Sexual dimorphic cell type and connectivity atlases of the aging and AD mouse brains

衰老和 AD 小鼠大脑的性二态性细胞类型和连接图谱

• 批准号: 10740308
• 负责人: Hong-Wei Dong
• 金额: $ 145.07万
• 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: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740308
• 关键词: 3-Dimensional; Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Amyloid; Anatomy; Androgen Receptor; Atlases; BRAIN initiative; Brain; Catalogs; Communities; Data; Data Set; Deterioration; Diffusion Magnetic Resonance Imaging; Disease Progression; Dorsal; ESR1 gene; Early Onset Alzheimer Disease; Elderly; Etiology; Female; Genetic; Glutamates; Hippocampus; Image; Impaired cognition; Informatics; Interneurons; Label; Late Onset Alzheimer Disease; Light; Manuals; Maps; Methods; Microscopy; Molecular; Morphology; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neurosciences Research; Online Systems; Pathogenesis; Pathologic; Pathology; Process; Regional Anatomy; Research; Resolution; Rodent; Senile Plaques; Sex Differences; Sex Differentiation; Stains; Synapses; Synaptophysin; Technology; Tracer; Transgenic Mice; Translating; Visualization; Work; aging brain; aging hippocampus; cell type; data portal; data visualization; experience; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; male; molecular domain; mouse model; multimodality; neural circuit; normal aging; prevent; reconstruction; resilience; response; sex; sexual dimorphism; superresolution imaging; tau Proteins; tool; transmission process; virtual reality

Project Abstract In response to NOT-21-039 and related PAR-22-093, we propose this project to address several urgent needs in the field. Mouse models spanning different ages and sexes are routinely used to quantify anatomic, molecular, and pathologic changes in neurodegenerative diseases like Alzheimer’s Disease (AD). Yet, the only available standard mouse brain atlases are constructed from 2-month-old adult male mice. Furthermore, although both normal aging and AD neurodegeneration display sexually dimorphic features, the scientific community lacks the sexually differentiated rodent brain atlases necessary to study these attributes. By applying cutting edge technologies, we have developed for BRAIN Initiative connectomic and cell type mapping projects, we will (1) generate sexually dimorphic 3D aging and AD brain atlases with granular hippocampus (HPF) molecular domains, that can be used as standard atlas templates for all HPF work and (2) we will comprehensively characterize morphological dystrophies, as well as connectional and synaptic disruptions, in aging and AD. In Specific Aim 1, publicly available standard 3D HPF atlases of aging and AD brains will be created. Data will be generated in 2-, 9-, and 18-month-old wildtype (WT), 5xFAD (early AD onset), and MAPT(H1)*N279K (late AD onset) male and female mice. Fine HPF domain delineations will be facilitated by 3D volumetric images of cyto- and myeloarchitecture, while additional histopathological markers (Aβ plaques/tau tangles) and chemoarchitectural details (glutamate, GABA, PV, SST, Calb1) will be mapped to create comprehensive histopathological and chemoarchitectural HPF atlases. In Specific Aim 2, We will systematically apply a genetic MORF3 sparse labeling approach to label, reconstruct, and analyze cell type specific neuronal morphology of all HPF regions at the granular level of their domains in WT, Vglut1.MORF3/5xFAD, PV.MORF3/5xFAD, Vglut1.MORF3/MAPT(H1)*N279K, and PV.MORF3/MAPT(H1)*N279K mice across age and sex. Our whole brain 3D clearing, immunostaining, imaging, and 3D neuronal reconstruction pipeline will be applied. Given that an etiology of AD-related cognitive decline is selective HPF synaptic disruptions, with dorsal HPF nodes being some of the earliest affected in AD, in Specific Aim 3, will examine progressive connectional disruptions along amyloid and tau pathology progression. Male and female MORF3 and double transgenic mice, MORF3/5xFAD and MORF3/MAPT(H1)*N279K, at 2m, 9m, and 18m of age will be used to reveal potential connectivity changes across aging and AD. The same groups will be used to determine synaptic-level HPF disruptions with the application of Expansion Microscopy that will capture super-resolution images of synaptic connections. In Specific Aim 4, we will create a web-based data portal that enables visualization, comparison, and analysis of neural circuits and cell types in 3D aging and AD brains. Our team, with decades of experience in connectomics, brain atlasing, and online visualization, is sure to deliver standard HPF atlas templates for all neuroscience research and to determine sexually dimorphic anatomic regions vulnerable across age and AD progression.

项目摘要 为了响应NOT-21-039和相关的PAR-22-093，我们建议该项目解决一些紧急需求 跨越不同年龄和性别的小鼠模型通常用于量化解剖学，分子， 以及像阿尔茨海默氏病（AD）这样的神经退行性疾病的病理变化。但是，唯一可用的 标准小鼠脑图集是由2个月大的成年雄性小鼠构建的。此外，尽管两者兼而有之 正常衰老和AD神经变性显示性二态特征，科学界缺乏 性别分化的啮齿动物大脑图谱需要研究这些属性。通过施加尖端 技术，我们已经开发了用于大脑启动连接组和细胞类型映射项目的开发，我们将（1） 用颗粒状海马（HPF）分子产生性二态3D衰老和AD脑图 域，可以用作所有HPF工作的标准地图集模板，（2）我们将全面 在衰老和AD中表征形态营养不良以及连接和突触破坏。 将创建特定的目标1，公开可用的标准3D HPF大脑。数据将是 以2个，9个月和18个月大的Wildtype（WT），5xFad（早期AD发作）和MAPT（H1）*N279K（晚期AD AD）产生 发作）男性和雌性小鼠。精细的HPF结构域描绘将通过细胞的3D体积图像制备 和骨髓结构，同时其他组织病理学标记（Aβ斑块/tau缠结）和 化学结构细节（谷氨酸，GABA，PV，SST，CALB1）将被映射以创建综合 组织病理学和化学结构的HPF地带。在特定目标2中，我们将系统地应用通用 MORF3稀疏标记方法，用于标记，重建和分析细胞类型的特定神经元形态 wt，vglut1.morf3/5xfad，pv.morf3/5xfad的HPF区域的HPF区域 VGLUT1.MORF3/MAPT（H1）*N279K和PV.MORF3/MAPT（H1）*N279K跨年龄和性别的N279K小鼠。我们的整体 将应用大脑3D清除，免疫染色，成像和3D神经元重建管道。鉴于 与广告相关的认知下降的病因是选择性HPF突触中断，背侧HPF节点为 广告中最早受影响的一些特定目标3，将检查沿着渐进的连接破坏 淀粉样蛋白和tau病理的进展。男性和女性MORF3和双转基因小鼠，Morf3/5xfad Morf3/mapt（H1）*N279K，2m，9m和18m年龄将用于揭示潜在的连通性变化 跨老化和广告。相同的组将用于确定突触级的HPF干扰 扩展显微镜的应用，该显微镜将捕获突触连接的超分辨率图像。在 特定目标4，我们将创建一个基于Web的数据门户，该门户能够可视化，比较和分析 3D衰老和广告大脑中的神经回路和细胞类型。我们的团队，拥有数十年的连接经验， 大脑蚀刻和在线可视化肯定会为所有神经科学提供标准的HPF地图集 研究并确定在年龄和广告进展中易受伤害的性二态解剖区域。