The Role of Mouse Motor Thalamus Realying Basal Ganglia Outflow

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氏症活动模式传递到大脑皮层。我们将使用 同时记录基底神经节、丘脑和皮质的电生理记录， 唤醒小鼠，以确定病理活动模式的存在，以及它们之间的关系 结构.该建议的一个优点是使用体内细胞内丘脑记录， 将使我们能够检验在PD中观察到的强基底神经节爆发活动将触发 丘脑中出现抑制后的反弹。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 从丘脑到大脑皮层还不清楚我们将对具体机制进行详细分析 在脑切片制备中，我们测试了小鼠运动丘脑中的突触整合。 通过帕金森输入模式控制动作电位起始。最后，我们将确定 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钙通道阻断剂）可用于降低 病理活动从基底神经节经丘脑向皮质的传递。 该项目与埃默里尤德尔中心赠款的其他项目紧密结合 应用：我们与项目2分享对丘脑处理的关注，在项目2中，它将在灵长类动物中进行检查 MPTP导致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。我们对病理性电流的分析 由埃默里大学的米勒博士开发的VMAT 2L 0小鼠的活动模式将有助于验证这一点。 模型我们获得了待测试对丘脑加工的特定作用的药理学化合物 通过我们与项目4的互动这些化合物是很有前途的新型特效药 受体激动剂和拮抗剂以及通道阻滞剂

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