Cholinergic Mechanisms in Lewy Body Dementia

项目总结/摘要 α-突触核蛋白（α-syn）在路易体和路易神经突中的积累是路易体的标志 痴呆症（LBD），路易体痴呆症和帕金森病痴呆症。此外，一些大脑 阿尔茨海默氏病中的区域具有病理性α-syn。因此，α-syn可能是认知障碍的主要原因。 在几种痴呆症中下降。核心认知障碍的一个可能机制是 LBD患者执行功能受损的原因可能是基底节投射神经元的丢失或功能障碍， 前脑产生乙酰胆碱（ACh）。在LBD中，基底节的胆碱能细胞严重丢失， 前脑，其投射到前边缘内侧前额叶皮层（PL-mPFC），这是已知的用于 执行功能基底前脑ACh通过烟碱和毒蕈碱ACh受体（mAChR）发挥作用， 调节对正常执行功能至关重要的PL-mPFC突触能投射神经元。最近的证据 进一步完善了ACh调节PL-mPFC的机制，并提出了M1的关键作用 mAChR调节执行功能。尽管ACh和M1在PL-mPFC中具有重要的神经调节作用， 在执行功能中，很少有研究在α-syn相关的背景下检查这种重要的关系， 痴呆症这导致了我们的总体假设，即认知能力下降与α-syn相关 痴呆是由mPFC中ACh信号传导中断引起的。我们使用了预成型原纤维（PFF） α-突触核蛋白病模型，以显示输入到PL-mPFC显示增强的ACh依赖性长期 PFF注射小鼠的抑郁症。此外，PL-mPFC的第5层锥体细胞表现出降低的兴奋性 与对照组相比，注射PFF的小鼠中，可能归因于ACh依赖性的内源性 这些细胞的特性。这表明α-syn通过以下途径使PL-mPFC的多个方面失调： ACh释放或信号传导的改变。为了严格测试这一点，我们将进行一系列的电生理学检查， 行为实验，以确定，定义和剖析α-ayn如何通过损失的PL-mPFC失调， ACh信号或释放。在目标1中，我们将检验α-syn通过以下方式失调PL-mPFC输入的假设： 改变ACh信号传导。在目标2中，我们将检验α-syn改变PL-1的内在性质和输出的假设。 mPFC投射神经元通过ACh信号丢失。在目标3中，我们将检验一个假设， 胆碱能信号将挽救执行功能的缺陷。这些目标的实现，将为 了解α-syn如何失调ACh信号传导损害LBD的执行功能。

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.