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: 7271908
• 负责人: MICHAEL H CHASE
• 金额: $ 36.27万
• 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/7271908
• 关键词: CNS; Sites; Mediating; Cognition; Mood

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(申请人提供)：拟议研究的目标是生成与神经认知缺陷和情绪障碍(如抑郁症)有关的电路、神经递质和神经调节器的基本数据，这些障碍是由于阻塞性睡眠呼吸暂停综合征中的呼吸暂停而引起的。因此，在新开发的慢性复发性呼吸暂停动物(CAT)模型中，对CA3-CA1海马区通路的细胞内和体外研究将与电生理学、微离子电导和形态学研究相结合；这些研究将侧重于对伴随长时间复发性呼吸暂停而出现的积极睡眠所引起的缺陷的分析。我们还将不仅对海马体进行与呼吸暂停相关的光镜和电子显微镜分析，还将对与神经认知和情绪有关的其他结构进行分析，如杏仁核和前额叶、岛叶和扣带回皮质。 在我们的初步研究中，我们已经证明了刺激CA3诱发的海马区顺向CA1场电位在体内CAT准备中呼吸暂停后被增强；以前，这种现象几乎只在体外研究中被探索过。因此，基于这些数据，我们打算探索呼吸暂停在多大程度上单独以及与其他因素一起影响CA1神经元的细胞活动。我们的初步研究表明，在卡巴胆碱诱导的活跃(REM)睡眠中，由呼吸暂停引起的功能障碍会加剧。因此，我们的所有范例都将包括对作为活跃睡眠存在的函数而发生的影响的检查。我们假设，反复发作的呼吸暂停后，海马区功能的损害是由于致病过程，如谷氨酸诱导的兴奋性毒性，以及促成因素，如谷氨酸能受体激活一氧化氮合酶。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能机制的下丘脑对CA1的兴奋调节。还将评估各种其他神经递质和神经调节剂的假定贡献和保护作用，如神经生长因子和腺苷。 拟议的实验至关重要，因为它们将提供与呼吸暂停有关的基本数据，特别是当这种情况发生在活动(REM)睡眠期间，而患有阻塞性睡眠呼吸暂停的人更容易发生严重的呼吸暂停发作。因此，这些研究将为开发治疗阻塞性睡眠呼吸暂停的治疗方法提供基础，包括由于这种病理而发生的神经认知和情绪障碍。