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.

摘要 认知缺陷是创伤性脑损伤（TBI）后的普遍残疾。到目前为止， 治疗这些后遗症。神经化学（神经传递）和白色物质的改变 连接性被认为是TBI后学习和记忆行为缺陷的两个因素。的 神经递质乙酰胆碱（ACh）是调节认知功能，特别是学习的关键因素 和记忆对实验性TBI的研究显示胆碱能功能的缺陷和蛋白质的改变， 与胆碱能神经传递有关近年来研究发现，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）可以增加胆碱乙酰转移酶（ChAT）的蛋白质水平， 囊泡乙酰胆碱转运蛋白（VAChT）和乙酰胆碱酯酶（AChE）。这使我们相信ATRA可以 作为一种潜在的治疗方法，以改善实验性TBI后的认知行为。这个的主要目标 该项目的目的是提供概念验证证据，证明ATRA可以减轻TBI后的胆碱能缺陷。此外，委员会认为， 为了支持这一效应，我们提供的初步数据表明，ATRA治疗可以 减轻实验性TBI后的空间记忆保留缺陷。胆碱能缺陷也可能，至少 部分归因于白色物质损伤。内侧隔和Broca斜角带神经元 通过穹窿海马伞束支配海马体。在实验研究中，对海马伞/穹窿的损伤 在海马中产生胆碱能去神经支配，伴随认知和ACh缺陷 神经传递临床上，弥散MRI纤维束成像研究发现穹窿海马伞完整性降低 在TBI之后临床前TBI中的高清纤维束成像评估非常适合了解全球 连接性，并代表高翻译结果，以评估ATRA治疗。的主要假设 本研究旨在为RA减轻TBI后胆碱能损伤提供实验依据。这一假设将是 目的是阐明ATRA对ACh系统的影响，并评估RA对ACh系统的影响。 胆碱能脑区之间轴突连接的完整性。目标1将确定ATRA治疗是否可以 减弱对乙酰胆碱神经传递重要的关键胆碱能蛋白（AChE，Cha T）的丢失 和（VAChT）。为了提高评估ATRA对胆碱能功能影响的特异性， 将使用挑战范例。东莨菪碱是一种毒蕈碱受体拮抗剂， 剂据报道，在实验性TBI后，东莨菪碱对TBI的敏感性降低， 扰乱记忆在目的2中，实验性TBI对胆碱能相关白色物质束的影响， 没有ATRA治疗的患者将接受检查。如果成功，该项目将首次展示 RA减轻TBI后胆碱能蛋白和白色物质缺陷的治疗效用。