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病运动体征经常通过单侧或双侧帕金森病引起的多巴胺耗竭来研究。 双侧6-OHDA注射入正中前脑束或纹状体。纹状体多巴胺的丢失导致 基底神经节-丘脑皮质运动回路元件中的异常神经元活动，包括增加 β频率振荡，增加神经元的爆发活动，增加神经元之间的同步， 改变了峰值频率这些变化主要与MPTP治疗的灵长类动物中发现的变化相似， 帕金森氏症的人类患者。病理活动模式已经从他们的纹- 丘脑起源于苍白球、黑质网状部和丘脑底核。一个重要空白 在我们对多巴胺耗竭的后果的理解中，缺乏关于神经前体的数据， 在运动区和运动前区表现出帕金森症状。对这个问题的调查需要一个细胞 皮层神经活动的类型特异性分析，因为复杂的皮层微电路导致预期 不同亚型的神经元参与帕金森氏症的活动模式不同。在这个项目中，我们- 提高我们在单神经元水平上将联合收割机行为研究和机制研究结合起来的能力， 啮齿类动物，以解决整体假设，皮质脊髓投射神经元（CSNs）和神经投射py- 分支束神经元（PT-TRN）不同地参与帕金森病活动模式。约1/3的PT- 脊髓神经元也投射到脊髓，但预计是少数的CSN，并可能投射到不同的神经元。 脊髓靶点。在目标1下，我们将通过研究CSN在系统层面上解决这一假设 小鼠前肢尾侧和喙侧区域（分别为CFA和RFA）中的PT-CRP活性与 双侧多巴胺去甲小鼠的运动任务、反应抑制和食物到达行为， 通过6-OHDA注射到背外侧纹状体中完成。为了评估帕金森病网络活动， 因此，我们将采用细胞类型特异性电压成像与遗传表达的电压指标（GEVI）。 此外，我们将记录CFA和RFA中的单个单位活动，长期植入硅探针和光电探测器。 标记CSN和PT-1神经元。在目标2中，我们将研究这些细胞功能障碍的细胞基础， 通过大脑切片记录来揭示内在和突触性质的变化。我们将使用计算机 建模以确定观察到的变化对两种细胞的突触整合性质的影响 类型计划中的研究与项目2密切相关，项目2解决了大脑皮质脊髓神经元的活动， 灵长类动物补充运动区和初级运动皮层多巴胺耗尽与MPTP， 项目3检查皮层网络中突触连接的变化，项目4观察 帕金森病患者运动皮层活动中的振荡成分和行为表现 在反应抑制任务中。

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.