Cortico-basal ganglia connectivity in a non-human primate model of Huntington's disease

亨廷顿病非人类灵长类动物模型中的皮质基底节连接

基本信息

批准号：
9215293
负责人：
Jodi L. McBride
金额：
$ 71.29万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9215293
关键词：
Affect Animal Model Animals Area Atrophic Basal Ganglia Behavior Behavior assessment Behavioral Biological Neural Networks Brain Brain region CAG repeat Cell Nucleus Characteristics Chorea Clinical Cognition Disorders Cognitive Complex Corpus striatum structure DARPP Data Data Set Dendritic Spines Dependovirus Deterioration Development Diffusion Magnetic Resonance Imaging Disease Disease Progression Disease model Dopamine Dopamine Receptor Dystonia Electrophysiology (science)Exhibits Fright Functional Magnetic Resonance Imaging Funding Future Gene Transfer Genes Gliosis Globus Pallidus Glutamate Receptor Glutamates Glutamine Goals Histological Techniques Human Huntington Disease Huntington gene Image Impaired cognition Inclusion Bodies Injection of therapeutic agent Intervention K-Series Research Career Programs Laboratories Lead Length Macaca Macaca mulatta Magnetic Resonance Imaging Manuscripts Mediating Modeling Molecular Monkeys Morphology Motor Motor Cortex Motor Skills Movement Disorders Mutation National Institute of Neurological Disorders and Stroke Nerve Degeneration Neurobiology Neurodegenerative Disorders Neuronal Dysfunction Neurons Neurosciences Pathology Patients Phenotype Preparation Proteins Research Rest Scientist Short-Term Memory Slice Statistical Data Interpretation Stretching Structure Substantia nigra structure Techniques Technology Testing Therapeutic Use Study Transcript adeno-associated viral vector astrogliosis cognitive development disease phenotype executive function experience frontal lobe gain of function image guided in vivo motor control motor disorder mutant neuroimaging neuron loss neuropathology neurosurgery neurotransmission nonhuman primate novel putamen touchscreen transmission process vector genome white matter

项目摘要

PROJECT SUMMARY The goal of the proposed research in this application is to characterize alterations in cortico-basal ganglia connectivity in a novel non-human primate model of Huntington's disease (HD) recently developed in my laboratory. Previous K99/R00 funding (2010-2015) from the NINDS supported the development of this new model, wherein we found that AAV-mediated expression of mutant HTT in the caudate and putamen of rhesus macaques lead to a wide array of behavioral manifestations of disease including the progressive development of both motor and cognitive phenotypes also seen in human HD patients. Brains from HD NHPs showed DARPP-32 loss, inclusion formation and gliosis, along with reduced levels of key striatal transcripts, including reduced glutamate and dopamine receptor levels (manuscript in preparation). In addition to striatal pathology, we found mHTT expression, inclusion bodies and gliosis in numerous cortical areas (frontal and motor) and regions throughout the basal ganglia (globus pallidus, substantia nigra), likely owing to transport of the AAV vector. These findings strongly suggest that basal ganglia connectivity may be disrupted in our NHP HD model. The objective of this current proposal is to characterize cortico-basal ganglia connectivity in the brains of our HD NHPs using resting state fMRI and diffusion tensor imaging to assess functional connectivity and white matter integrity, respectively (Aim 1). Additionally, we will evaluate glutamate and dopamine neurotransmission in the caudate and putamen using electrophysiological analyses (Aim 2). We will test our central hypothesis that there is a progressive decline in basal ganglia connectivity in our HD NHP brains that correlates with 1) the longitudinal development of cognitive and motor phenotypes, 2) reduced glutamate and dopamine transmission in cortico-striatal and nigro-striatal connections with medium spiny neurons in the caudate and putamen and 3) neuropathology including inclusion formation, gliosis and neuronal dysfunction. I have assembled an excellent team of scientists to accomplish these goals with cumulative expertise in resting state fMRI analysis of cortico-striatal functional connectivity (Dr. Christopher Kroenke), electrophysiological recordings of medium spiny neurons in the rhesus macaque striatum (Dr. Verginia Cuzon Carlson), statistical analysis of complex datasets (Dr. Byung Park), as well as my background and expertise in HD neurobiology, AAV-mediated gene transfer, NHP MRI-guided neurosurgery, complex NHP motor and cognitive behavioral assessment and the use of molecular and histological techniques to assess HD neuropathology. By the end of the studies proposed here, we will have characterized alterations in basal ganglia connectivity in a novel AAV- mHTT mediated monkey model of HD, elucidating potential pathophysiological mechanisms that underlie motor and cognitive decline. Additionally, the data obtained from these studies will provide the unique opportunity to identify imaging, behavioral, electrophysiological and neuropathological endpoints that will be used for future therapeutic studies using this model.

项目概要本申请中拟议研究的目标是表征皮质基底神经节的变化我最近开发的一种新型非人类灵长类亨廷顿病（HD）模型中的连通性实验室。 NINDS 之前的 K99/R00 资金（2010-2015 年）支持了这一新产品的开发模型中，我们发现 AAV 介导的恒河猴尾状核和壳核中突变型 HTT 的表达猕猴会导致一系列疾病的行为表现，包括逐渐发展在人类 HD 患者中也观察到了运动和认知表型的变化。 HD NHP 的大脑显示 DARPP-32 丢失、包含物形成和神经胶质增生，以及关键纹状体转录物水平降低，包括谷氨酸和多巴胺受体水平降低（手稿正在准备中）。除了纹状体病理学之外，我们在许多皮质区域（额叶和运动区域）发现了 mHTT 表达、包涵体和神经胶质增生，整个基底神经节区域（苍白球、黑质），可能是由于 AAV 的运输向量。这些发现强烈表明，我们的 NHP HD 模型中基底神经节的连接可能会受到破坏。当前提案的目标是表征我们大脑中的皮质基底神经节连接性 HD NHP 使用静息态 fMRI 和扩散张量成像来评估功能连接和白分别是物质完整性（目标 1）。此外，我们将评估谷氨酸和多巴胺神经传递使用电生理学分析对尾状核和壳核进行观察（目标 2）。我们将检验我们的中心假设我们的 HD NHP 大脑中基底神经节连接性逐渐下降，这与 1) 认知和运动表型的纵向发展，2）谷氨酸和多巴胺减少皮质纹状体和黑质纹状体与尾状核和中型多棘神经元连接的传递壳核和 3) 神经病理学，包括包涵体形成、神经胶质增生和神经元功能障碍。我有组建了一支优秀的科学家团队，通过在静息状态下积累的专业知识来实现这些目标皮质纹状体功能连接的 fMRI 分析（Christopher Kroenke 博士）、电生理学恒河猴纹状体中型多刺神经元的记录（Verginia Cuzon Carlson 博士），统计复杂数据集的分析（Byung Park 博士），以及我在 HD 神经生物学方面的背景和专业知识， AAV 介导的基因转移、NHP MRI 引导的神经外科手术、复杂的 NHP 运动和认知行为评估以及使用分子和组织学技术来评估 HD 神经病理学。到年底根据这里提出的研究，我们将描述一种新型 AAV- 中基底神经节连接的变化 mHTT 介导的 HD 猴子模型，阐明潜在的病理生理机制运动和认知能力下降。此外，从这些研究中获得的数据将提供独特的有机会识别影像学、行为学、电生理学和神经病理学终点用于使用该模型的未来治疗研究。