Breathing is a complex repetitive behavior in which a centrally generated rhythm is translated into a precise motor pattern. Fast synaptic inhibition, mediated by transmitters such as GABA and glycine, arises from neurons intrinsic to the network generating respiratory rhythm and is generally believed to be important in the generation and control of this respiratory rhythm and pattern in the adult mammal in vivo. A recently discovered second type of fast GABAergic inhibition, termed extrinsic inhibition, arises externally to the network of phasic respiratory neurons and underlies a proportional gain control of the activity of phasically active respiratory neurons. While this form of inhibition is likely to have a variety of physiological roles, its powerful influence on respiratory motor output suggests it may contribute to respiratory protective reflexes (eg, cough, sneeze) or contribute to the integration of breathing with other systems during complex behaviors such as locomotion or vocalization. The importance of this form of inhibition derives from its ability to regulate a neuron's overall level of activity while maintaining the information content inherent in the detailed pattern of respiratory neuron discharge within each respiratory phase. This inhibition is tonically active under resting conditions, reducing the spontaneous level of activity in bulbospinal premotor neurons to about 20-30 percent of their discharge rate in the absence of this input. Thus, physiological conditions that result in either an increase or decrease in the magnitude of this ongoing inhibition can elicit marked changes in respiratory motor output. As a critical initial step toward elucidating its physiological role, parallel anatomical and electrophysiological approaches will identify extrinsic sources of tonic inhibition contributing to gain control, the efferent synaptic contacts of these neurons and the electrophysiological consequences of this inhibitory input to postsynaptic neurons. The three major goals are to determine: 1) what are the presynaptic sources of GABAergic inhibitory input to respiratory neurons and how do GABAergic terminals and receptors distribute on their surface, 2) how broadly does gain control participate in the establishment of respiratory neuron discharge (ie, what categories of respiratory neurons exhibit GABA-mediated gain control), and 3) is gain control mediated by pre- and/or post-synaptic inhibition and, if it is postsynaptic, what are its effects on intrinsic cell properties? Identification of the neuronal pathways controlling respiratory rhythm and pattern are prerequisite for full understanding of a variety of clinical disorders such as sleep apnea and central hypoventilation syndrome.
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