Reciprocal interactions between cortical circuit dysfunction and α-synuclein pathology

皮质回路功能障碍与 α-突触核蛋白病理之间的相互作用

• 批准号: 10555803
• 负责人: William Abel Zeiger
• 金额: $ 54.32万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555803
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Anatomy; Autopsy; Biological Models; Biology; Brain; Calcium; Caregivers; Cells; Cessation of life; Chronic; Clinical Trials Design; Corpus striatum structure; Dementia; Dementia with Lewy Bodies; Denervation; Deposition; Development; Diagnosis; Disease; Disease Progression; Exhibits; Functional disorder; Future; Genetic; Hallucinations; Human Pathology; Image; Impaired cognition; Impairment; Individual; Knowledge; Label; Lead; Lewy Bodies; Lewy body pathology; Lewy neurites; Link; Mediating; Modeling; Monitor; Motor Cortex; Mus; Neocortex; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathologic; Pathology; Patients; Pattern; Population; Process; Proteins; Recombinants; Research; Resolution; Rodent; Role; Site; Societies; Source; Symptoms; System; Testing; Therapeutic Uses; Time; Transgenic Mice; Viral; Visualization; alpha synuclein; area striata; behavioral study; beta amyloid pathology; care costs; designer receptors exclusively activated by designer drugs; disability; experimental study; functional disability; imaging modality; imaging system; in vivo; in vivo imaging; innovation; mild cognitive impairment; motor symptom; mouse model; neocortical; neural; neural circuit; neuroregulation; novel; postsynaptic; pre-formed fibril; presynaptic; prevent; serial imaging; symptom treatment; synucleinopathy; tool; translational study; transmission process; two-photon

Project Summary / Abstract Parkinson disease (PD) is the second most common neurodegenerative disease, leading to disability and death for individuals, and significant costs for caregivers and society. Cognitive impairment is a common cause of functional impairment in PD and a central feature of the related disorder Dementia with Lewy Bodies (DLB). To date, there are no disease-modifying therapies to prevent the development or progression of these symptoms. In both PD and DLB, intraneuronal inclusions of the protein alpha-synuclein (α-syn) in limbic and cortical regions correlates with cortical hypometabolism, hallucinations, and progression to dementia, suggesting a central role for α-syn in cognitive impairment. However, the specific effects and mechanisms by which α-syn pathology impacts the function of cortical neurons and circuits remain unknown. In addition, the cortex exhibits regional vulnerability, both to the deposition of α-syn and to the degree of functional impairment, for unknown reasons. Thus, major gaps remain in our understanding of how cortical circuits become dysfunctional in PD and DLB and how specific features of cortical circuits impact the spread and accumulation of α-syn. Here, Dr. Zeiger will lead a research group to test the hypothesis that a reciprocal relationship exists between α-syn pathology and neuronal activity, such that cortical α-syn accumulation directly disrupts neuronal activity, and conversely, that changes in neuronal activity influence the progression of α-syn pathology. In Aim 1, Dr. Zeiger’s group will use a novel model system in a mouse model of PD to directly define how α-syn impacts the function of different disease-relevant cortical circuits. Innovative longitudinal two-photon imaging methods will be used to simultaneously monitor neuronal activity and the accumulation of α-syn inclusions with single-cell resolution. This will then be correlated with behavioral studies to better understand how α-syn-mediated circuit dysfunction leads to cognitive and motor symptoms. The impact of co-existing Alzheimer’s disease amyloid-beta pathology on α-syn-mediated circuit dysfunction will also be tested. In Aim 2, Dr. Zeiger’s group will test the hypothesis that changes in activity can increase or decrease the accumulation of α-syn in the cortex. Advanced transgenic mouse lines and viral tools will be used to specifically manipulate the activity of different components of corticostriatal circuits to define how the activity of specific sub-populations of neurons contribute to the progression of PD pathology. Together, these studies will uncover basic mechanisms about how cortical circuits are affected in PD and DLB. This information is also of great importance for future translational studies aiming to use therapeutic neuromodulation to treat symptoms arising from cortical circuit dysfunction or potentially even slow disease progression in PD and DLB.

项目总结/摘要 帕金森病（PD）是第二常见的神经退行性疾病，导致残疾和死亡 对个人来说，以及对照顾者和社会的巨大成本。认知障碍是一种常见的原因， PD中的功能损害和相关疾病路易体痴呆（DLB）的中心特征。到 迄今为止，没有疾病修饰疗法来预防这些症状的发展或进展。 在PD和DLB中，在边缘和皮质区域的蛋白质α-突触核蛋白（α-syn）的神经元内包涵体 与皮质代谢减退、幻觉和痴呆的进展相关，表明 α-syn在认知障碍中的作用然而，α-syn病理学的具体作用和机制， 影响皮层神经元和回路的功能仍然未知。此外，大脑皮层表现出区域性的 由于未知的原因，α-syn沉积和功能损伤程度都很脆弱。 因此，在我们理解皮层回路如何在PD和DLB中变得功能障碍方面仍然存在重大差距， 皮质回路的特定特征如何影响α-syn的传播和积累。在这里，Zeiger博士将领导 一个研究小组，以测试假设之间存在互惠关系α-syn病理和 神经元活动，例如皮质α-syn积累直接破坏神经元活动，相反， 神经元活性的变化影响α-syn病理学的进展。在目标1中，Zeiger博士的团队将使用 一种新的模型系统，在PD小鼠模型中直接定义α-syn如何影响不同的功能， 疾病相关的皮层回路创新的纵向双光子成像方法将用于 同时监测神经元活动和α-syn内含物的积累与单细胞分辨率。 这将与行为研究相关联，以更好地了解α-syn-mediated电路功能障碍 导致认知和运动症状阿尔茨海默病与β淀粉样蛋白病理共存的影响 对α-syn-mediated电路功能障碍也将进行测试。在目标2中，Zeiger博士的研究小组将检验以下假设： 活性的变化可以增加或减少α-syn在皮质中的积累。高级转基因 小鼠品系和病毒工具将被用于特异性地操纵不同组分的活性， 皮质纹状体回路，以确定特定神经元亚群的活动如何有助于 PD病理学进展。总之，这些研究将揭示大脑皮层回路 受PD和DLB影响。这一信息对未来的翻译研究也非常重要， 使用治疗性神经调节来治疗由皮层回路功能障碍引起的症状，或者甚至潜在地 减缓PD和DLB的疾病进展。