Dopamine Modulation of Cortical Spine Synapses and Cognition in MPTP Monkeys

描述（由申请人提供）：帕金森病通常被表征为运动障碍;然而，大多数患者的认知能力，如工作记忆和执行功能，在疾病的早期阶段下降。认知缺陷背后的大脑变化还没有得到很好的理解。我们假设，减少多巴胺在前额叶皮层在帕金森氏病的传输是一个预兆，在前额叶皮层的锥体神经元的功能是必要的正常认知有害的形态变化。我们的数据表明，部分损失多巴胺神经支配的前额叶皮质在猴子引起的系统性低剂量MPTP治疗产生认知缺陷的前额叶皮质依赖的任务。其他初步数据显示，MPTP处理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。总之，这些研究结果表明，前额叶皮层树突上的棘突触的数量是多巴胺依赖性的，可能是该地区多巴胺神经传递持续减少引起的认知缺陷的形态学基质。脊髓突触数量的调制代表了多巴胺的一种新的神经可塑性功能。认知缺陷在运动无症状MPTP治疗的猴子中持续存在，表明这是帕金森病阶段的良好模型，其中存在很少（如果有的话）明显的运动异常，但存在显著的可检测的认知缺陷。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，研究GDNF基因转移和恢复的药理学策略，使用生物化学，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动物设施。这项研究将使用最好的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产生了重大影响，而且现有治疗方法无效，但很少受到研究关注。 公共卫生相关性：帕金森氏病目前影响着1至150万美国人，预计这一数字将随着人口老龄化而增加：它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。帕金森氏病中观察到的认知变化尚未得到很好的理解，并且在研究中受到的关注相对较少，尽管它们对患者和护理人员产生了重大影响。拟议的研究使用灵长类动物模型来寻求大脑中可能导致认知缺陷的生化和形态学变化的新线索，并测试改善功能障碍的新基因疗法和药理学策略。

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.