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: 7113121
• 负责人: MICHAEL H CHASE
• 金额: $ 37.35万
• 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/7113121
• 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神经认知缺陷和情绪障碍（例如抑郁症）有关的电路、神经递质和神经调节剂相关的基本数据，这些障碍是由于呼吸暂停而发生的阻塞性睡眠呼吸暂停综合征。因此，CA3-CA1海马通路的细胞内和细胞外研究将与新开发的慢性复发性呼吸暂停动物（猫）模型中的电生理学、微离子电渗疗法和形态学研究相结合；这些研究将强调分析因积极睡眠与长时间反复呼吸暂停相结合而出现的缺陷。我们还将对海马体以及涉及神经认知和情绪的其他结构（例如杏仁核和前额叶、岛叶和扣带皮层）进行与呼吸暂停相关的光和电子显微镜分析。 在我们的初步研究中，我们已经证明，在猫体内制剂中，呼吸暂停后刺激 CA3 诱发的海马顺向 CA1 场电位得到增强；此前，这种现象几乎完全是在体外研究中探索的。因此，基于这些数据，我们打算探讨呼吸暂停单独或与其他因素结合对 CA1 神经元细胞活动的影响程度。我们的初步研究表明，在卡巴胆碱诱导的快速眼动睡眠期间，呼吸暂停引起的功能缺陷会加剧。因此，我们所有的范例都将包括对主动睡眠的存在所产生的影响的检查。我们假设反复发生呼吸暂停后海马功能受损是由于致病过程（例如谷氨酸诱导的兴奋性毒性）以及促成因素（例如谷氨酸能受体激活一氧化氮合酶）造成的。我们还假设存在自然发生的呼吸暂停保护因素，包括 GABA 能机制对 CA1 的抑制控制和 GABA 能机制的下丘脑分泌素的兴奋性调节。还将评估各种其他神经递质和神经调节剂（例如神经生长因子和腺苷）的假定贡献和保护作用。 拟议的实验至关重要，因为它们将提供处理呼吸暂停的基本数据，特别是当这种情况发生在活跃（REM）睡眠期间时，患有阻塞性睡眠呼吸暂停的个体优先遭受严重的呼吸暂停发作。因此，这些研究将为阻塞性睡眠呼吸暂停的治疗方法的开发奠定基础，包括由于这种病理学而发生的神经认知和情绪障碍。