Corticosubthalamic Plasticity in the Parkinsonian State

抽象RACT 在目前帕金森氏病(PD)的病理生理学方案中，神经元活动的变化与帕金森病(PD)有关。 丘脑底核索氏运动区(STN)在帕金森病的发生发展中起核心作用。直到 最近，STN活性的变化被认为完全是由于外部抑制的减少所致 苍白球(GPE)。然而，最近对晚期帕金森症动物模型的研究结果表明 谷氨酸能皮质-下丘脑终末的严重丧失和GABA能神经元强度的增强 苍白球下丘脑突触可能参与了STN的活动变化和帕金森病的发生。 索尼派。我们的初步数据显示，皮质-下丘脑终末的丢失也存在于 进展期帕金森病患者的感觉运动STN领域。然而，目前尚不清楚这些解剖和 生理变化与黑质纹状体多巴胺丢失的程度和帕金森病的表现有关。 此外，尚不清楚这些变化是否也影响到STN的非运动区，可能有助于认知- 情绪性或情绪性帕金森病症状。我们将用神经病理学和电生理学来检查这些问题。 对不同程度MPTP诱导的多巴胺丢失(目标1)和纵向7T的猴子的研究 早期帕金森病患者的超高场磁共振研究(目标2)。在目标1中，我们将记录STN神经元的反应 对大脑皮质和苍白球传入的光遗传激活，这些猴子在手术后仍然没有症状。 接触小剂量的多巴胺耗竭神经毒素MPTP或接触后成为帕金森病患者 (大剂量)MPTP。我们还将评估局部场电位(LFP)和异常尖峰的变化 STN的活动，以及STN LFP和运动皮质脑电之间的一致性。在尸检中 对相同动物的研究，我们将使用高分辨率的显微免疫组织化学研究和3D-EM 重建以评估谷氨酸和氨基丁酸能神经元的数量、定位和形态 随着多巴胺的丢失，STN中的突触也会发生变化。我们还会比较皮质醇的数量- 帕金森病和帕金森病患者丘脑底核终末和短暂性核组织GABA能标记物的变化 年龄匹配的对照组。在目标2中，我们将使用最先进的扩散和静息状态功能磁共振来测试 早期帕金森病患者是否表现出体积和微结构组织的显著变化 ，并确定这些变化是否与基因表达有关 以及运动和非运动障碍的进展。同样的患者将在登记和30名患者中进行研究 几个月后检查核磁共振测量的变化。这个项目的成果将增进我们的理解 帕金森病相关的STN可塑性变化的时间演变，并确定它们的潜力 与疾病的运动和非运动体征和症状的发展和严重程度的关系。这些 研究可能导致新的干预措施来控制或预防STN的异常放电模式，并可能有助于 开发成像生物标记物来识别帕金森病的早期阶段和疾病进展的预测因素。

ABST RACT In current schemes of the pathophysiology of Parkinson’s disease (PD), neuronal activity changes in the sen- sorimotor region of the subthalamic nucleus (STN) play a central role in the development of parkinsonism. Until recently, the changes in STN activity were thought to result solely from reduced inhibition from the external globus pallidus (GPe). However, recent findings from animal models of advanced parkinsonism have suggested that a profound loss of glutamatergic cortico-subthalamic terminals and an increased strength of GABAergic pallidosubthalamic synapses may contribute to activity changes in the STN and to the development of parkin- sonism. Our preliminary data demonstrate that a loss of cortico-subthalamic terminals is also present in the sensorimotor STN territory of people with advanced PD. It remains unclear, however, how these anatomical and physiologic changes relate to the degree of nigrostriatal dopamine loss and to the expression of parkinsonism. Further, it is unknown if these changes also affect non-motor regions of the STN, perhaps contributing to cogni- tive or affective PD symptoms. We will examine these issues with neuropathological and electrophysiological studies in monkeys with different degrees of MPTP-induced dopamine loss (Aim 1), and with longitudinal 7T ultra-high field MRI studies in people with early PD (Aim 2). In Aim 1, we will record responses of STN neurons to optogenetic activation of cortical and pallidal inputs in monkeys that remained either asymptomatic after ex- posure to small dose of the dopamine-depleting neurotoxin MPTP or became parkinsonian after exposure to (larger doses of) MPTP. We will also assess changes in local field potentials (LFPs) and abnormal spiking activity in STN, and in the coherence between STN LFPs and motor cortical electrocorticograms. In postmortem studies of the same animals, we will use high resolution microscopic immunohistochemical studies and 3D-EM reconstructions to assess whether the number, localization, and morphology of glutamatergic and GABAergic synapses in the STN changes as a function of dopamine loss. We will also compare the number of cortico- subthalamic terminals and examine changes in GABAergic markers in STN tissue from patients with PD and age-matched controls. In Aim 2, we will use state-of-the-art diffusion and resting state functional MRI to test whether humans with early stage PD exhibit significant changes in the volume and microstructural organization of the STN and its cortical and pallidal afferents, and determine if these changes are related to the expression and progression of motor and non-motor impairments. The same patients will be studied at enrollment and 30 months later to examine changes in the MRI measures. The results of this project will increase our understanding of the temporal evolution of parkinsonism-associated plastic changes in the STN, and determine their potential relationships to the development and severity of motor and non-motor signs and symptoms of the disease. These studies may lead to novel interventions to control or prevent abnormal firing patterns in STN and may contribute to the development of imaging biomarkers to identify early stages of PD and predictors of disease progression.