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（由适用提供）：大多数精神障碍患者（例如精神分裂症，阿尔茨海默氏症和帕金森氏病）发生睡眠问题，并且在许多其他疾病（例如疼痛，癌症，脑损伤，中风）中很常见。由神经精神疾病，其他疾病或工作/生活方式引起的嗜睡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，在驾驶过程中入睡）。许多人会用刺激物（例如咖啡馆）进行自我治疗，以临时恢复机敏性，而从临床上讲，患者被处方药，例如莫达非尼（Modafinil）来治疗过度的嗜睡。但是，当前的治疗策略会产生许多副作用（身体耐受性，依赖性等）。这是肯定需要确定可以利用的新药物机制来防止嗜睡并提高认知能力。我们的实验室和其他人的先前工作表明，基本前脑（BF）作为一个醒目的促进中心的意义。其皮质预测系统在调节活动，可塑性和认知中起着重要作用。我们的新型初步DAT表明，将嘌呤能P2受体（P2R）激动剂应用于BF中会增加体内的清醒性，并激发BF假定的皮质预测神经元的体外。因此，调查BF P2RS在睡眠觉醒调节中的作用可能有助于发现新颖的治疗靶标，这可以极大地使公众在消除嗜睡，改善认知表现并预防错误/事故方面受益匪浅。我们将测试我们的总体假设，即BF P2RS的激活通过激发腐蚀的BF神经元引起唤醒。这两个具体目标（SAS）将在小鼠模型中进行测试，SA1的瑞士 - 网络小鼠和最先进的转基因小鼠模型（GAD67-GFP敲入小鼠），该模型允许在记录SA2之前识别GABA神经元。 SA1将通过使用反向微透析的局部药物输注并测量用脑电图（EEG）/肌电图（EMG）记录技术来测量局部药物输注的BF P2R系统，直接测试P2RS的作用。我们将使用多种P2R激动剂（对P2XR与P2YRS类具有不同的选择性），并将P2XR拮抗剂共融合到BF中，以确定BF中的P2XRS或P2YRS是否参与促进唤醒。我们还将研究急性和慢性部分睡眠剥夺引起的嗜睡是否可以通过BF P2R激活来逆转，这是转化研究的重要第一步。 SA2将通过重点关注BF可靠的胆碱能和GABA能神经元来研究细胞机制。我们将使用全细胞斑块夹记录对P2R激动剂的单个细胞反应，并确定P2XR或P2YR是否负责这些响应。我们在这里提出的研究将在操纵皮质活性时提高我们对BF嘌呤能系统的理解，并可能有助于鉴定新的治疗靶标，以消除嗜睡和改善认知。