"Uncoupling sleep deprivation-associated stressors from sleep loss in rodents"

描述(申请人提供)：许多关于大脑睡眠机制的结论来自动物睡眠剥夺(SD)实验。然而，动物的SD是由动物SD研究中使用的不可控制的(从动物的角度来看)厌恶刺激引起的。相比之下，人体实验中的睡眠不足是自愿的。这个项目的总体目标是使用颅内自我刺激(ICSS)作为一种奖励的、自我选择的方法来治疗啮齿动物SD，以便将当前动物SD协议中固有的不可控厌恶成分的影响与睡眠丧失本身的影响分开。我们将使用多导睡眠图、血浆ACTH、皮质酮和催乳素水平以及在持续注意任务中的表现来比较温和处理SD(GH-SD)、ICSS-SD和强制脑刺激(NCS-SD)的大鼠。因此，我们将分离意志和厌恶在SD方法中对每种测量的贡献。目标1的目的是比较GH-SD、NCS-SD和ICSS-SD的大鼠脑电和内分泌反应。中试数据表明，ICSS是治疗SD的一种有效技术。我们检验了以下假设：1)与GH-SD相比，ICSS-SD和NCS-SD大鼠表现出相似的睡眠反弹；2)GH-SD后血浆应激生物标志物的表达比NCS-SD和ICSS-SD升高。我们最近的数据表明，GH-SD后在大鼠精神运动警戒任务(RPVT)上的表现与人类PVT数据显示出重要的差异。我们开发了一种新的啮齿动物注意任务，即nRAT。目标2的目的是：1)对比每种SD类型后的nRAT表现；以及2)比较SD后的表现变化与SD人类PVT实验中的变化。我们测试的假设是，与其他SD类型相比，ICSS-SD会导致nRAT的性能缺陷，这更能代表人类PVT中SD之后发生的性能。拟议中的实验将区分不可控的厌恶刺激诱导的脑电和睡眠缺失诱导的脑电、内分泌和认知反应。这一建议是创新的，因为我们：a)比较了ICSS和GH-SD两种SD方法引起的反应；b)开发了一种新的自我强加的动物方法，以诱导不存在强迫和厌恶SD技术的睡眠损失；c)改变了nRAT中的SD类型，并将结果与人类PVT进行了比较；以及d)验证了nRAT作为人类SD后任务时间减少的模型。预期的结果将提供一种新的有益的自我给药SD方法和一种用于动物大脑机制研究的新的认知啮齿动物任务--这是该项目的长期目标。

DESCRIPTION (provided by applicant): Many conclusions about brain sleep mechanisms are derived from animal sleep deprivation (SD) experiments. However, SD in animals is induced by uncontrollable (from the animal's perspective) aversive stimuli used in animal SD studies. In contrast, sleep loss in human experiments is voluntary. The overall goal of this project is to use intracranial self-stimulation (ICSS) as a rewarding, self-chosen method for rodent SD in order to un- couple the effects of the uncontrollable aversive components inherent in current animal SD protocols from the effects of sleep loss per se. We will compare gentle handling SD (GH-SD) vs. ICSS-SD vs. imposed brain stimulation (NCS-SD) in rats using polysomnography, plasma levels of ACTH, corticosterone, and prolactin, and performance on a sustained attention task. Thus, we will isolate the contributions of volition and aversiveness in SD-methods on each measure. The objectives of Aim 1 are to compare rat EEG and endocrine responses in GH-SD, NCS-SD and ICSS-SD. Pilot data show that ICSS is an effective technique for SD. We test the hypotheses that; 1) compared to GH-SD, ICSS-SD and NCS-SD rats will show similar sleep rebound, and 2) plasma expression of stress biomarkers are elevated after GH-SD compared to NCS-SD and ICSS-SD. Our recent data indicate that post-GH-SD performance on the rat psychomotor vigilance task (rPVT) shows important discrepancies with human PVT data. We developed a new rodent attention task, the nRAT. The objectives of Aim 2 are to: 1) contrast nRAT performance after each SD-type; and 2) compare post-SD changes in performance to those from SD human PVT experiments. We test the hypothesis that compared to the other SD-types, ICSS-SD will result in performance deficits in the nRAT that are more representative of performance occurring after SD in the human PVT. The proposed experiments will distinguish between uncontrollable aversive stimuli-induced vs. sleep loss-induced EEG, endocrine and cognitive responses. This proposal is innovative because we: a) compare responses induced by both ICSS and GH-SD methods of SD, b) develop a new self-imposed animal method to induce sleep loss devoid of forced and aversive SD techniques, c) vary SD-types in the nRAT and compare results with human PVT; and d) validate the nRAT as a model of post-SD time-on-task decrements in humans. Anticipated results will provide a new rewarding self-administered SD method and a new cognitive rodent task for use in animal brain mechanism studies -- a long term goal of this project.