Rehabilitation Strategies for Memory Dysfunction after Traumatic Brain Injury

脑外伤后记忆障碍的康复策略

基本信息

批准号：
9130297
负责人：
COLEEN M. ATKINS
金额：
$ 44.37万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130297
关键词：
Acetylcholine Acute Affect Agonist Alzheimer&apos s Disease Aminobutyric Acids Animals Area Atrophic Binding Brain Injuries Cholinergic Agents Cholinergic Receptors Cholinesterase Inhibitors Chronic Clinical Clinical Research Clinical Trials Cognition Cognitive deficits Data Depressed mood Development Diagonal Band of Broca Dose Drug Kinetics Electrophysiology (science)FDA approved Fimbria of hippocampus Health Hippocampus (Brain)Impaired cognition Implant Injury Kinetics Knock-out Knockout Mice Learning Life Ligands Liquid substance Long-Term Potentiation Medial Memory Memory impairment Microglia Modeling Molecular Mus Neurons Operative Surgical Procedures Pathology Percussion Pharmacodynamics Pharmacological Treatment Pharmacology Phase Phase I Clinical Trials Phenotype Pre-Clinical Model Quality of life Rattus Recovery Reporting Research Proposals Schizophrenia Signal Transduction Slice Specificity Survivors Synapses Synaptic Transmission Synaptic plasticity Testing Therapeutic Theta Rhythm Time Translating Traumatic Brain Injury Wild Type Mouse alpha-bungarotoxin receptor awake base cholinergic cognitive function cognitive task controlled cortical impact desensitization disability improved improved outcome mind control multi-electrode arrays novel therapeutics positive allosteric modulator pre-clinical research preclinical study receptor rehabilitation strategy response sham surgery success white matter

项目摘要

DESCRIPTION (provided by applicant): Nearly 80% of people who have sustained a traumatic brain injury (TBI) report mild to moderate learning and memory impairments in the months to years following the initial brain trauma. Although there is some understanding of the changes that occur within the hippocampus after TBI, the underlying basis for learning deficits after TBI is still not completely understood. As a result, no FDA-approved pharmacological therapies are available to improve learning and memory deficits after TBI. The overarching objective of this proposal is to understand the chronic molecular mechanisms of learning and memory dysfunction after TBI and develop novel therapeutic strategies to translate to our chronic TBI survivors. An active area of both preclinical and clinical research is the use of cholinergic drugs to enhance cognition after TBI. Strong rationale exists for this therapeutic approach. Cholinergic receptors are important for modulating hippocampal long-term potentiation (LTP) and theta rhythm during spatial learning and cholinergic signaling is decreased after TBI. However, treatment with cholinesterase inhibitors or cholinergic receptor agonists have had limited clinical success. An exciting breakthrough has been the development of positive allosteric modulators of the α7 nicotinic AChR (nAChR). Positive allosteric modulators enhance current only when the receptor is bound to agonist. This maintains the natural spatial and temporal integrity of cholinergic signaling. Using AVL-3288, a positive allosteric modulator of the α7 nAChR, both hippocampal LTP and cognitive deficits were rescued in animals at 3 months after moderate fluid-percussion brain injury. Based on these preliminary data, the main hypothesis of this proposal is that targeting the α7 nAChR with a positive allosteric modulator will be sufficient to rescue LTP, improve theta oscillations, and promote cognitive functioning in the chronic recovery period of TBI. To test this hypothesis, the following aims are proposed: 1) To determine if positive allosteric modulation of α7 nAChRs is sufficient to restore hippocampal LTP and theta rhythms after TBI, 2) To determine if positive allosteric modulation of α7 nAChRs improves chronic cognitive deficits after TBI, and 3) To mechanistically determine if positive allosteric modulation of α7 nAChRs improves hippocampal synaptic plasticity and reduces chronic cognitive deficits after TBI through the α7 nAChR. Using two preclinical models of TBI, fluid-percussion brain injury and controlled cortical impact, and two animal species, rats and mice, AVL-3288 will be thoroughly and critically evaluated to determine if this therapeutic approach is efficacious. In addition, multielectrode array recordings will be utilized to determine how α7 nAChRs contribute to hippocampal circuitry changes after TBI. The clinical potential of these studies is very high given that AVL-3288 is already in Phase I clinical trials for cognitive impairment associated with schizophrenia. This proposal is supported by an interdisciplinary team with expertise in TBI, electrophysiology, cognition and pharmacology. Findings from this research proposal have the potential to be rapidly translated to clinical trials and will develop a new therapeutic for chronic TBI survivors to improve cognitio and quality of life.

描述（由适用提供）：近80％的脑损伤（TBI）的患者报告说，在最初的脑创伤后的几个月至几年中，学习和中度的学习和记忆力障碍。尽管对TBI之后海马体内发生的变化有一定的了解，但学习定义在TBI之后定义的基础仍未完全了解。结果，没有通过FDA批准的药物疗法来改善学习和记忆在TBI之后定义。该提案的总体目的是了解TBI后学习和记忆功能障碍的慢性分子机制，并制定新的治疗策略，以转化为我们的慢性TBI存活。临床前和临床研究的活性区域是使用胆碱能药物来增强TBI后的认知。这种治疗方法存在很强的理由。胆碱能受体对于在空间学习过程中调节海马长期潜力（LTP）和theta节律很重要，TBI后胆碱能信号传导降低。但是，用胆碱酯酶抑制剂或胆碱能受体的治疗动力学家的临床成功率有限。令人兴奋的突破是开发了α7烟碱ACHR（NACHR）的阳性变构调节剂。仅当受体与激动剂结合时，阳性变构调节剂才能增强电流。这保持了胆碱能信号传导的自然空间和暂时完整性。使用AVL-3288，α7NACHR的阳性变构调节剂，海马LTP和认知定义在中度液体 - 渗透脑损伤后3个月都在动物中做出了反应。基于这些初步数据，该提案的主要假设是，针对阳性变构调节剂的α7NACHR足以挽救LTP，改善theta振荡并在TBI慢性恢复期间促进认知功能。为了检验该假设，提出了以下目的：1）确定α7NACHR的阳性变构调节是否足以恢复TBI之后的海马LTP和THETA节律，2）确定α7NACHR的阳性变构是否能改善α7NACHR的阳性呈阳性，并在TBI之后的慢性不足，并确定3）的机制，即NACHR改善了海马突触可塑性，并通过TBI通过α7NACHR减少了慢性认知缺陷。使用TBI的两种临床前模型，流体 - 渗透脑损伤和受控的皮质影响，以及两种动物物种，大鼠和小鼠，AVL-3288将进行彻底和认真的评估，以确定这种治疗方法是否有效。此外，多电极阵列记录将利用用于确定α7NACHR如何在TBI后贡献海马电路的变化。鉴于AVL-3288已经处于I期，这些研究的临床潜力很高与精神分裂症相关的认知障碍的临床试验。该建议得到了一个跨学科团队的支持，该团队在TBI，电生理学，认知和药理学方面具有专业知识。这项研究建议的发现有可能快速转化为临床试验，并将为慢性TBI存活而开发一种新的治疗方法，以改善知识和生活质量。