Basal forebrain purinergic P2 receptor mechanisms of sleep-wake regulation

基底前脑嘌呤能P2受体睡眠-觉醒调节机制

基本信息

批准号：
9112174
负责人：
Chun Yang
金额：
$ 6.44万
依托单位：
HARVARD MEDICAL SCHOOL
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：
2016-06-23 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9112174
关键词：
Accidents Action Potentials Acute Adenosine Adenosine Triphosphate Adverse effects Agonist Alzheimer&apos s Disease Animal Model Animals Arousal Attenuated Automobile Driving Bathing Behavior Brain Brain Injuries Brain region Caffeine Cations Cells Cessation of life Chronic Cognition DNQX Data Dependence Development Disease Drowsiness Drug Tolerance Effectiveness Electroencephalogram Energy-Generating Resources Excision General Population Glutamates Health Homeostasis Impaired cognition Impairment In Vitro Individual Infusion procedures Investigation Knock-in Mouse Laboratories Lead Life Life Style Light Measures Mediating Mediator of activation protein Medicine Membrane Mental disorders Microdialysis Modafinil Mus Neuroglia Neurons Organism Parkinson Disease Patients Performance Pharmaceutical Preparations Play Presynaptic Terminals Productivity Property Purinergic P1 Receptors Purinergic P2 Receptors Quality of life Receptor Activation Recovery Regulation Research Role Safety Schizophrenia Sleep Sleep Deprivation Sleep Disorders Sleep Fragmentations Slice Stroke System Techniques Testing Tetrodotoxin Time Transgenic Mice Traumatic Brain Injury Wakefulness Work alertness analog basal forebrain base cancer pain cell type cellular targeting cholinergic cognitive performance falls gamma-Aminobutyric Acid improved in vivo mouse model nervous system disorder neuropsychiatric disorder neuropsychiatry new therapeutic target novel patch clamp presynaptic prevent public health relevance pyridoxal phosphate-6-azophenyl-2&apos ,4&apos -disulfonic acid receptor response therapeutic target translational study treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Sleep problems occur in most people with mental disorders (e.g. Schizophrenia, Alzheimer's and Parkinson's diseases) and are common in many other disorders (e.g. pain, cancer, brain injury, stroke). Drowsiness caused by neuropsychiatric conditions, other disorders or work/life-style has a negative impact on our health & cognitive performance and sometimes can even lead to death (e.g. falling asleep during driving). Many people self-medicate with stimulants such as caffeine to temporarily restore alertness, while clinically, patients are prescribed medications such as modafinil to treat excessive sleepiness. However, current treatment strategies produce many side effects (physical tolerance, dependence, etc.). Thus, there is a substantial need to identify new pharmacological mechanisms that can be utilized to prevent drowsiness, and improve cognitive performance. Previous work from our laboratory and others has demonstrated the significance of basal forebrain (BF) as a wakefulness-promoting center. Its cortically-projecting systems play an important role in regulating cortical activity, plasticity and cognition. Our novel preliminary dat suggest that a purinergic P2 receptor (P2R) agonist applied into BF increases wakefulness in vivo and excites BF putative cortically-projecting neurons in vitro. Therefore, investigation of BF P2Rs' role in sleep-wake regulation may contribute to the discovery of novel therapeutic targets, which can greatly benefit the general public in removing drowsiness, improving cognitive performance and preventing errors/accidents. We will test our overarching hypothesis that activation of BF P2Rs induces wakefulness by exciting cortically-projecting BF neurons. Both specific aims (SAs) will be tested in mouse models, with Swiss-Webster mice for SA1 and a state-of-the-art transgenic mouse model (GAD67-GFP knock-in mice) which allows the identification of GABA neurons prior to recording for SA2. SA1 will directly test the role of P2Rs by specifically stimulating the BF P2R system with local drug infusion using reverse microdialysis and measuring the changes of sleep-wake states and power spectra with electroencephalogram (EEG)/electromyogram (EMG) recording techniques. We will use multiple P2R agonists (with different selectivity to class P2XRs vs class P2YRs) and co-infusion of a P2XR antagonist into BF to determine whether P2XRs or P2YRs in BF are involved in promoting wakefulness. We will also investigate if acute and chronic partial sleep-deprivation-induced drowsiness can be reversed with BF P2R activation, an essential first step towards translational studies. SA2 will investigate the cellular mechanisms by focusing on BF cortically-projecting cholinergic and GABAergic neurons. We will use whole-cell patch clamp to record the individual cellular responses to the P2R agonists and determine if P2XRs or P2YRs are responsible for these responses. Our study proposed here will advance our understanding of the BF purinergic system in manipulating cortical activity and could contribute to the identification of novel therapeutic targets for removing drowsiness and improving cognition.

描述（由申请人提供）：大多数精神障碍患者（例如精神分裂症、阿尔茨海默病和帕金森病）都会出现睡眠问题，并且在许多其他疾病（例如疼痛、癌症、脑损伤、中风）中也很常见。其他疾病或工作/生活方式会对我们的健康和认知表现产生负面影响，有时甚至会导致死亡（例如，在驾驶过程中睡着）。使用咖啡因等兴奋剂来暂时恢复警觉性，而临床上则给患者开莫达非尼等药物来治疗过度嗜睡。然而，目前的治疗策略会产生许多副作用（身体耐受性、依赖性等）。我们实验室和其他人之前的工作已经证明了基底前脑（BF）作为觉醒促进中心的重要性。皮质投射系统在调节皮质活动、可塑性和认知方面发挥着重要作用，我们的新初步数据表明，应用于 BF 的嘌呤能 P2 受体 (P2R) 激动剂可增加体内的清醒度，并在体外激发 BF 假定的皮质投射神经元。、BF的调查 P2R 在睡眠-觉醒调节中的作用可能有助于发现新的治疗靶点，这可以极大地有益于公众消除睡意、提高认知能力和预防错误/事故。我们将测试我们的总体假设，即 BF P2R 的激活会诱发这种假设。通过刺激皮质投射 BF 神经元来实现觉醒。这两个特定目标 (SA) 将在小鼠模型中进行测试，其中 SA1 的 Swiss-Webster 小鼠和最先进的转基因小鼠模型。（GAD67-GFP 敲入小鼠）允许在记录 SA2 之前识别 GABA 神经元，SA1 将通过使用反向微透析通过局部药物输注特异性刺激 BF P2R 系统并测量睡眠的变化来直接测试 P2R 的作用。 -使用脑电图 (EEG)/肌电图 (EMG) 记录技术的唤醒状态和功率谱我们将使用多种 P2R 激动剂（对 P2XR 类与类的选择性不同）。 P2YRs）和将 P2XR 拮抗剂共同注入 BF 中，以确定 BF 中的 P2XR 或 P2YR 是否参与促进觉醒。我们还将研究是否可以通过 BF P2R 激活来逆转急性和慢性部分睡眠剥夺引起的嗜睡。 SA2 将通过关注 BF 皮质投射胆碱能和 GABA 神经元来研究细胞机制。将使用全细胞膜片钳记录单个细胞对 P2R 激动剂的反应，并确定 P2XR 或 P2YR 是否负责这些反应。我们在此提出的研究将增进我们对 BF 嘌呤能系统在操纵皮质活动中的理解，并可能有助于促进这些反应。确定消除睡意和改善认知的新治疗靶点。