Cortical Connectivity and Activity Changes in Motor Preparation and Execution in 6-OHDA-Lesioned Mice

项目摘要-项目1 啮齿类动物的帕金森运动体征经常被研究为单侧或单侧或双侧引起的多巴胺耗竭 双侧前脑正中束或纹状体注射6-OHDA。纹状体多巴胺的丧失导致 基底节-丘脑皮质运动神经回路的异常神经元活动，包括增加 贝塔频率振荡，神经元爆发性活动增加，神经元之间的同步性增加， 并改变了峰值频率。这些变化与MPTP处理的灵长类动物和 人类帕金森氏症患者。病理活动模式已经从他们的条纹中被遵循- Tal起源于苍白球、黑质网状部和丘脑底核。一个重要的差距 在我们对多巴胺耗竭后果的理解中，缺乏关于神经前体的数据。 运动区和运动前区出现帕金森氏症。对这一问题的调查需要一个小组 对皮质神经活动的特定类型分析，因为复杂的皮质微电路导致了预期 不同亚型的神经元在帕金森氏症的活动模式上存在差异。在这个项目中，我们将- 提高我们在单个神经元水平上结合行为研究和机制研究的能力，可在 啮齿类动物应对皮质脊髓投射神经元(CSN)和STN投射Py-Py的总体假设。 中枢束神经元(PT-STN)参与帕金森病的不同活动模式。约1/3的PT- STN神经元也投射到脊髓，但预计是CSN的一小部分，并可能投射到不同的脊髓。 不同的脊髓目标。在目标1下，我们将通过研究CSN在系统级别上解决这一假设 和PT-STN活性在小鼠尾侧和头端前肢区(分别为CFA和RFA)与 小鼠双侧去多巴胺后的运动任务、反应抑制和进食行为 通过向背外侧纹状体注射6-羟基多巴胺。为了评估帕金森病患者的网络活动- TERN，我们将使用带有遗传表达电压指示器(GEVI)的细胞类型特定电压成像。 此外，我们将在CFA和RFA中使用长期植入的硅探针和光电子显微镜记录单个单位的活动。 CSNS和PT-STN神经元的标记。在目标2中，我们将研究这些细胞功能障碍的细胞基础。 通过脑片记录来揭示内在和突触属性的变化。我们将使用计算机 建模以确定观察到的变化对两个细胞的突触整合特性的影响 类型。计划中的研究与项目2密切相关，该项目研究大脑皮质脊髓神经元的活动。 用MPTP治疗多巴胺耗竭后的灵长类辅助运动区和初级运动皮质 项目3检查大脑皮层网络中突触连接的变化，项目4查看 帕金森病患者运动皮质活动中的振荡成分和行为表现 曼斯在做反应抑制任务。

Project Summary – Project 1 Parkinsonian motor signs in rodents are frequently studied with dopamine depletion initiated by unilateral or bilateral 6-OHDA injections into the median forebrain bundle or striatum. The striatal dopamine loss leads to abnormal neuronal activity in elements of the basal ganglia-thalamocortical motor circuit, including an increase of beta frequency oscillations, increased bursting activities of neurons, increased synchrony between neurons, and changed spike rates. These changes are principally similar to those found in MPTP treated primates and human patients with Parkinson’s disease. The pathological activity patterns have been followed from their stria- tal origin to the globus pallidus, substantia nigra pars reticulata, and the subthalamic nucleus. An important gap in our understanding of the consequences of dopamine depletion is the lack of data concerning the neural pro- cessing in the parkinsonian condition in motor and premotor areas. Investigations into this issue require a cell type-specific analysis of neural activity in cortex, as the complex cortical microcircuitry leads to the expectation that different subtypes of neurons engage differentially in parkinsonian activity patterns. In this project, we lev- erage our ability to combine behavioral studies and mechanistic studies on the single-neuron level available in rodents to address the overall hypothesis that corticospinal projection neurons (CSNs) and STN projecting py- ramidal tract neurons (PT-STN) are differentially involved in parkinsonian activity patterns. About 1/3rd of PT- STN neurons also project to the spinal cord, but are expected to be a minority of CSNs and likely project to dif- ferent spinal cord targets. Under aim 1, we will address this hypothesis at the systems level by studying CSN and PT-STN activity in the caudal and rostral forelimb areas of mice (CFA and RFA, respectively) in relation to a locomotor task, response inhibition, and food reaching behavior in mice that are bilaterally dopamine-de- pleted through 6-OHDA injections into the dorsolateral striatum. To assess parkinsonian network activity pat- terns, we will employ cell type-specific voltage imaging with genetically expressed voltage indicators (GEVIs). Further, we will record single unit activities in CFA and RFA with chronically implanted silicon probes and opto- tagging of CSNs and PT-STN neurons. In aim 2, we will study the cellular basis of dysfunction in these cell types through brain slice recordings to uncover intrinsic and synaptic property changes. We will use computer modeling to determine the impact of the observed changes on the synaptic integration properties of both cell types. The planned studies are closely aligned with project 2 that addresses corticospinal neuron activity in the primate supplementary motor area and primary motor cortex following dopamine depletion with MPTP, with project 3 that examines changes in synaptic connectivity in the cortical network, and with project 4 that looks at oscillatory components in motor cortical activity in human Parkinson’s disease patients and behavioral perfor- mance in a response inhibition task.