Intrinsic and synaptic determinants of activity in GPe neurons in PD models

基底节网络是大脑的运动开关，这个大环路的输出是依赖的 关于两条相对的路径，即直接路径和间接路径的平衡。这一至关重要的问题的破坏 在帕金森氏症等运动障碍中观察到的衰弱效应是相互作用的基础。 新出现的证据表明，苍白球外球，传统上被认为曾经只是 中继核被认为比之前认为的要复杂得多。苍白球外球连通 通过复杂的循环反馈环与其他神经元在间接通路中的作用，表明它在 间接途径功能。我们的工作和其他人一起，提出了球体的复杂细胞构成 苍白球。在即将到来的赠款期间，我们寻求更好地描述这些类型的神经元是如何连接的 基底节的其余部分。拟议的多学科研究战略将结合使用 电生理、光遗传、转基因、病毒、转录和解剖技术， 慢性帕金森氏病小鼠模型。在目标1中，使用CRE/LOX方法，苍白球亚型 神经元将被鉴定，并进行FACS纯化或膜片钳。苍白球的内在特性 神经元亚型将被测量，并与离子通道表达的分子图谱相关联。在AIM 2、研究苍白球神经元亚型与丘脑底核的联系。vbl.使用 下丘脑-苍白球的电生理途径、生物物理性质及受体互补 将对输入进行测量。药理学方法、转录分析和遗传方法将是 用于证实从电生理研究中得出的推论。在Aim 3中，使用 光遗传学方法，将研究苍白球纹状体输入的功能特性。已识别的纹状体 神经元将被膜片钳固定，参与苍白球纹状体传递的信号机制将被研究。 药理学、免疫细胞化学和基因敲除方法将补充这一努力。在……里面 目的4我们将确定在慢性多巴胺缺乏时间接通路的亚回路是如何改变的。 模仿帕金森氏症的模型。转录、电生理和解剖学分析将是 已执行。

The basal ganglia network is the motor switchboard of the brain and the output of this macrocircuit is dependent on the balance of two opposing pathways, i.e. the direct and indirect pathways. The disruption of this crucial interplay underlies the debilitating effects observed in movement disorders, such as Parkinson's disease. Emerging evidence suggests that the external globus pallidus, traditionally thought to once function as a mere relay nucleus, is believed to be more complex than previously thought. The external globus pallidus is connected with other neurons in the indirect pathway through complex recurrent feedback loops, suggesting its key role in indirect pathway function. Our work, along with others, has suggested a complex cellular makeup of the globus pallidus. In this upcoming grant period, we seek to better characterize how these types of neurons are connected with the rest of the basal ganglia. The proposed multidisciplinary research strategy will use a combination of electrophysiological, optogenetic, transgenic, viral, transcriptomic, and anatomical techniques in a 6-OHDA, chronic mouse model of Parkinson's disease. In Aim 1, using a Cre/lox approach, subtypes of globus pallidus neurons will be identified and either FACS-purified or patch-clamped. The intrinsic properties of globus pallidus neuron subtypes will be measured and correlated with molecular profiling of ion channel expression. In Aim 2, the connectivity of globus pallidus neuron subtypes with the subthalamic nucleus will be studied. Using an electrophysiological approach, biophysical properties and receptor complement of the subthalamopallidal input will be measured. Pharmacological methods, transcriptomic analysis, and genetic approaches will be used in conjunction to corroborate the inferences drawn from electrophysiological studies. In Aim 3, using an optogenetic approach, the functional properties of the pallidostriatal input will be studied. Identified striatal neurons will be patch-clamped and signaling mechanisms involved in pallidostriatal transmission will be studied. Pharmacological, immunocytochemical, and genetic knockdown approaches will complement this effort. In Aim 4 we will determine how subcircuits of the indirect pathway are altered in a chronic dopamine depletion model that mimics Parkinson's disease. Transcriptomic, electrophysiological, and anatomical analyses will be performed.