Limbic-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边缘-基底神经节连接

• 批准号: 9811798
• 负责人: Alison Ruth Weiss
• 金额: $ 4.43万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2020-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9811798
• 关键词: Address; Adult; Affect; Affective; Aggressive behavior; Amygdaloid structure; Anatomy; Anhedonia; Animal Disease Models; Anterior; Anxiety; Area; Atrophic; Award; Basal Ganglia; Behavioral; Behavioral Assay; Brain; CAG repeat; Caregivers; Chromosomes, Human, Pair 4; Cognitive; Corpus striatum structure; Dependovirus; Depression and Suicide; Development; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Disease model; Emotional; Faculty; Fellowship; Fiber; Functional Magnetic Resonance Imaging; Funding; Future; Gene Mutation; Genes; Goals; Histologic; Histological Techniques; Human; Huntington Disease; Huntington protein; Hyperactive behavior; Image; Impaired cognition; Impairment; Inclusion Bodies; Inherited; Injections; Intervention; Knowledge; Laboratories; Light; Limbic System; Macaca mulatta; Magnetic Resonance Imaging; Measures; Mediating; Mentors; Modeling; Molecular; Molecular Analysis; Moods; Motor; Movement Disorders; Mutation; National Institute of Neurological Disorders and Stroke; National Research Service Awards; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neuroglia; Neurons; Neurosciences; Neurosciences Research; Operative Surgical Procedures; Pathologic; Patients; Personality; Phenotype; Production; Psychiatric therapeutic procedure; Quality of life; Reporting; Research; Rest; Stretching; Structure; Sucrose; Sum; Symptoms; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; United States National Institutes of Health; Western Blotting; brain circuitry; cingulate cortex; cognitive function; cognitive neuroscience; density; disturbance in affect; emotion regulation; gain of function; in vivo; interest; mRNA Expression; member; mood symptom; motor deficit; motor symptom; multidisciplinary; mutant; neuroimaging; neuromechanism; neuropathology; nonhuman primate; novel; preference; prospective; protein aggregate; protein expression; psychiatric symptom; putamen; retrograde transport; skills; tenure track; therapeutic development; white matter

Huntington's disease (HD) is a degenerative neurological disorder caused by an expanded CAG repeat sequence in the dominantly-inherited HTT gene on chromosome 4. When the CAG repeat stretch exceeds 40 repeats the encoded mutant huntingtin protein (mHTT) misfolds, resulting in a toxic gain of function that is neurodegenerative. HD symptoms are detrimental to the patient's quality of life, as they suffer from a progressive hyperkinetic movement disorder accompanied by deteriorating cognitive function and profound personality changes/mood disturbances. The emotional and physical burden on both the patient and the caregiver are tremendous, and patients often report their mood symptoms to be the most burdensome to both themselves and their caretakers. To address this need, the central goal of my project will be to characterize the impact of HD neuropathology on limbic-basal ganglia connectivity and behavioral phenotypes relevant to the mood/psychiatric symptoms. I will use behavioral assays to assess mood and affect in our HD animal model, and I will perform neuroimaging, histological, and molecular analyses, focusing on specific regions of interest in limbic (amygdala, anterior cingulate cortex, orbitofrontal cortex) and basal ganglia (caudate and putamen) regions. In sum, I will take a multifaceted approach using both in vivo (neuroimaging and behavioral assays in Aim 1 and 2) and ex vivo (histological and molecular in Aim 3) techniques. The strength of my studies lays in their ability to identify prospective neuroimaging changes that can be connected with a wide array of behavioral and neuropathological phenotypes of HD.

亨廷顿氏病（HD）是由CAG重复扩展引起的退化性神经系统疾病 染色体4上主要亲属HTT基因的序列。当CAG重复拉伸超过40时 重复编码的突变体亨廷顿蛋白（MHTT）错误折叠，导致功能的有毒增益为 神经退行性。高清症状不利于患者的生活质量，因为它们患有 进行性超动运动障碍伴随着认知功能恶化和深刻 个性改变/情绪障碍。患者和患者的情感和身体负担 照料者非常巨大，患者经常报告自己的情绪症状是最繁重的 自己和他们的看护人。为了满足这一需求，我项目的核心目标是表征 高清神经病理学对边缘基 - 基础神经节连通性和与行为表型有关的影响 情绪/精神病症状。我将使用行为分析来评估我们的高清动物模型中的情绪和影响， 我将进行神经影像学，组织学和分子分析，重点关注特定的感兴趣区域 边缘（杏仁核，前扣带回皮层，眶额皮层）和基底神经节（尾状和壳壳） 地区。总而言之，我将使用体内（神经影像学和行为测定法）采用多方面的方法 AIM 1和2）和离体（AIM 3中的组织学和分子）技术。我的学习力量置于 他们识别可以与广泛行为相关的前瞻性神经影像学变化的能力 HD的神经病理表型。