Dopamine Modulation of Cortical Spine Synapses and Cognition in MPTP Monkeys

MPTP 猴皮质脊柱突触和认知的多巴胺调节

• 批准号: 8499436
• 负责人: JOHN D ELSWORTH
• 金额: $ 40.65万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499436
• 关键词: Affect; Aging; American; Animal Model; Attention; Behavioral; Biochemical; Biomedical Research; Brain; Caregivers; Cognition; Cognitive; Cognitive deficits; Corpus striatum structure; Data; Dendrites; Dendritic Spines; Dependency; Dependovirus; Disease; Dopamine; Dose; Effectiveness; Electrons; Evaluation; Excitatory Synapse; Foundations; Functional disorder; GDNF gene; Gene Transfer; Goals; Human; Impaired cognition; Investigation; Methods; Microscopic; Modeling; Monkeys; Motor; Movement Disorders; Neuronal Plasticity; Neurotoxins; Outcome; Parkinson Disease; Parkinsonian Disorders; Patients; Performance; Pharmaceutical Preparations; Population; Prefrontal Cortex; Primates; Process; Publishing; Reporting; Research; Retrieval; Rodent; Serotyping; Short-Term Memory; Site; Specificity; Staging; Synapses; Testing; United States National Institutes of Health; Vertebral column; Viral Vector; caudate nucleus; clinically relevant; cognitive change; cognitive function; dopamine system; dopaminergic neuron; executive function; gene therapy; hippocampal pyramidal neuron; motor disorder; nerve supply; neurotransmission; neurotrophic factor; novel; olanzapine; overexpression; public health relevance; restoration; transmission process

DESCRIPTION (provided by applicant): Parkinson's disease is usually characterized as a movement disorder; however cognitive abilities, such as working memory and executive function, decline at early stages of the disease in most patients. The changes in brain that underlie the cognitive deficits are not well understood. We hypothesize that reduced dopamine transmission in the prefrontal cortex in Parkinson's disease is a harbinger of detrimental morphological changes in pyramidal neurons in the prefrontal cortex whose function is necessary for normal cognition. Our data show that a partial loss of dopamine innervation to the prefrontal cortex in monkeys elicited by systemic low-dose MPTP treatment produces cognitive deficits in prefrontal cortex-dependent tasks. Other preliminary data show that there is a decrease of asymmetric (excitatory) synapses on the spines of dendrites on pyramidal neurons in the dorsolateral prefrontal cortex of MPTP-treated monkeys. Together these findings suggest that the number of spine synapses on dendrites in the prefrontal cortex is dopamine-dependent and may be a morphological substrate of the cognitive deficits induced by sustained reductions in dopamine neurotransmission in this region. Modulation of spine synapses number represents a novel neuroplasticity function for dopamine. That cognitive deficits are persistent in the motor-asymptomatic MPTP-treated monkey suggests that this is a good model for the stage of Parkinson's disease in which there are few if any noticeable motor abnormalities, but significant detectable cognitive deficits. The Specific Aims of this proposal will examine this new direction, by investigating the dopamine dependency and specificity of spine synapse changes in the motor-asymptomatic primate MPTP model, examining GDNF gene transfer and pharmacological strategies for their restoration, using biochemical, electron microscopic and behavioral methods, and taking advantage of the primate facilities at the St Kitts Biomedical Research Foundation. This research will use the best animal model available to examine causes and treatments for cognitive decline in Parkinson's disease, which has received scant research attention, despite its substantial impact on patients and caregivers, and ineffectiveness of available therapy. PUBLIC HEALTH RELEVANCE: Parkinson's disease presently affects 1 to 1.5 million Americans, and this number is expected to increase with aging of the population: it is commonly viewed as movement disorder, but it also affects many facets of cognition even at early stages of the disease. The cognitive changes seen in Parkinson's disease are not well understood and have received relatively scant attention in research, despite the substantial impact they have on the patient and caregivers. The proposed research uses a primate animal model to pursue new leads on biochemical and morphological changes in the brain that may underlie the cognitive deficits, and tests novel gene therapy and pharmacological strategies for ameliorating the dysfunction.

描述（由申请人提供）：帕金森病通常以运动障碍为特征；然而，大多数患者的认知能力，例如工作记忆和执行功能，会在疾病早期阶段下降。认知缺陷背后的大脑变化尚不清楚。我们假设帕金森病中前额叶皮质中多巴胺传递的减少是前额叶皮质锥体神经元有害形态变化的先兆，而前额叶皮质的锥体神经元的功能对于正常认知是必需的。我们的数据表明，全身低剂量 MPTP 治疗引起的猴子前额皮质多巴胺神经支配的部分丧失会导致前额皮质依赖性任务的认知缺陷。其他初步数据表明，经 MPTP 治疗的猴子背外侧前额叶皮层锥体神经元树突棘上的不对称（兴奋性）突触减少。这些发现共同表明，前额皮质树突上的棘突触数量是多巴胺依赖性的，并且可能是该区域多巴胺神经传递持续减少引起的认知缺陷的形态学基础。脊柱突触数量的调节代表了多巴胺的一种新的神经可塑性功能。在经过 MPTP 治疗的无运动症状的猴子中，认知缺陷持续存在，这表明这是帕金森病阶段的一个很好的模型，在帕金森病阶段，几乎没有明显的运动异常，但有显着的可检测到的认知缺陷。该提案的具体目标将研究这一新方向，通过研究运动无症状灵长类 MPTP 模型中的多巴胺依赖性和脊柱突触变化的特异性，检查 GDNF 基因转移和恢复的药理学策略，使用生化、电子显微镜和行为方法，并利用圣基茨生物医学研究基金会的灵长类设施。这项研究将使用现有的最佳动物模型来研究帕金森病认知能力下降的原因和治疗方法，尽管帕金森病对患者和护理人员有重大影响，而且现有治疗无效，但研究关注很少。 公共卫生相关性：帕金森病目前影响 1 至 150 万美国人，预计这一数字会随着人口老龄化而增加：帕金森病通常被视为运动障碍，但即使在疾病的早期阶段，它也会影响认知的许多方面。尽管帕金森病对患者和护理人员产生了重大影响，但帕金森病中的认知变化尚未得到充分理解，并且在研究中相对较少受到关注。拟议的研究使用灵长类动物模型来寻找可能导致认知缺陷的大脑生化和形态变化的新线索，并测试改善功能障碍的新基因疗法和药理学策略。