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 - 体内痴呆症，包括帕金森氏病痴呆症和痴呆症的痴呆症是 毁灭性的，多系统疾病和全球痴呆症的主要原因。患者具有特征 表明前网功能障碍的症状，包括计划的困难，引起人们的注意 并损害了灵活的学习。痴呆症患者的病理包括 额叶皮质和其他二聚体区域中的蛋白质α-核蛋白（𝛼-Syn）。尽管有这种关联，但 𝛼多巴胺能系统以外的𝛼-Syn病理的作用尚不清楚。迫切需要 了解-syn如何影响网络功能以开发路易身体痴呆症的治疗方法。 我们的长期目标是通过靶向电路级功能障碍来开发Lewy身体痴呆的治疗方法。我们的 总体假设是，皮质中的局部-syn聚集破坏了前额叶电路，导致执行 功能障碍。测试该总体假设需要确定𝛼-Syn对细胞活性的区域影响 孤立的神经元可塑性定义了次要到其他主要神经递质系统 到皮质。为了实现这一目标，该提案使用位于前额叶的-Syn的病毒过表达 皮质。通过成像单个神经元的活性和树突状刺的可塑性，我们可以学习如何 皮质细胞对这种神秘的，疾病相关的蛋白质反应。我们建议使用2光量经颅 显微镜确定神经元活性（AIM 1）和突触可塑性（AIM 2）如何应对区域 在衰老过程中-Syn的过表达。在AIM 3中，我们将使用规则学习，逆转和规则 - 转移任务适用于头部固定应用程序，以确定前额外依赖的学习和灵活性 负责皮质-syn。同时，我们将将认知表现与解剖学可塑性相关联 神经元活性。这项拟议的研究的结果将为未来的研究提供目标，以恢复皮质 通过电路级操作来处理和治疗症状。另外，通过比较跨越的结果 三个目标，我们将能够将结构可塑性，神经元活动和前认知行为连接起来 对前额叶皮层提供广泛的见解。