BASAL FOREBRAIN HYPOCRETIN REGULATION OF WAKING

基底前脑下丘脑分泌素对清醒的调节

• 批准号: 7356357
• 负责人: Priyattam J. Shiromani
• 金额: $ 28.18万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7356357
• 关键词: Acetylcholine; Adenosine; Adenosine A1 Receptor; Affect; Agonist; Arousal; Automobile Driving; Behavioral; Brain; Brain Stem; Cells; Cholinergic Agents; Conscious; Cortical Desynchronizations; Data; Electroencephalography; FOS gene; Fire - disasters; Histamine; Hour; Hypothalamic structure; Immunoglobulin G; In Vitro; Lateral; Lesion; Level of Evidence; Link; Localized; Measures; Mediating; Metabolic; Methodology; Microdialysis; Mitochondrial Carnitine Palmitoyltransferase Pathway; Modeling; Monitor; Neurons; Neuropeptides; Phenotype; Population; Prosencephalon; Published Comment; REM Sleep; Rattus; Recovery; Regulation; Role; Sleep; Sleep Deprivation; Slow-Wave Sleep; System; Testing; Thinking; Time; Transducers; Transgenic Organisms; Wakefulness; Work; awake; basal forebrain; basal forebrain cholinergic neurons; cholinergic; cholinergic neuron; extracellular; falls; hypocretin; innovation; nerve supply; non rapid eye movement; orexin B; pressure; receptor; research study; response; sleep regulation; transport inhibitor

How the brain regulates states of consciousness is not known, but first-order circuits detailing interactions between wake-active and sleep-active neurons have been proposed. Here we focus on a portion of the wake circuit that involves the basal forebrain (BF) and link it to the neuropeptide hypocretin (HCRT). The basal forebrain (BF)has been implicated in regulating wakefulness (Szymusiak, 2000), and contains neurons that are preferentially wake/REM-active or sleep-active (Szymusiak, 2000). The sleep-active neurons are GABAergic (Manns et al.,-2003) and could oppose the wake-active neurons (Jones, 2004). The wake-active neurons are thought to be driven by ascending influences from other arousal populations (Semba, 2000), and are hypothesized to shut-off by the localized build-up of adenosine (AD) (Porkka- Heiskanen et al., 1997). Although in the BF adenosine levels rise with wakefulness and then fall with sleep, would adenosine levels rise with prolonged waking if the cholinergic neurons were absent? This is an important question that surprisingly has never been investigated, but which can easily be answered by using 192-lgG-saporin to lesion the BF cholinergic neurons and measuring adenosine in the BF that is devoid of cholinergic neurons. Here we propose four aims utilizing overlapping methodologies and transgenic rats to test a specific circuit. Aim 1 will test the hypothesis that in the absence of the BF cholinergic neurons adenosine will not build in the BF in response to waking. Aim 2 will test the hypothesis that in the absence of the BF cholinergic neurons adenosine or the adenosine A1 receptor agonist CHA will not induce sleep. Aim 3 will link the HCRT system with the BF cholinergic system by demonstrating that ascending influences from this prominent arousal system drives the BF. We will directly test this possibility by demonstrating that in 192-lgG sap lesioned rats HCRT will be less effective in evoking wakefulness. In aim 4 we will utilize the ataxin-HCRT transgenic rats to test this circuit. We will measure AD levels in the BF of the transgenic rats and hypothesize that in response to prolonged waking they will be lower compared to wild-type control rats, since the HCRT neurons are lost and not driving the BF neurons. Then 192-lgG saporin will be used in the transgenic rats to lesion the BF cholinergic neurons and we hypothesize that with both the BF cholinergic and HCRT neurons lost, the rats should have more sleep compared to single lesions.

大脑如何调节意识状态，但详细介绍相互作用的一阶电路 已经提出了唤醒活性和睡眠活跃神经元之间。在这里，我们关注的一部分 涉及基础前脑（BF）并将其与神经肽降压素（HCRT）联系起来的唤醒电路。这 基础前脑（BF）与调节清醒有关（Szymusiak，2000），并包含 优先唤醒/恢复活性或睡眠活性的神经元（Szymusiak，2000）。睡眠活跃 神经元是Gabaergic（Manns等，-2003），可以反对唤醒神经元（Jones，2004）。这 唤醒活性神经元被认为是由其他唤醒人群的上升影响驱动的 （Semba，2000年），并假设腺苷（AD）的局部堆积将其关闭（Porkka-- Heiskanen等，1997）。尽管在BF腺苷水平随着觉醒而上升，然后随着睡眠而跌落，但 如果缺乏胆碱能神经元，腺苷水平会随着长时间的唤醒而上升吗？这是一个 令人惊讶地从未调查过的重要问题，但是可以通过使用很容易回答 192-lgg---果蛋白到病变，BF胆碱能神经元和测量BF中的腺苷 胆碱能神经元。在这里，我们提出了四个目标，利用重叠的方法和转基因大鼠到 测试特定电路。 AIM 1将检验以下假设：在没有BF胆碱能神经元的情况下 腺苷不会以醒来的形式建立在BF中。 AIM 2将检验以下假设 BF胆碱能神经元腺苷或腺苷A1受体激动剂CHA不会引起睡眠。目的 3将通过证明上升的影响，将HCRT系统与BF胆碱能系统联系起来 这种突出的唤醒系统驱动了BF。我们将通过证明在 192-LGG SAP病变的大鼠HCRT在唤起清醒方面的有效性较低。在AIM 4中，我们将利用 ataxin-hcrt转基因大鼠测试该电路。我们将测量转基因大鼠BF中的AD水平 并假设，与野生型对照大鼠相比，响应长时间的醒来，它们将较低 由于HCRT神经元丧失并且不驱动BF神经元。然后，将使用192-lgg saporin 转基因大鼠对BF胆碱能神经元病变，我们假设这两个BF胆碱能 与单个病变相比，HCRT神经元失去了，大鼠应该有更多的睡眠。