Cortical Mechanisms in Lewy Body Dementia

项目总结/摘要 路易体痴呆是一种常见的退行性痴呆。这些疾病使人衰弱， 幻视、意识波动、睡眠紊乱、福尔斯和抑郁症，所有这些都导致丧失 独立、残疾和照顾者负担沉重。在这些疾病中，α-突触核蛋白 聚集成特异性的“路易体”和“路易神经突”。路易体痴呆患者有 弥漫性细胞内皮质路易体、皮质变薄和神经元解剖结构（包括树突）缺失 还有刺这些变化可能是由于α-突触核蛋白寡聚体引起的钙调节改变而发生的， 其在病理条件下积累。人类α-突触核蛋白的过度表达导致家族性 疾病，包括痴呆，因此提供了一个有用的模型，以评估神经元的机制， 功能障碍该提案使用小鼠皮层中α-突触核蛋白的病毒过表达来检查小鼠大脑皮层中α-突触核蛋白的表达。 当蛋白质积累时皮层神经元发生的病理变化。具体来说，这个提案首先 检验了局部α-突触核蛋白积累诱导树突棘不稳定性，导致 树突棘随时间减少这是使用纵向，活体动物，双光子成像重复测试 随着病理学的发展，观察单个树突棘。其次，该建议评估钙是否 由于α-突触核蛋白的积累，网络的潜在机制， 功能障碍和解剖病理学。这项提案的发现将证明a-突触核蛋白如何发挥作用， 其在皮质细胞中的病理作用并评估基于Ca 2+动力学的机制模型。通过包括 随着时间的推移，这些研究更有可能模拟人类疾病的各个方面，并导致可翻译的结果。 治疗。作为一个职业发展补助金，这个建议是理想的;它利用申请人过去的技能，在2- 使用Ca 2+的树突棘的互补、机械和计算方法的光子成像 成像，这对申请人来说是新颖的。该机构致力于提供支持和资源， 申请人成功的必要条件。在建议的研究领域有很强的指导， 并辅以顾问指导和正式讲习班。这将提供关键的培训， 机会，这将促进申请人的职业生涯作为一个学术物理学家，科学家专注于 了解和治疗路易体痴呆症

Project Summary/Abstract Lewy Body dementias are a common form of degenerative dementia. These diseases are debilitating, causing visual hallucinations, fluctuations in consciousness, disturbed sleep, falls, and depression, all leading to loss of independence, disability and significant caregiver burden. In these disorders, the protein alpha-synuclein accumulates into pathognomonic “Lewy bodies” and “Lewy neurites”. Patients with Lewy Body dementia have diffuse intracellular cortical Lewy Bodies, cortical thinning, and loss of neuronal anatomy, including dendrites and spines. These changes may occur due to altered calcium regulation caused by alpha-synuclein oligomers, which accumulate under pathologic conditions. Overexpression of alpha-synuclein in humans leads to familial disease, including dementia, and therefore provides a useful model to evaluate the mechanisms of neuronal dysfunction. This proposal uses viral overexpression of alpha-synuclein in the cortex of mice to examine the pathological changes occurring in cortical neurons as the protein accumulates. Specifically, this proposal first tests the hypothesis that local alpha-synuclein accumulation induces dendritic spine instability, leading to dendritic spine loss overtime. This is tested using longitudinal, live animal, 2-photon imaging to repeatedly observe individual dendritic spines as pathology develops. Secondly, this proposal evaluates if calcium dynamics change over time due to alpha-synuclein accumulation, a potential mechanism for network dysfunction and anatomical pathology. The findings from this proposal will demonstrate how a-synuclein exerts its pathological effect in cortical cells and evaluate a mechanistic model based on Ca2+ dynamics. By including evaluation over time, these studies are more likely to model aspects of human disease and lead to translatable treatments. As a career development grant this proposal is ideal; it leverages the applicant’s past skills in 2- photon imaging of dendritic spines with a complementary, mechanistic and computational approach using Ca2+ imaging, which is novel to the applicant. The institution is dedicated to providing the support and resources necessary for the applicant’s success. There is strong mentorship available in areas of research proposed, supplemented with instruction by consultants and formal workshops. Together, this will provide key training opportunities that will advance the applicant’s career as an academic physician-scientist focusing on understanding and treating Lewy Body Dementias.