CNS Sites Mediating Cognition and Mood: Impact of Apnea

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（如抑郁症）相关的回路、神经递质和神经调质的基本数据，这些神经认知缺陷和情绪障碍是阻塞性睡眠呼吸暂停综合征背景下呼吸暂停引起的。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、微离子电渗和形态学研究相结合;这些研究将强调对与长期复发性呼吸暂停相关的主动睡眠引起的缺陷的分析。我们还将进行相关的呼吸暂停相关的光和电子显微镜分析，不仅对海马，而且对其他与神经认知和情绪有关的结构，如杏仁核和前额叶，岛叶和扣带皮层。 在我们的初步研究中，我们已经证明，海马顺向CA1场电位引起的刺激CA3增强呼吸暂停后，在体内猫的准备，以前，这种现象已被探索几乎完全在体外研究。因此，基于这些数据，我们打算探索呼吸暂停，单独和与其他因素相结合，影响CA1神经元的细胞活性的程度。我们的初步研究表明，由呼吸暂停引起的功能缺陷在卡巴胆碱诱导的主动（REM）睡眠期间加剧。因此，我们所有的范例都将包括对作为活跃睡眠存在的函数而发生的效应的检查。我们推测，海马功能的损害后，呼吸暂停复发是由于致病过程，如谷氨酸诱导的兴奋性毒性，以及促成因素，例如，激活一氧化氮合酶的谷氨酸能受体。我们还假设存在自然发生的呼吸暂停保护因子，包括GABA能机制对CA 1的抑制性控制和GABA能机制的下丘脑泌素的兴奋性调节。还将评估各种其他神经递质和神经调质（如神经生长因子和腺苷）的假定贡献和保护作用。 所提出的实验是至关重要的，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主动（REM）睡眠期间时，阻塞性睡眠呼吸暂停的个体优先受到严重的呼吸暂停发作。因此，这些研究将为开发阻塞性睡眠呼吸暂停的治疗方法提供基础，包括因这种病理而发生的神经认知和情绪障碍。

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.