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尚不清楚，但一阶回路详细说明了相互作用 唤醒活跃和睡眠活跃神经元之间的联系。在这里，我们集中在一部分的 唤醒回路涉及基底前脑（BF），并将其与神经肽下丘脑泌素（HCRT）联系起来。的 基底前脑（BF）与调节觉醒有关（Szymusiak，2000）， 神经元优先处于觉醒/REM活动或睡眠活动状态（Szymusiak，2000）。睡眠活跃 神经元是GABA能的（Manns等人，- 2003），并可能反对唤醒活跃的神经元（琼斯，2004）。的 唤醒活跃神经元被认为是由其他唤醒群体的上升影响所驱动的 （Semba，2000），并且假设通过腺苷（AD）的局部积聚而关闭（Porkka，2000）。 Heiskanen等人，1997年）。虽然在BF中腺苷水平随着觉醒而上升，然后随着睡眠而下降， 如果没有胆碱能神经元，腺苷水平会随着长时间的清醒而升高吗？这是一 令人惊讶的是，这是一个从未被研究过的重要问题，但可以很容易地通过使用 192-lgG-皂草素损伤BF胆碱能神经元，并测量缺乏192-lgG-皂草素的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， 测试特定的电路。目的1将检验在BF胆碱能神经元缺失的情况下， 腺苷不会响应于清醒而在BF中建立。目标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不会诱导睡眠。目的 3将连接HCRT系统与BF胆碱能系统，通过证明， 这个显著的唤醒系统驱动BF。我们将直接测试这种可能性，证明在 192-IgG sap损伤的大鼠HCRT在唤醒觉醒方面效果较差。在目标4中，我们将利用 ataxin-HCRT转基因大鼠来测试这个回路。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组大鼠相比， 因为HCRT神经元丢失并且不驱动BF神经元。然后将192-lgG皂草素用于 转基因大鼠损伤BF胆碱能神经元，我们假设， 并且HCRT神经元丢失，与单个损伤相比，大鼠应该有更多的睡眠。