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.
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