Differential mechanisms and consequences of Purkinje cell loss in an adult and pediatric model of global cerebral ischemia

成人和儿童全脑缺血模型中浦肯野细胞丢失的不同机制和后果

• 批准号: 9096261
• 负责人: Nidia Quillinan
• 金额: $ 22.51万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096261
• 关键词: Acute; Address; Adolescent; Adult; Age; Ataxia; Behavioral; Birth; Blinking; Brain region; Calcium; Cardiopulmonary Resuscitation; Cell Death; Cerebellum; Cerebral Ischemia; Childhood; Cognitive; Corpus striatum structure; Data; Development; Electrophysiology (science); Excitatory Amino Acid Antagonists; Excitatory Synapse; Foundations; Future; Genetic; Health; Heart Arrest; Hippocampus (Brain); Image; Impairment; Injury; Ischemia; Knock-out; Laboratories; Learning; MK801; Mediating; Memory impairment; Modeling; Motor; Mus; Myocardial Infarction; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Pathway interactions; Patients; Play; Population; Purkinje Cells; Recovery; Reperfusion Injury; Research Proposals; Resuscitation; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; behavior test; cell injury; conditioning; design; excitotoxicity; functional disability; functional outcomes; glutamatergic signaling; improved; inhibitor/antagonist; live cell imaging; mouse model; neurobehavioral test; neuron loss; neurophysiology; prevent; receptor expression; receptor function; research study; therapeutic target

 DESCRIPTION (provided by applicant): Global ischemia caused by a heart attack results in motor, cognitive, memory deficits in the many patients who survive. Purkinje cells in the cerebellum are particularly sensitive to ischemic injury but few studies have focused on this population of neurons despite their key role in coordinating motor function. Purkinje cells undergo a late developmental onset of NMDA receptor expression at 4-6 weeks after birth. This suggests that glutamate signaling, plasticity and excitotoxicity mechanisms may be fundamentally different in juveniles versus adults. Using our laboratories pediatric and adult mouse models of cardiac arrest and cardiopulmonary resuscitation (CA/CPR) this proposal will test the hypothesis that injury mechanism in adult and pediatric mice converge on CAMKII activation to mediate injury. To address excitotoxicity mechanisms following CA/CPR, glutamate receptor antagonists and CAMKII inhibitors will be administered and Purkinje cell loss will be examined. This proposal will also examine the functional consequences of global cerebral ischemia on Purkinje cell excitability and motor coordination deficits. It will also examine whether plasticity and cerebellar dependent learning are impaired. Experiments outlined in this proposal will use electrophysiology, live cell imaging and neurobehavioral testing to investigate changes in the adult and juvenile after CA/CPR. Results obtained will further our understanding of injury mechanisms in Purkinje cells and help to identify therapeutic targets to improve motor coordination deficits after heart attack.

 描述（由申请人提供）：心脏病发作引起的全身缺血导致许多存活患者的运动、认知和记忆缺陷。小脑中的浦肯野细胞对缺血性损伤特别敏感，但很少有研究关注这群神经元，尽管它们在协调运动功能中起着关键作用。浦肯野细胞在出生后4-6周经历NMDA受体表达的晚期发育发作。这表明，谷氨酸信号，可塑性和兴奋性毒性机制可能是根本不同的青少年与成人。使用我们的实验室儿童和成年小鼠模型的心脏骤停和心肺复苏（CA/CPR），该提案将测试的假设，在成年和儿童小鼠的损伤机制收敛于CAMKII激活介导的损伤。为了解决CA/CPR后的兴奋性毒性机制，将给予谷氨酸受体拮抗剂和CAMKII抑制剂，并检查浦肯野细胞损失。这项建议也将检查浦肯野细胞兴奋性和运动协调缺陷的功能性后果的全脑缺血。它还将检查可塑性和小脑依赖性学习是否受损。本提案中概述的实验将使用电生理学，活细胞成像和神经行为测试来研究CA/CPR后成人和青少年的变化。获得的结果将进一步我们的浦肯野细胞损伤机制的理解，并有助于确定治疗目标，以改善心脏病发作后的运动协调缺陷。