑到海马神经发生在学习、记忆和情绪功能中的作用，这些发现表明，神经发生的大幅下降可能是海湾战争疾病中学习和记忆障碍以及抑郁和焦虑增加的基础。在这种情况下，大大增强海马神经发生的策略似乎有助于逆转海湾战争疾病中观察到的认知功能障碍和抑郁症和焦虑症。事实上，我们的初步研究表明，在联合暴露于化学品（PB + DEET+氯菊酯）和压力后，给予抗抑郁药如氟西汀（FLU）或咯利普兰（ROL）有望改善海马神经发生以及认知功能。因此，使用上述海湾战争疾病大鼠模型，我们建议严格分析不同临床适用策略对增强海马神经发生和认知功能以及逆转抑郁和焦虑样行为的功效。在具体目标1中，我们将检验以下假设：在海湾战争疾病的大鼠模型中，联合应用抗抑郁药物（FLU或ROL）和抗氧化药物（姜黄素[CUR]或白藜芦醇[RESV];具有抗氧化、抗炎和神经发生增强特性的膳食补充剂）极大地增强了海马神经发生、认知功能和情绪。在具体目标2中，我们将讨论这样一个假设，即联合应用抗抑郁药（FLU或ROL）或抗氧化药（CUR或RESV）和物理治疗，如自愿体育锻炼（PE），极大地促进海马神经发生，认知功能以及海湾战争疾病大鼠模型的情绪。在这两个目标中，我们将首先将大鼠暴露于三种化学物质（PB、避蚊胺和氯菊酯）和轻度应激（即5分钟的束缚应激）28天，并确定认知功能障碍和抑郁和焦虑样行为的程度。然后动物将接受如上所述的治疗，并在治疗结束后6周进行认知功能和抑郁和焦虑样行为的测试。在此之后，它们在行为测试中的表现将与海马神经发生的程度、神经干细胞（NSC）的增殖行为以及与神经发生和氧化应激抑制相关的基因的表达模式相关。整个研究旨在确定不同治疗方法的治疗效果。因此，本项目中拟定的研究与海湾战争RFA（BX-09 - 014）高度相关，因为本项目使用了模拟波斯湾战争-1退伍军人经历的各种暴露的大鼠模型，并且实验重点是开发逆转海湾战争疾病相关的几种CNS损伤的治疗策略。

DESCRIPTION (provided by applicant): While the Gulf war illness displays multiple central nervous system (CNS) impairments, cognitive dysfunction, memory loss, depression and anxiety are the most common symptoms. Intake of the prophylactic drug pyridostigmine bromide (PB), prolonged exposure to pesticides (such as DEET and permethrin), and the combat-related stress during the Persian Gulf War-1 are believed to be the underlying causes of Gulf war illness. Consistent with this supposition, studies in our laboratory using a rat model demonstrate that a combined exposure to low doses of the above chemicals (PB, DEET & Permethrin) and mild stress for 28 days causes considerable impairments in the hippocampus- dependent functions, which include impaired ability for new spatial learning, declined ability for making new memories, and increased depressive- and anxiety- like behavior. Analyses of hippocampal tissues further revealed that the behavioral impairments are linked with greatly declined neurogenesis but mostly intact neuronal cell layers in the hippocampus. Considering the role of hippocampal neurogenesis in learning, memory and mood functions, these findings suggest that a greatly declined neurogenesis likely underlies learning & memory impairments and increased depression & anxiety in Gulf war illness. In this context, strategies that greatly enhance hippocampal neurogenesis appear useful for reversing the cognitive dysfunction and the depression and anxiety observed in Gulf war illness. Indeed, our preliminary studies suggest that administration of antidepressants such as fluoxetine (FLU) or rolipram (ROL) after a combined exposure to chemicals (PB+DEET+Permethrin) and stress has promise for improving the hippocampal neurogenesis as well as cognitive function. Therefore, using the above rat model of Gulf war illness, we propose to rigorously analyze the efficacy of distinct clinically applicable strategies for enhancing the hippocampal neurogenesis & cognitive function, and reversing the depressive & anxiety-like behaviors. In Specific Aim 1, we will test the hypothesis that combined applications of an anti-depressant drug (FLU or ROL) and an antioxidant drug (Curcumin [CUR] or Resveratrol [RESV]; dietary supplements having anti-oxidant, anti-inflammatory, and neurogenesis enhancing properties) greatly enhance hippocampal neurogenesis, cognitive function and mood in the rat model of Gulf war illness. In Specific Aim 2, we will address the hypothesis that combined applications of an anti-depressant drug (FLU or ROL) or an antioxidant drug (CUR or RESV) and physical therapy such as the voluntary physical exercise (PE) greatly boost hippocampal neurogenesis, cognitive function as well as mood in the rat model of Gulf war illness. In both aims, we will first expose rats to the three chemicals (PB, DEET & Permethrin) and mild stress (i.e. 5 minutes of restraint stress) for 28 days and ascertain the extent of cognitive dysfunction and depressive & anxiety- like behaviors. Animals will then receive the treatments as described above and undergo testing at 6- weeks after the conclusion of the treatment for cognitive function and depressive & anxiety-like behavior. Following this, their performance in the behavioral tests will be correlated with the extent of hippocampal neurogenesis, the proliferative behavior of neural stem cells (NSCs), and the pattern of expression of genes related to neurogenesis and to suppression of oxidative stress. The overall research is designed to ascertain the therapeutic efficacy of different treatment approaches. Thus, the studies proposed in this project are highly relevant to the Gulf war RFA (BX-09-014) because, this project utilizes a rat model that simulates the various exposures experienced by the Persian Gulf War-1 veterans and the experiments are focused on developing therapeutic strategies for reversing several CNS impairments associated with Gulf war illness.