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: 7179249
• 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/7179249
• 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：大脑如何调节意识状态尚不清楚，但已经提出了详细描述唤醒活跃神经元和睡眠活跃神经元之间相互作用的一阶电路。在这里，我们重点关注涉及基底前脑 (BF) 的唤醒回路的一部分，并将其与神经肽下丘脑分泌素 (HCRT) 连接起来。基底前脑 (BF) 与调节觉醒有关 (Szymusiak, 2000)，并且包含优先觉醒/快速眼动活动或睡眠活动的神经元 (Szymusiak, 2000)。睡眠活跃神经元是 GABA 能的（Manns 等，2003），并且可以对抗唤醒活跃神经元（Jones，2004）。唤醒活动神经元被认为是由其他唤醒群体的上升影响驱动的（Semba，2000），并假设由于腺苷（AD）的局部积累而关闭（Porkka-Heiskanen 等，1997）。尽管在 BF 中，腺苷水平随着清醒而上升，然后随着睡眠而下降，但如果胆碱能神经元不存在，腺苷水平会随着长时间清醒而上升吗？这是一个重要的问题，令人惊讶的是从未被研究过，但通过使用 192-IgG-皂草素损伤 BF 胆碱能神经元并测量缺乏胆碱能神经元的 BF 中的腺苷，可以轻松回答该问题。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来测试特定的电路。目标 1 将检验以下假设：在没有 BF 胆碱能神经元的情况下，腺苷不会响应醒来而在 BF 中积聚。目标 2 将检验以下假设：在缺乏 BF 胆碱能神经元的情况下，腺苷或腺苷 A1 受体激动剂 CHA 不会诱导睡眠。目标 3 将通过证明这一突出的唤醒系统的上行影响驱动 BF，将 HCRT 系统与 BF 胆碱能系统联系起来。我们将通过证明在 192-IgG 汁液损伤的大鼠中 HCRT 在唤起觉醒方面效果较差，来直接测试这种可能性。在目标 4 中，我们将利用 ataxin-HCRT 转基因大鼠来测试该电路。我们将测量转基因大鼠 BF 中的 AD 水平，并假设在对长时间清醒的反应中，与野生型对照大鼠相比，AD 水平会较低，因为 HCRT 神经元丢失并且不再驱动 BF 神经元。然后将192-IgG皂草素用于转基因大鼠以损伤BF胆碱能神经元，我们假设随着BF胆碱能神经元和HCRT神经元的丧失，与单一损伤相比，大鼠应该有更多的睡眠。