CYCLICAL HYPOXIA--SUSCEPTIBILITY TO NEURONAL INJURY

Yale University, New Haven CT

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Abstract

In considering how neurons and glia in the central nervous system respond, adapt or get injured when exposed to short and long term hypoxia using cellular and molecular techniques, it has now become clear that the responses to hypoxia and the mechanisms that underlie these responses are dependent on a number of factors, such as severity of hypoxia, history of previous hypoxic exposure, and ontogeny. One of the important consequences of obstructive sleep apnea/hypoventilation syndrome (OSHA) in both children and adults is a cyclical hypoxia with a major O2 desaturations that can occur with every cycle. This cyclical hypoxia generally occurs throughout the night and can repeat itself tens to hundreds of times. The effects of this cyclical hypoxia on behavior and neural function are ill defined. Although there has been a substantial amount of work to delineate the molecular mechanisms of O2 sensing, there are still many important questions that are unanswered. Because cortical neurons have been shown to be vulnerable to hypoxic exposure, the work will focus on the neocortex. Since 1) repetitive hypoxia in OSAH can be severe and can occur over prolonged periods of months and years and 2) the impact of cyclical hypoxia may depend on the level of CNS maturation, the investigators have formulated the following 3 specific hypothesis: 1) in-vivo cyclical hypoxia renders neurons more susceptible to injury, as evidenced by poor ionic homeostasis and mitochondrial dysfunction, especially when stressed subsequently with hypoxia: 2) in-vivo cyclical hypoxia alters gene expression and renders neurons more susceptible to programmed cell death, and 3) in vivo- cyclical hypoxia has a more profound impact on the inherent electrophysiologic properties of neurons, their metabolism, and their susceptibility to injury and cell death when exposure occurs in early life, as compared to that in the mature rodent. This work may shed light on mechanisms of a variety of diseases, including OSAH, apnea of infancy, postnatal cardiorespiratory diseases that reduce O2 delivery, myocardial infarcts, and cerebro-vascular accidents and stroke.