HYPOXIC EFFECTS ON MAMMALIAN RESPIRATORY NEURAL NETWORK

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DESCRIPTION (Adapted from the applicant's abstract): Every year numerous victims suffer brain damage from hypoxic and anoxic insults. To understand the underlying cellular mechanisms this project examines the anoxic effects on the central respiratory network of mice. This network can be isolated in a brainstem slice preparation which generates spontaneously respiratory rhythmic activity. Slices obtained from mice older than one week respond to anoxia in a very similar way as the chemoafferent-denervated but otherwise intact respiratory system. Therefore this preparation will be employed as a model to study the anoxic response of the central respiratory network. The research plan bridges the network, cellular and molecular level using various electrophysiological and pharmacological techniques. Extra and intracellular recording techniques as well as mapping and lesion experiments are performed to identify and characterize different portions of the respiratory system: a network in the so called pre- Boetzinger complex (pBC) which is responsible for generating normal respiration and its anoxia-induced interaction with a neural network which may be responsible for gasping. A model is proposed how the interaction between these neuronal networks leads to the biphasic response to anoxia, which includes an initial augmentation, depression, apnea and then gasping. To understand the neural mechanisms underlying this biphasic response, whole cell, cell attached, outside-out and inside-out patch clamp recording techniques are used. The planned experiments aim at characterizing in great detail the direct anoxic effects on different calcium and potassium channel subtypes. However, this characterization will be supplemented with an analysis of how these direct cellular changes affect indirectly the activation of other cellular properties that are involved in the generation of the respiratory rhythm. Thus, it is only possible to understand the biphasic response in an integrated multi-level approach. A hypothetical model is proposed as to how a suppression of the N-type calcium channel leads indirectly to changes in synaptic transmission and the open probability of calcium-dependent potassium channels. In this model, these alterations result in a decreased activation of the Ih current which will alter the mechanisms of respiratory rhythm generation. To examine this hypothesis, the cascade of these cellular and network events will be analyzed. A better understanding of these neural mechanisms will provide an important foundation for a more rational treatment of various breathing disorders that result in a cessation of breathing such as sleep apnea, recurrent apnea of the newborn and sudden infant death syndrome.