The long-range goal of this research is to explain the generation and control of respiratory pattern in terms of the biophysical, synaptic and network properties of brainstem neurons. This is a proposal to identify and functionally characterize the central nervous system elements underlying the generation and control of inspiratory and expiratory durations. The goal is to identify the neurons mediating changes in respiratory timing in response to activation of selected afferent pathways. A particular emphasis will be placed on inputs from slowly adapting pulmonary stretch receptors (SAR). SAR are activated by lung inflation and give rise to the Breuer-Hering reflex in which inspiration is shortened and expiration lengthened. To attain this goal, a series of electrophysiological, neuroanatomical and pharmacological techniques will be employed. The sites of termination and the terminal arborization patterns of SAR primary afferent fibers within the nucleus of the tractus solitarius (NTS) will be identified using intra-axonal injection of Neurobiotin. The projection patterns of NTS neurons receiving SAR input will be determined using both intracellular and extracellular labeling techniques. A potential role in the Breuer-Hering reflex will be inferred for neurons within the identified terminal fields if: 1) reversible interruption of synaptic transmission within the region blocks the reflex, and 2) activation of neurons within the region (by excitatory amino acid injection) mimics the physiologically activated reflex. Within regions meeting these criteria, the activity patterns and synaptic drive of neurons activated during reflexive changes in expiratory duration will be determined using intracellular and extracellular recording. Responses of individual neurons will be correlated with changes in expiratory duration. The underlying premise of these experiments is that neurons which have a causal role in determining expiratory duration will have discharge patterns that maintain a fixed relationship to expiratory rhythm. By contrast, the activity of neurons that are not causative in the determination of expiratory duration may exhibit coincident changes in discharge pattern under some conditions but the relationship will not be maintained when a wide range of expiratory durations is considered. Expiratory duration will be manipulated over as wide a range as possible by activation of a variety of central and peripheral afferent inputs. Lastly, the axonal projection patterns and post-synaptic connections will be determined for neurons which are identified as candidates for mediating the Breuer-Hering reflex. Identification of the neuronal pathways producing these effects will aid our understanding of the generation and reflex control of respiratory pattern.
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