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（由申请人提供）：创伤性脑损伤 (TBI) 是导致儿童和年轻人死亡和残疾的主要原因，在美国，TBI 每年影响大约 200 万人，并且不存在与 TBI 相关的神经损伤的有效治疗方法。包括学习和记忆缺陷以及癫痫发作的风险增加，海马体与这两种现象密切相关，并且极易受到创伤性脑损伤的损害。正常的海马体依赖性认知需要正常的海马体。 TBI 既减少了海马输出，又损害了海马 CA1 区的海马输出减少，主要是由于抑制作用的增加，特别是抑制性神经元的抑制，即胆囊收缩素输出 (CCK)。最近显示，CCK 篮状细胞中间神经元在损伤后增加，可提供体周抑制作用，有助于调节 CA1 锥体神经元（输出细胞）的动作电位放电。损伤后海马神经元的刺激诱发动作电位显着降低，最近显示用大麻素 WIN55,212-2 抑制 CCK 中间神经元的抑制可恢复 CA1 锥体神经元的正常刺激诱发动作电位。该提案旨在测试以下中心假设：创伤性脑损伤导致海马 CA1 区 CCK 中间神经元的抑制增强。抑制会减少海马输出并导致认知障碍，选择性抑制 CA1 中的 CCK 中间神经元将恢复正常海马输出并减轻损伤引起的认知障碍，我们将通过在激活化学遗传学之前和之后测量海马输出来检验这一假设。 CCK 中间神经元中的“神经元沉默器”hM4Di。开发 TBI 的有效治疗策略需要清楚地了解哪些细胞类型受到影响，以及纠正其潜在的方法目前的提案旨在实现这些目标，并将为靶向和修复 TBI 受损神经元的转化方法奠定基础。