Dopamine Modulation of Cortical Spine Synapses and Cognition in MPTP Monkeys

描述(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，如工作记忆和执行功能，在疾病的早期阶段就会下降。认知缺陷背后的大脑变化还没有被很好地理解。我们推测，帕金森病患者前额叶皮质多巴胺传递减少是前额叶皮质锥体神经元形态发生有害变化的先兆，其功能是正常认知所必需的。我们的数据显示，全身小剂量MPTP治疗导致猴子前额叶皮质多巴胺神经支配的部分丧失，导致前额叶皮质依赖任务的认知障碍。其他初步数据显示，MPTP处理的猴子前额叶皮质背外侧锥体神经元上的树突脊椎上的不对称(兴奋性)突触减少。综上所述，这些发现表明，前额叶皮质树突上的棘突触数量是多巴胺依赖的，可能是该区域多巴胺神经传递持续减少所导致的认知障碍的形态基础。脊髓突触数目的调节代表了多巴胺的一种新的神经可塑性功能。在接受MPTP治疗的无运动症状的猴子中，认知缺陷是持续存在的，这表明这是帕金森病阶段的一个很好的模型，在这个阶段，几乎没有明显的运动异常，但有显著的可检测到的认知缺陷。这项建议的具体目标将检验这一新方向，通过研究运动-无症状灵长类MPTP模型中的多巴胺依赖和脊柱突触变化的特异性，使用生化、电子显微镜和行为方法，检查GDNF基因转移和恢复它们的药理学策略，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好的动物模型来研究帕金森氏症认知能力下降的原因和治疗方法，尽管帕金森氏症对患者和照顾者有重大影响，而且现有治疗方法无效，但研究人员对其关注很少。 公共卫生相关性：帕金森氏症目前影响着100至150万美国人，这个数字预计会随着人口老龄化而增加：它通常被视为运动障碍，但它也会影响认知的许多方面，即使在疾病的早期阶段也是如此。帕金森氏症中的认知变化尚未得到很好的了解，研究中相对较少的关注，尽管它们对患者和照顾者有实质性的影响。这项拟议的研究使用灵长类动物模型来寻找大脑生化和形态变化的新线索，这些变化可能是认知缺陷的基础，并测试新的基因疗法和药物策略来改善这种功能障碍。

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.