Cholinergic Mechanisms in Lewy Body Dementia

路易体痴呆的胆碱能机制

• 批准号: 10662018
• 负责人: Mark S Moehle
• 金额: $ 52.61万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662018
• 关键词: Acetylcholine; Alzheimer' s Disease; Anatomy; Animal Model; Attention; Basal Cell; Behavioral; Brain; Brain region; Cell Nucleus; Cells; Cognition; Cognitive; Data; Data Correlations; Dementia; Dementia with Lewy Bodies; Electrophysiology (science); Executive Dysfunction; Functional disorder; Glutamates; Impaired cognition; Impairment; Lead; Lewy Bodies; Lewy Body Dementia; Lewy neurites; Link; Long-Term Depression; Measures; Medial; Modeling; Mus; Muscarinic Acetylcholine Receptor; Neurons; Neurotransmitters; Nicotinic Receptors; Output; Parkinson Disease; Parkinson' s Dementia; Pathologic; Patients; Prefrontal Cortex; Property; Pyramidal Cells; Regulation; Role; Series; Signal Transduction; Source; Symptoms; Synapses; Synaptic plasticity; System; Testing; alpha synuclein; basal forebrain; cholinergic; comparison control; designer receptors exclusively activated by designer drugs; executive function; experimental study; flexibility; hippocampal pyramidal neuron; insight; mouse model; nervous system disorder; neuron loss; neuronal circuitry; neuronal excitability; neuroregulation; novel therapeutic intervention; novel therapeutics; pharmacologic; postsynaptic; pre-formed fibril; presynaptic; receptor; synucleinopathy

Project Summary/Abstract Accumulation of α-synuclein (α-syn) into Lewy Bodies and Lewy Neurites is a hallmark of the Lewy Body Dementias (LBD), Dementia with Lewy Bodies and Parkinson’s Disease-Dementia. Additionally, some brain regions in Alzheimer’s Disease have pathological α-syn. Therefore, α-syn is likely a major cause of cognitive decline across several dementias. One possible mechanism underlying the core cognitive impairments centered around impaired executive function in LBD may be loss or dysfunction of projection neurons from the basal forebrain that produce acetylcholine (ACh). Across LBD, there is profound loss of cholinergic cells of the basal forebrain, which project to the prelimbic medial prefrontal cortex (PL-mPFC), a known key brain nucleus for executive function. Basal forebrain ACh acts through nicotinic and muscarinic ACh receptors (mAChR) to modulate PL-mPFC glutamatergic projection neurons critical for normal executive function. Recent evidence has further refined the mechanisms by which ACh regulates the PL-mPFC, and has suggested a key role for the M1 mAChR in regulating executive function. Despite this critical neuromodulatory role of ACh and M1 in the PL-mPFC in executive function, there are few studies that examine this important relationship in the context of α-syn related dementias. This has led to our overall hypothesis that cognitive decline in the context of α-syn linked dementias results from disrupted ACh signaling in the mPFC. We have used the pre-formed fibril (PFF) model of α-synucleinopathies to show that inputs into the PL-mPFC show enhanced ACh dependent long term depression in PFF injected mice. Additionally, layer 5 pyramidal cells of the PL-mPFC show decreased excitability in PFF injected mice compared to controls that may be attributable to ACh dependent changes in intrinsic properties of these cells. This suggests that α-syn dysregulates multiples aspects of the PL-mPFC through alterations in ACh release or signaling. To rigorously test this, we will perform a series of electrophysiology and behavioral experiments to determine, define, and dissect how α-ayn dysregulates the PL-mPFC through loss of ACh signaling or release. In Aim 1, we will test the hypothesis that α-syn dysregulates PL-mPFC inputs through altering ACh signaling. In Aim 2, we will test the hypothesis that α-syn alters intrinsic properties and output of PL- mPFC projection neurons through loss of ACh signaling. In aim 3, we will test the hypothesis that boosting cholinergic signaling will rescue deficits in executive function. Completion of these aims will provide fundamental understanding of how α-syn dysregulates ACh signaling to impair executive function in LBD.

项目摘要/摘要 α-突触核蛋白（α-syn）积聚到路易体和路易神经突中是Lewy体的标志 痴呆症（LBD），痴呆症，有路易的身体和帕金森氏病。另外，有些大脑 阿尔茨海默氏病的区域具有病理α-syn。因此，α-Syn可能是认知的主要原因 几个痴呆症的下降。核心认知障碍以中心为中心的一种可能机制 LBD中的执行功能受损可能是基本的投射神经元的损失或功能障碍 产生乙酰胆碱（ACH）的前脑。在LBD中，基本的胆碱能细胞丧失 前脑，将其投射到前培养基前额叶皮层（PL-MPFC），这是一种已知的关键脑核 执行功能。基础前脑ACH通过烟碱和毒蕈碱ACH受体（MACHR）起作用 调节对正常执行功能至关重要的PL-MPFC谷氨酸能投射神经元。最近的证据有 进一步完善了ACH调节PL-MPFC的机制，并提出了M1的关键作用 监管执行职能的MACHR。尽管ACH和M1在PL-MPFC中的神经调节作用 在执行功能中，很少有研究在与α-Syn相关的背景下研究这种重要关系 痴呆症。这导致了我们的总体假设，即α-Syn的背景下的认知能力下降 痴呆症是由MPFC中的ACH信号中断引起的。我们已经使用了预制的原纤维（PFF） α-核核病的模型表明，对PL-MPFC的输入显示出增强的ACH长期 PFF注射小鼠的抑郁症。此外，PL-MPFC的第5层锥体细胞显示出兴奋的降低 在PFF注射小鼠中，与可能归因于ACH依赖性变化的对照组相比 这些细胞的特性。这表明α-syn通过PL-MPFC的多个方面失调 ACH释放或信号的改变。为了严格测试这一点，我们将执行一系列电生理学和 行为实验以确定，定义和剖析α-AYN如何通过丢失而使PL-MPFC失调 ACH信号或释放。在AIM 1中，我们将测试以下假设：α-Syn通过PL-MPFC输入失调 改变ACH信号。在AIM 2中，我们将测试以下假设：α-Syn改变了固有特性和PL-的输出 MPFC投影神经元通过丧失ACH信号传导。在AIM 3中，我们将测试提升的假设 胆碱能信号将挽救在执行功能中定义。这些目标的完成将提供基本 了解α-Syn如何失去ACH信号传导以损害LBD中的执行功能。