Impact of sleep apnea exacerbation on brain cholinergic signaling and cognition

睡眠呼吸暂停加重对大脑胆碱能信号和认知的影响

基本信息

批准号：
9336425
负责人：
Irina Topchiy
金额：
$ 39.41万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
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：
2016-09-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9336425
关键词：
Activities of Daily Living Acute Address Adherence Affect Agonist Alcohol consumption American Apnea Area Autoreceptors Brain Brain region Carbachol Cholinergic Receptors Chronic Cognition Cognitive Cognitive deficits Complex Corpus striatum structure Data Development Disease Dorsal Drug Targeting EKG P Wave Episodic memory Exhibits Female Fostering Frequencies Functional disorder Goals Health Hippocampus (Brain)Hyperoxia Hypersensitivity Impaired cognition Individual Infection Intervention Knowledge Laboratories Learning Literature Memory Memory impairment Microdialysis Modeling Muscarinic Acetylcholine Receptor M3 Muscarinics Neurons Non-Prescription Drugs Output Patients Pedunculopontine Tegmental Nucleus Performance Process Productivity Psyche structure Public Health Quality of life REM Sleep Rattus Rattus norvegicus Receptor Signaling Research Research Project Grants Research Proposals Reversal Learning Sampling Short-Term Memory Signal Transduction Sleep Sleep Apnea Syndromes System Testing Translating Wakefulness Work alertness behavior test cholinergic cholinergic neuron clinical investigation cognitive function cognitive performance effective therapy experience extracellular flexibility hypnotic improved individualized medicine insight male neurochemistry postsynaptic pressure presynaptic receptor respiratory sedative septohippocampal sustained attention

项目摘要

DESCRIPTION (provided by applicant): Most of the approximately 20 million Americans afflicted with sleep related breathing disorders (SRBD) develop cognitive deficits in areas such as alertness, sustained attention, working and long-term episodic memory, ability to learn new information and mental flexibility. Despite decades of research, clinical investigations have not clarified the mechanisms by which SRBD produce cognitive impairment. These cognitive impairments can be particularly debilitating following acute apnea exacerbation. This is an important problem as individuals with chronic SRBD often experience acute exacerbations inter-current to use of alcohol, sedative or hypnotic use, infections, allergies or poor adherence to positive airway pressure therapy. Very little is understood about how acute apnea exacerbation affects brain systems critical for cognition. Recent findings from our laboratory showed in Brown-Norway rats, which exhibit a moderate level of spontaneous sleep apneas, that acute apnea exacerbation produced both reversal learning and working memory deficits. Moreover, there is accumulating evidence that cholinergic signaling in the pedunculopontine tegmental nucleus (PPT), septohippocampal complex and dorsomedial striatum support working memory and cognitive flexibility. A central hypothesis of this research proposal is that acute exacerbatio of spontaneous sleep-related apnea perturbs brain cholinergic signaling, contributing to impaired cognitive functioning. Better understanding of how apnea exacerbation affects brain cholinergic signaling may provide new insights into SRBD pathophysiology and development of effective treatments to alleviate cognitive deficits attendant to acute apnea exacerbation. The proposed project will systematically investigate how acute apnea exacerbation affects brain cholinergic signaling at a cellular, extracellular and receptor level in multiple brain regions tha relates to working memory and cognitive flexibility deficits. This will be conducted in both male and female rats. Aim 1 will define the effect of apnea exacerbation on bursting of PPT cholinergic neurons. Aim 2 will test the hypothesis that acute exacerbation of SRBD alters ACh output in PPT, septohippocampal complex and dorsomedial striatum during sleep, wake and/or cognitive performance. Aim 3 will test the hypothesis that manipulation of muscarinic cholinergic receptor activity in the PPT, septohippocampal complex and/or dorsomedial striatum before acute apnea exacerbation or prior to behavioral testing can alleviate deficits in working memory and reversal learning. Our overall aim is to foster the development of important new knowledge regarding the neurochemical mechanisms underlying cognitive deficits induced by acute apnea exacerbation that can translate into better and individualized treatment approaches.

描述（由适用提供）：大约有2000万美国人患有与睡眠有关的呼吸障碍（SRBD）在诸如机敏，持续关注，工作和长期情节记忆，学习新信息和精神灵活性等领域的认知缺陷。尽管进行了数十年的研究，但尚未阐明SRBD产生认知障碍的机制。急性呼吸暂停执行后，这些认知障碍可能会特别使人衰弱。这是一个重要的问题，因为患有慢性SRBD的个体通常会经常经历急性执行，用于使用酒精，镇静或催眠的使用，感染，过敏或对阳性气道压力疗法的依从性不佳。关于急性呼吸暂停执行如何影响认知至关重要的大脑系统的理解很少。我们的实验室的最新发现显示了现代的赞助睡眠呼吸暂停，急性呼吸暂停会导致学习和工作记忆不足。此外，有累积的证据表明，Pedunculopontine Technologus（PPT），Septohappocampal复合物和背侧纹状体支持工作记忆和认知灵活性的胆碱能信号传导。该研究提案的一个核心假设是，赞助与睡眠相关的呼吸暂停的急性发病症脑胆碱能信号传导，这有助于认知功能受损。更好地理解呼吸暂停如何影响脑胆碱能信号传导可能会为SRBD病理生理学和开发有效治疗以减轻急性呼吸暂停加剧的认知防御能力。拟议的项目将系统地研究急性呼吸暂停加重如何在多个大脑区域的细胞，细胞外和接收器水平上影响与工作记忆和认知灵活性不足的关系。这将在男性和雌性大鼠中进行。 AIM 1将定义呼吸暂停加重对PPT胆碱能神经元爆发的影响。 AIM 2将检验以下假设：在睡眠，唤醒和/或认知表现过程中，SRBD的急性加重会改变PPT，Septohampocampal复合物和背部纹状体的ACH输出。 AIM 3我们将测试以下假设：在急性呼吸暂停之前或行为测试之前，PPT，Septohappocampal复合物和/或背侧纹状体中毒蕈碱胆碱能受体活性的操纵可以减轻工作记忆和逆向学习中的缺陷。我们的总体目的是促进有关急性呼吸暂停引起的认知缺陷的神经化学机制的重要新知识的发展，这些知识可以转化为更好和个性化的治疗方法。