The Role of Mouse Motor Thalamus Realying Basal Ganglia Outflow

小鼠运动丘脑在基底神经节流出中的作用

基本信息

批准号：
8544549
负责人：
DIETER JAEGER
金额：
$ 12.53万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8544549
关键词：
Action Potentials Address Agonist Antiparkinson Agents Applications Grants Basal Ganglia Behavior Blood - brain barrier anatomy Brain Calcium Calcium Channel Calcium Channel Blockers Cell Nucleus Cerebral cortex Characteristics Disease Electric Stimulation Frequencies Human Injection of therapeutic agent Intervention Investigation Lead Lesion Link Membrane Potentials Modeling Motor Motor Cortex Mus Muscarinic Acetylcholine Receptor Muscarinics Neurons Operative Surgical Procedures Optics Output Parkinson Disease Parkinsonian Disorders Patients Pattern Pharmaceutical Preparations Pharmacological Treatment Preparation Primates Process Property Publications Rodent Rodent Model Role Shapes Signal Transduction Slice Structure Structure of subthalamic nucleus Symptoms Synapses Techniques Testing Thalamic structure Therapeutic Transgenic Mice Universities Validation Work awake behavior test channel blockers disease transmission in vivo innovation interest mouse model novel optogenetics public health relevance receptor response tool transmission process treatment strategy

项目摘要

We will examine how the motor thalamus In mouse models of Parkinson's disease (PD) Is Involved In transmitting Parkinsonian activity patterns generated In the basal ganglia to the cerebral cortex. We will use simultaneous electrophysiological recordings from basal ganglia, thalamus, and cortex In anesthetized and awake mice to determine the presence of pathological activity patterns, and their relations between structures. One strength of the proposal consists of the use of in vivo intracellular thalamic recordings, which will allow us to examine the hypothesis that strong basal ganglia bursting activity observed In PD will trigger postlnhibitory rebound bursting In thalamus. Previous work suggests that such bursting in the basal ganglia Is one of the characteristics of pathological activity patterns in PD, but the transmission of this activity through thalamus to cortex remains unclear. We will carry out a detailed analysis of the specific mechanisms of synaptic integration in motor thalamus of the mouse In the brain slice preparation, where we test the control of action potential initiation by Parkinsonian patterns of Input. Finally, we will determine whether pharmacological compounds known to Interact with thalamic cellular properties (M1 and M4 muscarinic receptor agonists or antagonists or selective Cav3 calcium channel blockers) can be used to reduce the transmission of pathological activity from the basal ganglia through thalamus to cortex. This project Is tightly Integrated with the other projects of the overall Emory Udall Center grant application: We share the focus on thalamic processing with project 2, where It will be examined In primates rendered parkinsonian with MPTP. We share the VMAT2L0 mouse model of PD with project 3, where It will be used to determine possible neuroprotective treatment strategies. Our analysis of pathological electrical activity patterns In the VMAT2L0 mouse developed by Dr. Miller at Emory will aid in the validation of this model. We obtain the pharmacological compounds to be tested for specific effect on thalamic processing through our interactions with project 4. These compounds mentioned above are promising novel specific receptor agonists and antagonists as well as channel blockers that are not otherwise available

我们将研究帕金森病 (PD) 小鼠模型中的运动丘脑如何参与将基底神经节产生的帕金森病活动模式传输到大脑皮层。我们将使用基底神经节、丘脑和皮质的同步电生理记录唤醒小鼠以确定病理活动模式的存在及其之间的关系结构。该提案的优势之一在于使用体内细胞内丘脑记录，这将使我们能够检验这样的假设：在 PD 中观察到的强基底神经节爆发活动将触发丘脑抑制后反弹爆发。先前的研究表明基底神经节的这种爆发是PD病理活动模式的特征之一，但这种活动的传播通过丘脑到皮质的途径仍不清楚。具体机制我们将进行详细分析小鼠运动丘脑中突触整合的影响在脑切片制备中，我们测试了通过帕金森输入模式控制动作电位的启动。最后，我们将确定是否已知与丘脑细胞特性相互作用的药理学化合物（M1 和 M4 毒蕈碱受体激动剂或拮抗剂或选择性 Cav3 钙通道阻滞剂）可用于减少病理活动从基底神经节通过丘脑传递到皮质。该项目与埃默里尤德尔中心整体拨款的其他项目紧密结合应用：我们与项目 2 一样关注丘脑加工，将在灵长类动物中进行检查用 MPTP 渲染帕金森病。我们与项目 3 共享 PD 的 VMAT2L0 小鼠模型，其中它将用于确定可能的神经保护治疗策略。我们对病理电的分析埃默里大学的 Miller 博士开发的 VMAT2L0 小鼠的活动模式将有助于验证这一点模型。我们获得待测试的药理学化合物对丘脑加工的具体影响通过我们与项目 4 的互动。上述这些化合物是有前途的新型特异性化合物受体激动剂和拮抗剂以及通道阻滞剂，这些药物是其他方法无法获得的