Excitability and plasticity alterations in a novel cerebellar stroke model

项目摘要 治疗小脑卒中导致的运动和认知缺陷的疗法的开发受到阻碍 我们目前缺乏小鼠模型来进行机械翻译研究。现时的建议 代表了向前迈出的重要一步，因为我们描述了一种新的可重复的小脑中风动物模型， 将用于表征小脑缺血性卒中的功能后果，并开始发展 改善功能成果的战略。这个提案的目的是利用我们的新型鼠标 小脑中风模型，以阐明小脑中风导致的网络改变。我们的中央 一种假说是小脑缺血引起丘脑过度兴奋，破坏感觉传递， 导致兴奋性和抑制性失衡。这一假设是根据初步数据提出的 在申请人的实验室中生成。提出研究的理由是，理解网络 中断将允许开发新的策略来改善神经功能， 神经保护策略的失败。该假设将通过追求三个具体的测试 目的：1）测试损伤的大小和位置是否与慢性神经损伤相关，2）测试丘脑是否 小脑中风后兴奋性改变3）决定兴奋性和抑制性突触输入的改变 导致海马体可塑性缺陷在第一个目标下，已经有了强有力的初步数据， 在这个新的小脑中风小鼠模型中证明了运动和认知缺陷。在第二和 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 海马突触可塑性受损这种方法是创新的，因为它提供了一个重要的工具， 进行机制研究，从神经保护策略转向专注于恢复 在延迟的时间点的神经生理功能。这项研究具有重要意义，因为它有望 扩大对导致长期缺陷的网络变化的理解。最终，这样一个 知识有可能为改善神经系统疾病的治疗策略的发展提供信息。 功能和生活质量的影响。

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.