Excitability and plasticity alterations in a novel cerebellar stroke model

项目摘要 治疗小脑中风引起的运动和认知障碍的治疗方法的开发受到阻碍 由于我们目前缺乏老鼠模型来进行机械性的翻译研究。目前的提案 代表着向前迈出的重要一步，因为我们描述了一种新的可复制的小脑卒中动物模型 将用于表征小脑缺血性中风的功能后果，并开始发展 改善功能结果的策略。这项提议的目的是利用我们的新型鼠标 建立小脑卒中模型以阐明小脑卒中引起的神经网络改变。我们的中央 假设小脑缺血导致丘脑过度兴奋，从而扰乱感觉传递和 导致兴奋性：抑制性失衡。这一假说是在初步数据的基础上提出的。 在申请人的实验室中产生。提出这项研究的理由是，理解网络 中断将允许开发新的策略来改善神经功能，独立于 神经保护策略未能转化为。这一假设将通过追求三个具体的 目的：1)测试损伤的大小和位置是否与慢性神经损害相关，2)测试丘脑 小脑中风后兴奋性改变3)确定兴奋性和抑制性突触输入的变化 导致海马区可塑性缺陷的基因。在第一个目标下，已经有强劲的初步数据 在这个新的小脑卒中小鼠模型中展示运动和认知缺陷。在第二个和 第三个目标，我们将使用神经生理学来询问兴奋性和可塑性的变化 小脑中风。初步数据表明，小脑缺血性中风导致丘脑过度兴奋 以及海马区突触可塑性受损。这种方法具有创新性，因为它提供了一个重要的工具 进行机械性研究，从神经保护策略转向专注于恢复 延迟时间点的神经生理功能。这项拟议的研究具有重要意义，因为预计它将 扩大对导致长期赤字的网络变更的理解。最终，这样的一个 知识有可能为改善神经学的治疗策略的发展提供信息 中风患者的功能和生活质量。

Project Summary Development of therapies to treat the motor and cognitive deficits resulting from cerebellar stroke is hindered by our current lack of mouse models to perform mechanistic translational studies. The current proposal represents an important step forward, as we describe a new reproducible animal model of cerebellar stroke that will be used to characterize the functional consequences of cerebellar ischemic stroke and begin to develop strategies to improve functional outcomes. The objective of this proposal is to take advantage of our novel mouse model of cerebellar stroke to elucidate network alterations that result from cerebellar stroke. Our central hypothesis is that cerebellar ischemia causes thalamic hyperexcitability that disrupts sensory transmission and causes excitatory: inhibitory imbalance. This hypothesis was developed on the basis of preliminary data generated in the applicant’s laboratory. The rationale for the proposed research is that understanding network disruptions will allow for the development of novel strategies to improve neurological function independent of neuroprotective strategies that have failed to translate. The hypothesis will be tested by pursuing three specific aims: 1) test if injury size and location correlates with chronic neurological impairments, 2) test if thalamic excitability is altered after cerebellar stroke 3) determine alterations in excitatory and inhibitory synaptic inputs that contribute to hippocampal plasticity deficits. Under the first aim, there is already strong preliminary data to demonstrate motor and cognitive deficits in this novel mouse model of cerebellar stroke. Under the second and third aims, we will use a neurophysiological to interrogate excitability and plasticity changes resulting from cerebellar stroke. Preliminary data indicate that cerebellar ischemic stroke results in thalamic hyperexcitability and impaired hippocampal synaptic plasticity. The approach is innovative as it provides an important tool for performing mechanistic studies and moves away from neuroprotective strategies to focus on restoring neurophysiological function at delayed time points. The proposed research is significant as it is expected to expand understanding of network alterations that contribute to long-lasting deficits. Ultimately, such a knowledge has the potential to inform the development of therapeutic strategies that improve neurological function and quality of life for stroke patients.