Cortical Alpha-Synuclein in Dementia

痴呆症中的皮质 α-突触核蛋白

• 批准号: 10563300
• 负责人: Georgina Aldridge
• 金额: $ 59.08万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563300
• 关键词: Affect; Aging; Alzheimer' s Disease; Anatomy; Attention; Automobile Driving; Autopsy; Behavior; Behavioral; Behavioral Paradigm; Behavioral Symptoms; Brain; Brain Stem; Cephalic; Characteristics; Cognitive; Corpus striatum structure; Cues; Data; Dementia; Dementia with Lewy Bodies; Dendritic Spines; Deposition; Disease; Dopamine; Elements; Environment; Etiology; Event; Executive Dysfunction; Functional disorder; Future; Genes; Genomics; Goals; Hallucinations; Head; Image; Impaired cognition; Impairment; Implant; Individual; Laboratories; Learning; Lewy Body Dementia; Measures; Mediating; Microscopy; Movement; Neurobehavioral Manifestations; Neuronal Plasticity; Neurons; Neurotransmitters; Outcome; Parkinson Disease; Parkinson' s Dementia; Pathologic; Pathology; Patients; Pattern; Performance; Prefrontal Cortex; Proteins; Publishing; Research; Risk; Role; Secondary to; Sensory; Symptoms; Synapses; Synaptic plasticity; System; Testing; Time; Training; Vertebral column; Viral; Visual Hallucination; alpha synuclein; behavior measurement; cell cortex; cognitive performance; density; excitatory neuron; experience; flexibility; frontal lobe; in vivo; insight; motor symptom; multimodality; nigrostriatal system; overexpression; postsynaptic; protein aggregation; psychiatric symptom; symptom treatment; two photon microscopy; two-photon

Abstract Lewy-Body dementias, including Parkinson’s disease Dementia and Dementia with Lewy Bodies, are devastating, multi-system diseases and a major cause of dementia worldwide. Patients have characteristic symptoms that suggest dysfunction of the frontal-network, including difficulty with planning, fluctuating attention and impaired flexible learning. The pathology of patients with dementia includes widespread aggregates of the protein alpha-synuclein (𝛼-syn) in the frontal cortex and other extra-nigral regions. Despite this association, the role of 𝛼-syn pathology beyond the dopaminergic system remains unclear. There is a critical need to understand how -syn affects network function to develop treatments for Lewy Body dementias. Our long-term goal is to develop treatments for Lewy Body Dementia by targeting circuit-level dysfunction. Our overall hypothesis is that local -syn aggregation in the cortex disrupts prefrontal circuits, leading to executive dysfunction. Testing this overall hypothesis requires determining the regional effect of 𝛼-syn on cellular activity and neuronal plasticity in isolation from deficits secondary to other major neurotransmitter systems that project to cortex. To accomplish this goal, this proposal uses viral overexpression of -syn localized to the prefrontal cortex. By imaging the activity of individual neurons and the plasticity of dendritic spines, we can learn how cortical cells respond to this enigmatic, disease-associated protein. We propose to use 2-photon transcranial microscopy to determine how neuronal activity (Aim 1) and synaptic plasticity (Aim 2) respond to regional overexpression of -syn over the course of aging. In Aim 3, we will use a rule-learning, reversal and rule- shifting tasks adapted for head-fixed applications to determine how prefrontal-dependent learning and flexibility respond to cortical -syn. In parallel, we will correlate cognitive performance with anatomical plasticity and neuronal activity. Findings from this proposed research will provide targets for future studies to restore cortical function and treat symptoms through circuit-level manipulation. In addition, by comparing outcomes across the three aims, we will be able to connect structural plasticity, neuronal activity and frontal-cognitive behavior to provide broad insights into the prefrontal cortex.

抽象的 路易体痴呆，包括帕金森病痴呆和路易体痴呆， 毁灭性的多系统疾病是全世界痴呆症的主要原因。 表明额叶网络功能障碍的症状，包括计划困难、注意力不稳定 痴呆症患者的病理学包括广泛的聚集。 尽管存在这种关联，但额叶皮层和其他黑区外区域的蛋白质 α-突触核蛋白 (𝛼-syn) 仍然存在。 𝛼-syn 病理学在多巴胺能系统之外的作用仍不清楚，目前仍不清楚。 了解 α-syn 如何影响网络功能，以开发路易体痴呆症的治疗方法。 我们的长期目标是通过针对回路水平功能障碍来开发路易体痴呆的治疗方法。 总体假设是，皮层中的局部 α-syn 聚集会扰乱前额叶回路，导致执行 检验这一总体假设需要确定 𝛼-syn 对细胞活动的区域影响。 和神经元可塑性，与其他主要神经递质系统继发的缺陷无关 为了实现这一目标，该提案使用了位于前额叶的 α-syn 的病毒过度表达。 通过对单个神经元的活动和树突棘的可塑性进行成像，我们可以了解如何做到这一点。 我们建议使用 2 光子经颅细胞对这种神秘的疾病相关蛋白做出反应。 显微镜来确定神经活动（目标 1）和突触可塑性（目标 2）如何响应区域 在衰老过程中α-syn 过度表达在目标 3 中，我们将使用规则学习、逆转和规则-。 适合头部固定应用的转移任务，以确定前额叶依赖性学习和灵活性如何 同时，我们将认知表现与解剖可塑性联系起来。 这项拟议研究的结果将为未来恢复皮质的研究提供目标。 此外，通过比较整个系统的结果来发挥作用并治疗症状。 为了实现这三个目标，我们将能够将结构可塑性、神经活动和额叶认知行为与 提供对前额皮质的广泛见解。