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: 8258633
• 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/8258633
• 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）： 许多人由于医学和非医学原因减少了睡眠，这种模式称为慢性睡眠限制（CSR）。减少几天的睡眠仅2小时，可能会损害心血管，免疫和内分泌功能，以及认知和白天的警惕。诸如CSR之类的睡眠障碍伴随并加剧了许多影响美国退伍军人的医疗状况，包括PTSD，心脏病，精神疾病和慢性疼痛。在实验中，人类报告了企业社会责任的2或3天后主观嗜睡的归一化（即，仅4h或6h/night的3夜）；但是，客观的睡眠发作潜伏期措施表明嗜睡稳定增加。在CSR的14天内，认知表现也稳步下降。因此，人类适应了CSR的某些感知和神经生理后果，而其他效果则不能适应。 AIM 1中描述了大鼠中类似的CSR结果。由于CSR的动物模型相对缺乏，CSR的生物学后果很少研究。该提案的总体目标是了解使用大鼠模型的CSR行为/生理后果的神经生物学。雄性大鼠将被允许4、6、14或24小时/天的睡眠机会最多10天，然后进行5次恢复天。笼子运动用于产生清醒周期。大鼠很容易适应此过程，没有表现出不适或压力的迹象。总体神经生物学假设是抑制性神经调节剂腺苷（AD）介导了与CSR相关的嗜睡和认知障碍。该VA功绩赠款的先前发现支持了以下假设：AD是短期睡眠损失后嗜睡的中介者，在这种作用中，其对基础前脑醒目神经元的抑制作用似乎尤为重要。短时间的睡眠损失还会增加AD A1受体mRNA，支持我们的预测，即CSR将增加A1受体数量以保持升高水平AD抑制性张力（即阳性反馈）。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惕性表现有何影响？ （使用睡眠记录，睡眠潜伏期测试和持续关注的操作测试）。预计CSR会在大鼠（如人类中）产生嗜睡和认知障碍。目标2。企业社会责任对空间学习和记忆（水迷宫）以及长期增强的影响是什么（LTP；对记忆形成重要的突触可塑性的量度）。我们预测，CSR诱导的空间记忆障碍是通过降低LTP的海马广告音调的增加来介导的。目标3。企业社会责任对脑广告音调有什么影响？ （测量脑细胞外广告水平； AD A1和A2A受体mRNA，A1密度和结合）。 AD受体的预测增加会改变对AD药物的行为和生理反应吗？在企业社会责任的第一天，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受体的变化保持了大脑中AD抑制水平的升高。 公共卫生相关性： 项目叙事与退伍军人的健康和/或医疗保健问题。所有人类的生命，甚至所有哺乳动物的生活都是由清醒和睡眠的时期塑造的，因此对基本机制的了解具有很大的生物学，社会和医学意义。对大脑如何调节自然睡眠的理解有望为影响退伍军人人群的睡眠障碍的理性发展提供基础，例如睡眠呼吸暂停，睡眠，失眠，失眠和与PTSD和创伤性脑损伤有关的睡眠障碍。关于内源性神经睡眠因素（例如腺苷）的基础研究可能会导致新一代的药物治疗失眠症，而相反，可以促进注意力和警惕。这项研究线的重要性强调了神经科学实验室主任罗伯特·W·麦卡利（Robert W. McCarley）根据实验室的腺苷工作，于2000年获得了米德尔顿奖。慢性睡眠限制的大鼠模型提出的外部有效性很高，因为我们社会中的许多人习惯地减少了他们获得的睡眠量。最近建立的慢性睡眠限制动物模型将为各种研究水平（从分子事件到行为影响）提供机会。 白天过度的嗜睡和保持警觉性的困难是非常普遍的医疗投诉，在老年男性（例如美国退伍军人）中的患病率更高。慢性睡眠限制会导致或加剧嗜睡症状，从而导致职业表现和安全性受损，并影响一般健康和生活质量。对于活跃的军事人员，居住培训中的医生以及紧急和运输工人的工作，在有限的睡眠条件下高水平表演的能力也非常重要。因此，对慢性睡眠限制的行为和神经生物学后果的更好理解对于退伍军人人口的医疗保健很重要。认识到睡眠卫生对VA医疗保健系统的重要性，我们最近开始研究一种慢性睡眠限制的动物模型。可以预期，这项研究将很快使VA人口受益。例如，在2年内，我们开发的大鼠模型将用于测试影响警觉性和睡眠的药物。此后不久，我们的合作者进行人类研究，可以进行实验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临床研究的直接途径，这可能会改善对退伍军人的医疗保健。