Adenosine and the Basal Forebrain in the Control of Behavioral State

腺苷和基底前脑控制行为状态

• 批准号: 7687191
• 负责人: ROBERT E STRECKER
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687191
• 关键词: Adenocarcinoma Cell; Adenosine; Adenosine A1 Receptor; Affect; Agar; Animal Model; Apoptosis; Attention; Award; Basic Science; Behavior Control; Behavioral; Behavioral Symptoms; Binding; Biological; Biological Assay; Brain; Cardiovascular system; Caring; Cell Cycle; Cell Death; Cell Proliferation; Cessation of life; Chronic; Clinical Data; Clinical Research; Clinical Trials; Cognition; Cognitive; Coupled; Data; Development; Emergency Situation; Endocrine; Epigenetic Process; Erinaceidae; Event; Excessive Daytime Sleepiness; FDA approved; Feedback; Flow Cytometry; Generations; Genetic; Goals; Grant; Growth; Health; Healthcare; Healthcare Systems; Heart Diseases; Hippocampus (Brain); Histones; Histopathology; Human; Hygiene; Image; Immune; Impaired cognition; Intervention; Investigation; Knowledge; Laboratories; Lead; Learning; Life; Long-Term Potentiation; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammals; Measures; Mediating; Mediator of activation protein; Medical; Memory; Memory impairment; Mental disorders; Messenger RNA; Microscopic; Military Personnel; Modeling; Molecular; Molecular Genetics; Motion; Mus; Names; Narcolepsy; Neurobiology; Neuromodulator; Neurons; Neurosciences; Occupational; Pancreas; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Pattern; Performance; Pharmaceutical Preparations; Physiological; Population; Post-Traumatic Stress Disorders; Prevalence; Procedures; Purinergic P1 Receptors; Quality of life; RNA; Rattus; Recovery; Regimen; Relative (related person); Reporting; Research; Research Personnel; Residencies; Resistance; Role; Safety; Shapes; Signal Transduction; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Sleep disturbances; Sleeplessness; Societies; Sonic Hedgehog Pathway; Stress; Symptoms; Synaptic plasticity; Testing; Therapeutic; Toxic effect; Training; Transportation; Traumatic Brain Injury; Treatment Efficacy; Veterans; Vorinostat; Wakefulness; Water; Work; Xenograft procedure; alertness; basal forebrain; base; cancer cell; chemotherapeutic agent; chronic pain; density; design; drug testing; extracellular; human SMO protein; improved; in vivo; inhibitor/antagonist; innovation; male; neurophysiology; novel; novel strategies; pancreatic cancer cells; pancreatic neoplasm; pre-clinical; protein function; public health relevance; receptor; relating to nervous system; research study; resistance mechanism; response; sleep onset; smoothened signaling pathway; social; success; therapy development; tumor; tumor growth; vigilance

DESCRIPTION (provided by applicant): Many people reduce their sleep due to medical and non-medical reasons, a pattern that is called chronic sleep restriction (CSR). Reducing sleep for as little as 2 h for several days can impair cardiovascular, immune, and endocrine functions, as well as cognition and daytime vigilance. Sleep disturbances, such as CSR, accompany and aggravate many medical conditions affecting US veterans including PTSD, heart disease, psychiatric disorders, and chronic pain. In experiments, humans report a normalization of subjective sleepiness after as little as 2 or 3 days of CSR (i.e., 3 nights of sleeping only 4h or 6h/night); however, objective sleep onset latency measures indicate that sleepiness increases steadily. Cognitive performance also declines steadily over 14 days of CSR. Thus, humans adapt to some of the perceptual and neurophysiological consequences of CSR, whereas other effects do not adapt. Similar CSR results in rats are described in Aim 1. The biological consequences of CSR have been little investigated due to the relative lack of animal models of CSR. The overall goal of this proposal is to understand the neurobiology underlying the behavioral/physiological consequences of CSR using a rat model. Male rats will be allowed 4, 6, 14, or 24h/day of sleep opportunity for up to 10 days, followed by 5 recovery days. Cage motion is used to produce the periods of wakefulness. Rats adapt readily to this procedure and show no signs of discomfort or stress. The overarching neurobiological hypothesis is that the inhibitory neuromodulator adenosine (AD) mediates the sleepiness and cognitive impairments associated with CSR. The previous findings of this VA merit grant support the hypothesis that AD is a mediator of the sleepiness that follows short periods of sleep loss, a role in which its inhibitory action on the basal forebrain wakefulness-promoting neurons appears especially important. Short periods of sleep loss also increase AD A1 receptor mRNA, supporting our prediction that CSR will increase A1 receptor number in order to maintain elevated levels AD inhibitory tone (i.e., positive feedback). The proposed aims will answer the following questions: Aim 1. What are the effects of CSR on sleepiness and vigilance performance? (using sleep recordings, sleep latency tests, and operant tests of sustained attention). CSR is predicted to produce sleepiness and cognitive impairments in rats (like in humans). Aim 2. What is the effect of CSR on spatial learning and memory (water maze), and on long term potentiation (LTP; a measure of synaptic plasticity important for memory formation). We predict that the CSR-induced spatial memory impairments are mediated by an increase in hippocampal AD tone which reduces LTP. Aim 3. What is the effect of CSR on brain AD tone? (measuring brain extracellular AD levels; AD A1 & A2a receptor mRNA, A1 density & binding). Do the predicted increases in AD receptors alter the behavioral & physiological response to AD drugs? On the first day of CSR, we predict that the behavioral symptoms will correlate with an elevation of BF AD levels, whereas on CSR days 3-10, changes in A1 & A2a receptors maintain elevated levels of AD inhibition in the brain. PUBLIC HEALTH RELEVANCE: Project Narrative Relevance to Veterans' health and/or healthcare issues. All human life, and indeed the life of all mammals, is shaped by periods of wakefulness and sleep, and thus knowledge of the underlying mechanisms is of great biological, social and medical significance. An understanding of how the brain regulates natural sleep holds the promise of providing a basis for the rational development of treatments for sleep disorders affecting the veteran population, such as sleep apnea, narcolepsy, insomnia, and sleep disturbance related to PTSD and traumatic brain injury. Basic research on endogenous neural sleep factors, such as adenosine, could lead to a new generation of medications to both treat insomnia and, conversely, promote attention & vigilance. The significance of this line of research is underscored by the fact that Robert W. McCarley, Director of the Lab of Neuroscience, received the Middleton Award in 2000 based on the adenosine work of the laboratory. The rat model of chronic sleep restriction proposed has high external validity, as many people in our society habitually reduce the amount of sleep they obtain. The recent establishment of an animal model of chronic sleep restriction will provide opportunities for studies aimed at all levels of investigation (from molecular events to behavioral effects). Excessive daytime sleepiness and difficulty maintaining alertness are very common medical complaints, with even greater prevalence in older males, such as the population of US veterans. Chronic sleep restriction can cause or aggravate the symptoms of sleepiness leading to impaired occupational performance and safety, as well as impacting on general health and quality of life. The ability to perform at a high level under the condition of limited sleep is also very important to active military personnel, doctors in residency training, and emergency & transportation workers, just to name a few. Hence, a better understanding of the behavioral and neurobiological consequences of chronic sleep restriction is important for the health care of the veteran population. Recognizing the importance sleep hygiene for the VA healthcare system, we recently began work on an animal model of chronic sleep restriction. This research can be expected to benefit the VA population rather quickly. For example, within 2 yr, the rat models we have developed will be available for testing drugs influencing alertness and sleep. Clinical trials of experimental medications or interventions could follow shortly thereafter via our collaborators doing human research. In conclusion, there is a direct path from our studies on animal models to related clinical research, which could lead to improved medical care of veterans.

描述（由申请人提供）： 许多人由于医疗和非医疗原因而减少睡眠，这种模式称为慢性睡眠限制（CSR）。连续几天减少睡眠只要 2 小时就会损害心血管、免疫和内分泌功能，以及认知和白天的警惕性。睡眠障碍（例如 CSR）会伴随并加剧影响美国退伍军人的许多健康状况，包括创伤后应激障碍（PTSD）、心脏病、精神疾病和慢性疼痛。在实验中，人类报告说，在短短 2 或 3 天的 CSR 后（即 3 个晚上每晚只睡 4 小时或 6 小时），主观睡意就恢复正常；然而，客观的入睡潜伏期测量表明，睡意稳步增加。在 CSR 的 14 天内，认知表现也会稳步下降。因此，人类适应了企业社会责任的一些感知和神经生理学后果，而其他影响则不适应。目标 1 中描述了大鼠中类似的 CSR 结果。由于相对缺乏 CSR 动物模型，CSR 的生物学后果很少被研究。该提案的总体目标是利用大鼠模型了解企业社会责任的行为/生理后果背后的神经生物学。雄性大鼠每天有 4、6、14 或 24 小时的睡眠机会，持续最多 10 天，然后是 5 天的恢复天。笼子运动用于产生觉醒周期。老鼠很容易适应这一过程，并且没有表现出不适或压力的迹象。最重要的神经生物学假设是，抑制性神经调节剂腺苷 (AD) 介导与 CSR 相关的嗜睡和认知障碍。这项 VA 奖学金的先前研究结果支持这样的假设：AD 是短期睡眠缺失后嗜睡的调节因素，其对基底前脑促觉醒神经元的抑制作用显得尤为重要。短期睡眠不足也会增加 AD A1 受体 mRNA，支持我们的预测，即 CSR 将增加 A1 受体数量，以维持 AD 抑制音水平升高（即正反馈）。拟议的目标将回答以下问题： 目标 1. 企业社会责任对嗜睡和警觉表现有何影响？ （使用睡眠记录、睡眠潜伏期测试和持续注意力的操作测试）。预计企业社会责任会导致大鼠（就像人类一样）出现困倦和认知障碍。目标 2. CSR 对空间学习和记忆（水迷宫）以及长时程增强（LTP；对记忆形成很重要的突触可塑性的测量）有什么影响。我们预测 CSR 引起的空间记忆障碍是由海马 AD 张力增加介导的，从而降低了 LTP。目标 3. CSR 对大脑 AD 张力有何影响？ （测量脑细胞外 AD 水平；ADA1 和 A2a 受体 mRNA、A1 密度和结合）。 AD 受体的预测增加是否会改变对 AD 药物的行为和生理反应？在 CSR 的第一天，我们预测行为症状将与 BF AD 水平的升高相关，而在 CSR 第 3-10 天，A1 和 A2a 受体的变化会维持大脑中 AD 抑制水平的升高。 公共卫生相关性： 项目叙述与退伍军人健康和/或医疗保健问题的相关性。所有人类的生命，实际上是所有哺乳动物的生命，都是由清醒和睡眠的时期决定的，因此了解其潜在机制具有重大的生物学、社会和医学意义。了解大脑如何调节自然睡眠有望为合理开发影响退伍军人群体的睡眠障碍（例如睡眠呼吸暂停、发作性睡病、失眠以及与 PTSD 和创伤性脑损伤相关的睡眠障碍）的治疗方法奠定基础。对内源性神经睡眠因子（例如腺苷）的基础研究可能会产生新一代药物，既可以治疗失眠，又可以提高注意力和警惕性。神经科学实验室主任罗伯特·W·麦卡利 (Robert W. McCarley) 因实验室在腺苷方面的工作而于 2000 年获得了米德尔顿奖，这一事实凸显了这一研究领域的重要性。所提出的慢性睡眠限制的大鼠模型具有很高的外部效度，因为我们社会中的许多人习惯性地减少他们获得的睡眠量。最近建立的慢性睡眠限制动物模型将为针对各个层面（从分子事件到行为影响）的研究提供机会。 白天过度嗜睡和难以保持警觉是非常常见的医疗投诉，在老年男性中患病率更高，例如美国退伍军人群体。长期睡眠限制会导致或加重嗜睡症状，从而导致职业表现和安全受损，并影响总体健康和生活质量。在睡眠有限的情况下保持高水平表现的能力对于现役军人、住院医师培训医生以及急救和运输人员等也非常重要。因此，更好地了解长期睡眠限制的行为和神经生物学后果对于退伍军人群体的医疗保健非常重要。认识到睡眠卫生对于退伍军人管理局医疗保健系统的重要性，我们最近开始研究慢性睡眠限制的动物模型。这项研究预计将很快使退伍军人管理局人口受益。例如，在两年内，我们开发的大鼠模型将可用于测试影响警觉性和睡眠的药物。此后不久，我们的合作者可能会进行人体研究，进行实验性药物或干预措施的临床试验。总之，从我们对动物模型的研究到相关的临床研究有直接的途径，这可以改善退伍军人的医疗保健。