Behavioral and synaptic plasticity of a genetically distinct population of GPe neurons in health and disease

 描述(申请人提供)：在帕金森病(PD)中，基底节(BG)是一组高度相互联系的皮质下结构，由于系统中多巴胺的慢性丢失，从根本上发生了改变。一种主要的假说认为苍白球(GPE)是这种环路功能障碍的主要组成部分。GPE是运动抑制通路中的中央核，历史上一直被认为是同质的神经元群体，因此在BG功能中起着统一的作用。BG核中细胞类型的多样性是常见的，发现细胞类型的作用大大提高了我们对电路功能和功能障碍的理解。最近的研究揭示了基于解剖投影、活体棘波活动和死后组织分析的苍白球种群，这些种群挑战经典模型，并基于连接性差异为苍白球神经元提供功能作用。尽管这些分类在很大程度上是有益的，但它们很难在模型和准备工作中推广。因此，我们已经确定了两个遗传上不同的神经元群体，它们在地形分布、内在生理学和轴突投射方面不同。表达小白蛋白的GPE群体(PV-GPE)更强烈地投射到丘脑底核(STN)，并向丘脑束旁核(PF)发送明显的输出投射。最值得注意的是，对PV-GPE投射的光刺激不会改变健康动物的总体运动，但会在低多巴胺的条件下恢复运动障碍。因此，这项建议的主要目标是确定健康和疾病中遗传上截然不同的GPE神经元群体的行为和突触相关性。目的1研究在对照(生理盐水)和多巴胺耗竭(6-OHDA)条件下，两种不同的输出投射对运动启动(STN)和行为灵活性(PF)至关重要的脑区的作用。在这里，我们将光学刺激PV-GPE投射，以获取这些健康区域的行为影响，并确定哪个投射是恢复疾病运动控制的最重要靶点。为了了解多巴胺丢失后电路是如何改变的，Aim 2将通过光刺激测量STN和PF中PV-GPE轴突的诱发突触反应，来确定这两个投射目标的解剖和突触变化。为了测试突触输入的变化是否基于遗传定义的人群而发生差异改变，Aim 3将使用电和光刺激的组合来识别控制和多巴胺耗竭条件下PV-GPE突触输入的变化来源。我们将共同检验这一假设，即PV-GPE神经元在与运动损伤相关的行为和突触功能障碍中发挥关键作用。长期目标是发现针对不同的神经元群体在治疗帕金森氏症衰弱运动功能障碍方面的治疗潜力。

 DESCRIPTION (provided by applicant): In Parkinson's disease (PD), the basal ganglia (BG), a set of highly interconnected subcortical structures, are fundamentally altered due to the chronic loss of dopamine in the system. A leading hypothesis places the globus pallidus externa (GPe) as major component in this circuit dysfunction. The GPe is a central nucleus in the motor-suppressing pathway that has historically has been identified as a homogenous population of neurons and thus a uniform role in BG function. Cell type diversity in BG nuclei is common and uncovering the role of cell-types has significantly improved our understanding of circuit function and dysfunction. Recent studies have revealed pallidal populations based on anatomical projections, in vivo spike activity, and post- mortem tissue analysis that challenge classical models and provide functional roles for pallidal neurons based on connectivity differences. Though these classifications have been largely beneficial, they have been difficult to generalize across models and preparations. Therefore, we have identified two genetically distinct populations of neurons that differ in their topographic distribution, intrinsic physiology and axonal projections. The GPe population that expresses parvalbumin (PV-GPe) projects more strongly to the subthalamic nucleus (STN) and sends a distinct output projection to the parafascicular nucleus of the thalamus (pf). Most notably, optical stimulation of PV-GPe projections does not alter gross locomotion in health animals but recues motor impairments in conditions of low dopamine. Thus, the primary objective of this proposal is to identify behavioral and synaptic correlates of a genetically distinct population of GPe neurons in health and disease. Aim 1 will investigate the role of two distinct output projections to brain areas importan for movement initiation (STN) and behavioral flexibility (pf) during control (saline) and dopamine-depleted (6-OHDA) conditions. Here, we will optically stimulate the PV-GPe projections to access the behavioral effect in these defined regions in health and determine which projection is most important to target for the restoration of motor control in disease. To understand how the circuit is altered after dopamine loss, Aim 2 will determine the anatomical and synaptic alterations in these two projection targets by measuring the evoked synaptic response of PV-GPe axons in the STN and pf using optical stimulation. To test whether the alterations in synaptic inputs is differential altered based on the genetically-defined populations, Aim 3 will use a combination of electrical and optical stimulation to identify sources of change in PV-GPe synaptic inputs in control and dopamine-depleted conditions. Together, we will test the hypothesis that PV-GPe neurons play a critical role in the behavioral and synaptic dysfunction associated with movement impairments. The long-term goal is to uncover the therapeutic potential of targeting a distinct neuronal population in the treatment of debilitating movement dysfunction in Parkinson's.