Severe brain hypoxia results in respiratory and sympathetic excitation. Respiratory excitation takes the form of gasping which is characterized by an abrupt onset, short duration, high amplitude burst of activity, associated exclusively with inspiratory discharge. Survival during hypoxia exposures appears to be critically dependent upon this integrated cardiorespiratory reflex which has been referred to as """"""""autoresuscitation"""""""", and is associated with rapid reoxygenation of arterial blood and restoration of blood pressure. Failure to gasp has been proposed as a potential cause of sudden infant death syndrome. The principle hypothesis of this proposal is that the putative respiratory pacemaker is located in the pre-Botzinger complex (the proposed locus of respiratory rhythm generation; pre-BotC), is hypoxia chemosensitive, and when released from strong GABAergic inhibition, exhibits chemosensitivity to systemic hypoxia over the range associated with chemoreception of the carotid bodies. Additionally, we propose that both disinhibition of GABA"""""""" ?receptors and direct hypoxic excitation of neurons (i.e., hypoxic chemosensitivity) located in the pre-BotC play complimentary roles in the genesis of hypoxia related gasping. The goal of the experiments proposed in this application is to examine the roles of direct hypoxic excitation of pre-BotC neurons, GABAergic disinhibition of pre-BotC neurons, and ionotropic excitatory amino acid (EAA) receptor activation of pre-BotC neurons as potential mechanisms for the respiratory excitation seen during gasping in response to severe brain hypoxia. Microinjection of neurotransmitter agonists and antagonists in conjunction with whole nerve and medullary single unit extracellular recordings will be used. Experiments will be conducted in both decerebrate and chloralose-anesthetized, vagotomized, deafferented, paralyzed, and ventilated cats.
The specific aims are: (1) test whether pre-inspiratory (I-driver) neurons located in the pre-BotC are activated by focal hypoxia, and whether focal hypoxia phase shifts and synchronizes other respiratory-modulated subtypes or respiratory neurons located in the pre-BotC to a gasp-synchronous discharge, (2) test whether pre-inspiratory (I-driver) neurons located in the pre-BotC are activated during severe systemic hypoxia phase shifts and synchronizes other inspiratory-modulated subtypes of respiratory neurons located in the pre-BotC to a gasp-synchronous discharge, (3) test whether GABA"""""""" -mediated disinhibition neurons located in the pre-BotC plays a facilitatory role in the production of respiratory excitation seen during hypoxia, and (4) test whether ionotropic EAA receptor activation of neurons located in the pre-BotC plays a modulatory role in the respiratory excitation seen during hypoxia-induced gasping.
Showing the most recent 10 out of 19 publications
