The objective of the proposed research is to generate basic data relating to the circuitry, neurotransmitters and neuromodulators that are involved in the deficiencies in hippocampal functioning (e.g., degradations in cognition, memory, learning, etc.) that occur as a result of hypoxia in Obstructive Sleep Apnea. Accordingly, intracellular and extracellular studies of the CA3-CA1 hippocampal pathway will be combined with electrophysiological, microiontophoretic and morphological studies. Experiments will be undertaken in acute cats as well as in chronic cats during states of sleep and wakefulness. In our preliminary studies, we were able to demonstrate that the orthodromic CA1 field potential evoked by stimulation of CA3 is potentiated following hypoxia 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 hypoxia, alone and in combination with other factors, affect the cellular activity of CA1 neurons in acute and chronic cats. With respect to the mechanisms responsible for the impairment of hippocampal functions following recurrent episodes of OSA, we hypothesize that there are 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 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.
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