CNS Sites Mediating Cognition and Mood: Impact of Apnea

中枢神经系统调节认知和情绪的部位：呼吸暂停的影响

• 批准号: 6824330
• 负责人: MICHAEL H CHASE
• 金额: $ 38.25万
• 依托单位: WEBSCIENCES INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6824330
• 关键词: REM sleep; apoptosis; behavioral /social science research tag; cats; central nervous system; cognition; disease /disorder model; electron microscopy; electrophysiology; gamma aminobutyrate; glutamates; hippocampus; immunocytochemistry; light microscopy; long term potentiation; mood disorders; necrosis; neuroanatomy; neuropsychology; neuroregulation; neurotransmitter receptor; neurotransmitter transport; orexin; sleep apnea; synapses

DESCRIPTION (provided by applicant): The objective of the proposed research is to generate basic data relating to the circuitry, neurotransmitters and neuromodulators that are involved in neurocognitive deficits and mood disorders, such as depression, that occur as a result of apnea within the context of the Obstructive Sleep Apnea syndrome. Accordingly, intracellular and extraceUular studies of the CA3-CA1 hippocampal pathway will be combined with electrophysiological, microiontophoretic and morphological studies in a newly developed Animal (cat) Model of Chronic Recurrent Apnea; these studies will emphasize an analysis of deficits that arise as a consequence of active sleep that occur in conjunction with prolonged periods of recurrent apnea. We will also carry out correlated apnea-related light and electronmicroscopic analysis not only of the hippocampus, but also of other structures that are involved in neurocognition and mood, such as the amygdala and prefrontal, insular and cingulate cortices. In our preliminary studies, we have demonstrated that the hippocampal orthodromic CA1 field potential evoked by stimulation of CA3 is potentiated following apnea in the in vivo cat preparation; previously, this phenomenon has been explored almost exclusively in in vitro studies. Accordingly, based upon these data, we intend to explore the extent to which apnea, alone and in combination with other factors, affect the cellular activity of CA1 neurons. Our Preliminary Studies indicate that the functional deficits that are induced by apnea are exacerbated during carbachol-induced active (REM) sleep. Consequently, all of our paradigms will include an examination of the effects that occur as a function of the presence of active sleep. We hypothesize that the impairment of hippocampal functions following recurrent episodes of apnea are due to causative processes, such as glutamate-induced excitotoxicity, as well as contributory factors, for example, activation of nitric oxide synthase by glutamatergic receptors. We also hypothesize that there are naturally occurring apnea protective factors, including the inhibitory control of CA1 by GABAergic mechanisms and excitatory modulation by hypocretin of GABAergic mechanisms. The putative contributory and protective roles of various other neurotransmitters and neuromodulators, such as nerve growth factor and adenosine, will also be evaluated. The proposed experiments are critically important for they will provide basic data dealing with apnea, especially when this condition occurs during active (REM) sleep, when individuals with Obstructive Sleep Apnea are preferentially subjected to severe apneic episodes. These studies will therefore provide a foundation for the development of therapeutic treatments for Obstructive Sleep Apnea, including the neurocognitive and mood disorders that occur as a consequence of this pathology.

描述（由申请人提供）：拟议研究的目的是生成与电路，神经递质和神经调节剂有关的基本数据，这些数据涉及神经认知缺陷和情绪障碍，例如抑郁症，例如抑郁症，这些数据是由于阻塞性睡眠呼吸症的上下文中引起的。因此，在慢性复发性呼吸暂停的新开发的动物（CAT）模型中，CA3-CA1海马途径的细胞内和外部研究将与电生理，微观噬菌学和形态学研究结合；这些研究将强调对由于活跃的睡眠与长时间复发性呼吸暂停结合而产生的缺陷的分析。我们还将不仅对海马，而且对与神经认知和情绪有关的其他结构进行相关的呼吸暂停相关光和电子显微镜分析，例如杏仁核和前额叶和前额叶，独立和纤维状皮质。 在我们的初步研究中，我们证明，在体内猫制剂中呼吸暂停后，通过刺激Ca3刺激引起的海马正质CA1场电位增强。以前，在体外研究中几乎完全探讨了这种现象。因此，基于这些数据，我们打算探索单独呼吸暂停并与其他因素结合的程度，影响CA1神经元的细胞活性。我们的初步研究表明，在卡尔巴乔诱导的活性（REM）睡眠期间，呼吸暂停引起的功能缺陷会加剧。因此，我们所有的范式都将包括对有效睡眠的函数的影响。我们假设呼吸暂停复发后海马功能的损害是由于致病过程（例如谷氨酸诱导的兴奋性兴奋性毒性，以及促谷氨酸氨基氨酸受体激活一氮氧化物合酶的激活）引起的。我们还假设存在天然存在的呼吸暂停保护因子，包括通过GABA能机制对CA1的抑制作用，以及通过降压素的GABAergic机制来调节兴奋性调节。还将评估其他各种神经递质和神经调节剂（例如神经生长因子和腺苷）的推定贡献和保护作用。 提出的实验至关重要，因为它们将提供与呼吸暂停有关的基本数据，尤其是当这种情况在活动（REM）睡眠期间发生时，当患有阻塞性睡眠呼吸暂停的个体受到严重呼吸暂停发作时。因此，这些研究将为开发用于阻塞性睡眠呼吸暂停的治疗治疗的基础，包括由于这种病理而导致的神经认知和情绪障碍。