Restoring Normal Output After Traumatic Brain Injury

脑外伤后恢复正常输出

基本信息

批准号：
9207489
负责人：
Akiva S Cohen
金额：
$ 21万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9207489
关键词：
Acetylcholine Action Potentials Affect Animals Area Basic Science Bathing Behavior Binding Brain Brain Injuries Cannabinoids Caring Cause of Death Cells Child Cholecystokinin Clinical Clinical Sciences Clozapine Cognition Coupled Couples DNA Sequence Development Direct Expenditure Economics Functional disorder G-substrate GTP-Binding Proteins Genetic Goals Healthcare Systems Hippocampus (Brain)Human Impaired cognition Impairment In Vitro Injection of therapeutic agent Injury Interneurons Intervention Lateral Learning Measures Mediating Medical Memory impairment Methods Mus Muscarinic Acetylcholine Receptor Mutate Myoepithelial cell Nature Neurologic Neurons Neuropeptides Output Oxides Pathology Patients Pharmacology Study Potassium Public Health Research Risk Rodent Seizures Services Slice Stimulus Study models Testing Translating Traumatic Brain Injury Treatment Efficacy United States Viral Work awake bench to bedside cell type conditioned fear cost design disability effective therapy fluid percussion injury hippocampal pyramidal neuron in vivo inhibitory neuron injured insight public health relevance repaired response synaptic inhibition young adult

项目摘要

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the primary cause of death and disability in children and young adults. TBI afflicts approximately two million people annually in the United States and no effective therapy exists. The neurological impairments associated with TBI include learning and memory deficits and increased risk of seizures. The hippocampus is critically involved in both of these phenomena and highly susceptible to damage by traumatic brain injury. Normal hippocampus-dependent cognition requires normal hippocampal output. TBI both diminishes hippocampal output and impairs hippocampus-dependent cognition. In area CA1 of the hippocampus the reduction in output after injury is due primarily to an increase in inhibition. In particular, inhibition from a subset of inhibitory neuros, the cholecystokinin (CCK) positive interneurons, was recently shown to increase after injury. CCK basket cell interneurons provide perisomatic inhibition and are instrumental in regulating action potential firing in CA1 pyramidal neurons, the output cells of the hippocampus. Stimulus-evoked action potentials in pyramidal neurons are significantly reduced after injury, and suppressing inhibition from CCK interneurons with the cannabinoid WIN55,212-2 was recently shown to restore normal stimulus-evoked action potentials in CA1 pyramidal neurons. The current proposal is designed to test the following CENTRAL HYPOTHESIS: Traumatic brain injury causes augmented inhibition from CCK interneurons in hippocampal area CA1. This increased inhibition diminishes hippocampal output and contributes to cognitive impairment. Selectively suppressing CCK interneurons in CA1 will restore normal hippocampal output and mitigate injury- induced cognitive impairment. We will test this hypothesis by measuring hippocampal output both in vitro and in vivo before and after activating the chemogenetic "neuronal silencer" hM4Di in CCK interneurons.. The development of effective therapeutic strategies for TBI will require a clear understanding of which cell types are affected, and a way to correct their underlying dysfunction. The current proposal is designed to meet these objectives, and will lay the groundwork for translational methods to target and repair TBI damaged neurons.

描述（由适用提供）：创伤性脑损伤（TBI）是儿童和年轻人死亡和残疾的主要原因。 TBI每年在美国影响大约200万人，并且不存在有效的治疗。与TBI相关的神经系统障碍包括学习和记忆定义并增加了癫痫发作的风险。海马在这类现象中非常重要，并且高度易受创伤性脑损伤的损害。正常的海马依赖性认知需要正常的海马输出。 TBI都会减少海马输出，并损害海马依赖性认知。在海马的CA1区域，受伤后输出的减少是由于抑制作用的增加。特别是，最近显示出抑制性神经元的抑制作用，即胆囊动蛋白（CCK）阳性中间神经元，最近显示出损伤后增加。 CCK篮细胞中神经元可提供par骨抑制作用，并有助于确定CA1锥体神经元（海马的输出细胞）中的动作电势发射。损伤后，锥体神经元中刺激诱发的作用电位显着降低，并且最近显示出与大麻素Win55,212-2抑制CCK中神经元的抑制作用，可恢复CA1锥体神经元中正常刺激诱发的动作电位。当前的建议旨在检验以下中心假设：脑外伤会导致海马区域CCK中间神经元CA1中CCK中间神经元的抑制作用。这种增加的抑制作用减少了海马产量，并导致认知障碍。有选择地抑制CA1中的CCK中间神经元将恢复正常的海马输出，并减轻损伤引起的认知障碍。我们将通过在激活CCK INTERNURONS中的化学遗传学“神经元消音器” HM4DI之前和之后测量体外和体内海马输出来检验这一假设。开发有效的TBI治疗策略，需要对哪些细胞类型进行清晰的了解，并纠正其无限型DydySfunution。当前的建议旨在实现这些目标，并将为靶向和修复TBI损坏神经元的转化方法奠定基础。