Cortical Alpha-Synuclein in Dementia

摘要 路易体痴呆症，包括帕金森氏病痴呆症和路易体痴呆症， 毁灭性的多系统疾病，也是全球痴呆症的主要原因。患者具有特征性 提示额叶网络功能障碍的症状，包括计划困难、注意力波动 以及灵活学习能力受损。痴呆患者的病理学包括广泛聚集的 蛋白质α-突触核蛋白（α-syn）在额叶皮层和其他外黑质区域。尽管有这种联系， 多巴胺能系统以外的β-syn病理学的作用仍不清楚。迫切需要 了解突触素如何影响网络功能，以开发路易体痴呆症的治疗方法。 我们的长期目标是通过靶向回路水平功能障碍来开发路易体痴呆症的治疗方法。我们 总的假设是，大脑皮层中的局部突触聚集扰乱了前额叶回路，导致执行性的 功能障碍检验这一总体假设需要确定β-syn对细胞活性的区域效应 和神经元可塑性，与继发于其他主要神经递质系统的缺陷隔离， 到皮层。为了实现这一目标，该建议使用病毒过表达定位于前额叶的β-syn， 皮层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 皮质细胞对这种神秘的疾病相关蛋白质产生反应。我们建议使用双光子经颅 显微镜下，以确定神经元活动（目标1）和突触可塑性（目标2）如何响应区域 随着衰老过程中β-syn的过度表达。在目标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的应用程序，以确定前额叶依赖性学习和灵活性 对皮质突触有反应。同时，我们将把认知表现与解剖可塑性联系起来， 神经元活动这项研究的结果将为未来的研究提供目标，以恢复大脑皮层 功能和治疗症状，通过电路水平的操作。此外，通过比较 三个目标，我们将能够连接结构可塑性，神经元活动和额叶认知行为， 提供了对前额叶皮层的广泛了解。

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.