Targeting Cholinergic Deficits with Retinoic Acid after TBI

使用视黄酸治疗 TBI 后的胆碱能缺陷

• 批准号: 10741924
• 负责人: C EDWARD DIXON
• 金额: $ 43.73万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-11 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741924
• 关键词: Acetylcholine; Acetylcholinesterase; Acetyltransferase; Alzheimer' s disease model; Animals; Arousal; Attention; Attenuated; Axon; Basal Nucleus of Meynert; Behavior; Binding; Brain region; Cerebral cortex; Choline; Choline O-Acetyltransferase; Clinical; Cognition; Cognitive; Cognitive deficits; Critical Pathways; Data; Denervation; Diagonal Band of Broca; Diffuse; Diffusion Magnetic Resonance Imaging; Disease; Fiber; Fimbria of hippocampus; Gene Expression; Genes; Genetic Transcription; Goals; Hippocampus; Image; Injury; Learning; Medial; Memory; Memory impairment; Muscarinic Acetylcholine Receptor; Neurons; Neurotransmitters; Outcome; Pathway interactions; Performance; Proteins; Regulation; Reporting; Scopolamine; Septal Area; Septal Nuclei; Severities; Specificity; Symptoms; Synapses; Synaptic Vesicles; System; Testing; Therapeutic; Time; Traumatic Brain Injury; Tretinoin; Vesicle; Vitamin A; acetylcholine transporter; antagonist; basal forebrain; cholinergic; cholinergic neuron; cognitive function; cognitive reappraisal; combat; controlled cortical impact; disability; experimental study; fimbria; improved; injured; memory retention; neurobehavioral; neurochemistry; neuroinflammation; neurotransmission; novel; pre-clinical; protein expression; receptor; septohippocampal; spatial memory; tractography; transcription factor; translational potential; transmission process; white matter; white matter damage

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.

抽象的 认知缺陷是创伤性脑损伤 (TBI) 后的一种普遍残疾。 对抗这些后遗症的治疗方法。 连接性已被确定为导致 TBI 后学习和记忆行为缺陷的两个因素。 神经递质乙酰胆碱 (ACh) 是调节认知功能的关键因素，特别是在学习方面 实验性创伤性脑损伤（TBI）研究显示胆碱能功能缺陷和蛋白质改变。 最近的研究发现，外源性全反式视黄酸参与胆碱能神经传递。 (ATRA) 是维生素 A 的活性代谢物，可以增加胆碱乙酰转移酶 (ChAT) 的蛋白质水平，ChAT 是 囊泡乙酰胆碱转运蛋白 (VAChT) 和乙酰胆碱酯酶 (AChE) 这使我们推测 ATRA 可以是。 用作改善实验性 TBI 后认知行为的潜在治疗方法。 该项目的目的是提供 ATRA 可以减轻 TBI 后胆碱能缺陷的概念验证证据。 为了支持 TBI 背景下的这种效果，我们提供了初步数据，证明 ATRA 治疗可以 至少也可以减轻实验性 TBI 后的空间记忆保留缺陷。 部分归因于内侧隔膜和布罗卡斜带的白质损伤。 在实验研究中，通过海马伞/穹窿束神经支配海马体。 在海马体中产生胆碱能去神经支配，并伴有认知和乙酰胆碱缺陷 临床上，扩散 MRI 纤维束成像研究发现海马伞/穹窿完整性降低。 临床前 TBI 中的高清纤维束成像评估非常适合了解全局。 连接性并代表了评估 ATRA 治疗的高转化结果。 该项目旨在提供证据证明 RA 可以减轻 TBI 后的胆碱能缺陷。 测试的两个目的是阐明 ATRA 对 ACh 系统的影响并评估 RA 对 目标 1 将确定 ATRA 治疗是否有效。 减弱胆碱能对乙酰胆碱神经传递很重要的关键胆碱能蛋白的损失（AChE、ChaT） (VAChT) 为增强评估 ATRA 对胆碱能功能影响的特异性，一种东莨菪碱。 将使用挑战范例，东莨菪碱是一种毒蕈碱受体拮抗剂，会干扰记忆。 据报道，实验性 TBI 后，东莨菪碱的敏感性降低。 在目标 2 中，实验性 TBI 对胆碱能相关白质束的影响，两者均具有影响。 如果成功的话，该项目将首次展示 RA 在减轻 TBI 后胆碱能蛋白和白质缺陷方面的治疗作用。