Targeting Cholinergic Deficits with Retinoic Acid after TBI

摘要 认知缺陷是创伤性脑损伤(TBI)后普遍存在的残疾。到目前为止，还没有 对抗这些后遗症的治疗方法。神经化学(神经传递)和白质的改变 连接性被认为是导致脑外伤后学习和记忆行为障碍的两个因素。这个 神经递质乙酰胆碱(ACh)是调节认知功能，特别是学习功能的关键因素。 和记忆。实验性脑外伤的研究显示胆碱能功能缺陷和蛋白质改变。 与胆碱能神经传递有关。最近的研究发现，外源性全反式维甲酸 维生素A的活性代谢物全反式维甲酸(ATRA)可增加胆碱乙酰转移酶(ChAT)的蛋白水平， 囊泡ACh转运蛋白(VAChT)和乙酰胆碱酯酶(AChE)。这导致我们假设全反式维甲酸可以 用作改善实验性脑外伤后认知行为的潜在疗法。这样做的主要目标是 该项目旨在提供概念验证证据，证明全反式维甲酸可以减轻脑外伤后的胆碱能缺陷。此外， 在脑损伤的情况下，为了支持这种效果，我们提供了初步数据，证明ATRA治疗可以 减轻实验性脑损伤后的空间记忆保持缺陷。胆碱能缺陷也可能是，至少 部分原因是脑白质受损。Broca内侧隔和斜角带的神经元 通过穹隆-海马束支配海马体。在实验研究中，对枕骨/穹隆的损伤 在海马区产生胆碱能失神经，并伴随认知和ACh障碍 神经传递。临床上，弥散磁共振纤维束成像研究发现海马伞/穹隆完整性降低。 在TBI之后。高清晰度纤维束成像在临床前脑损伤中的评估非常适合理解全球 连接性，并代表了评估ATRA治疗的高转译结果。的基本假设 本项目旨在为RA能减轻脑外伤后胆碱能缺陷提供证据。这一假设将是 目的是阐明全反式维甲酸对ACh系统的影响以及评估维甲酸对血管紧张素转换酶系统的影响。 胆碱能脑区之间轴突连接的完整性。AIM 1将确定ATRA治疗是否可以 减轻胆碱能对ACh神经传递(AChE、ChAT)至关重要的关键胆碱能蛋白的损失 和(Vacht)。为了提高评价全反式维甲酸对胆碱能功能影响的特异性 将利用挑战范式。毒扁豆碱受体拮抗剂东莨菪碱对记忆有干扰作用 探员。据报道，实验性脑损伤后，东莨菪碱的敏感性降低。 扰乱记忆。在目标2中，实验性脑外伤对胆碱能相关白质束的影响 且未接受全反式维甲酸治疗的患者，将接受检查。如果成功，这个项目将首次展示 维甲酸对减轻颅脑损伤后胆碱能蛋白和脑白质缺陷的治疗作用。

ABSTRACT Cognitive deficits are a pervasive disability following traumatic brain injury (TBI). As of yet, there are no treatments to combat these sequelae. Alterations in neurochemical (neurotransmission) and white matter connectivity have been identified as two contributors to deficits in learning and memory behaviors after TBI. The neurotransmitter acetylcholine (ACh) is a crucial factor in regulation of cognitive function, specifically in learning and memory. Studies in experimental TBI have shown deficits in cholinergic function, and alterations in proteins involved with cholinergic neurotransmission. Recent studies have found that exogenous all-trans retinoic acid (ATRA), an active metabolite of vitamin A, can increase protein levels of choline acetyltransferase (ChAT), the vesicle ACh transporter (VAChT), and acetylcholinesterase (AChE). This leads us to posit that ATRA can be used as a potential therapeutic to improve cognitive behavior after experimental TBI. The primary goal of this project is to provide proof-of-concept evidence that ATRA can attenuate cholinergic deficits after TBI. Moreover, in support of this effect in the context of TBI, we provide preliminary data demonstrates that ATRA treatment can attenuates spatial memory retention deficits after experimental TBI. Cholinergic deficits may also be, at least partially, attributable to white matter damage. Neurons of the medial septum and the diagonal band of Broca innervate the hippocampus via the fimbria–fornix bundle. In experimental studies, damage to the fimbra/fornix produces cholinergic denervation in the hippocampus with concomitant deficits in cognition and ACh neurotransmission. Clinically, diffusion MRI tractography studies have found decreased fimbria/fornix integrity after TBI. Assessment of high-definition fiber tractography in preclinical TBI are well suited to understand global connectivity and represent a high translational outcome to evaluate ATRA therapy. The primary hypothesis of this project is to provide evidence that RA can attenuate cholinergic deficits after TBI. This hypothesis will be tested in two Aims to elucidate the effects of ATRA on the ACh system and assess the effect of RA on the integrity of axonal connectivity between cholinergic brain regions. Aim 1 will determine if ATRA treatment can attenuate cholinergic the loss of key cholinergic proteins important for ACh neurotransmission (AChE, ChaT) and (VAChT). To enhance the specificity of assessing ATRA’s effects on cholinergic function, a scopolamine challenge paradigm will be utilized. Scopolamine, a muscarinic receptor antagonist, is a memory disturbing agent. After experimental TBI, it has been reported that there is a reduction in the sensitivity of scopolamine to disrupt memory. In Aim 2, the effects of experimental TBI on cholinergic-associated white matter tracts, both with and without ATRA therapy, will be examined. If successful, this project will demonstrate for the first time the therapeutic utility of RA to attenuate cholinergic protein and white matter deficits after TBI.