CSF AND THE CENTRAL CHEMICAL CONTROL OF BREATHING

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The control of breathing involves brainstem rhythm and pattern generators which depend, for normal function, on mechanical and chemical afferent information including that of CO2 and/or H+ sensing central chemoreceptors. This project will describe their locations, the type of single unit involved, and the mechanism of chemosensitivity. A new approach, a 1 nl injection of acetazolamide, produces a circumscribed region of lasting brainstem tissue acidosis (<350 micro in radius) in anesthetized rats and cats. Sites (marked by fluorescent microbeads) at which acetazolamide injection increases phrenic activity identify a chemoreceptor location (we know of at least 3 at present). This probe used with a multi-barrelled pipette for recording and injecting will allow identification of single chemosensitive units within the sphere of acetazolamide induced tissue acidosis and examination in vivo of chemoreceptor mechanisms including the role of synapses, imidazole- histidine, acetylcholinesterase, and the bicarbonate/chloride antiporter. Normal chemosensitivity requires the integrity of the retrotrapezoid nucleus (RTN), a region of the rostral ventrolateral medulla lying ventral to the facial nucleus at the border of the rostral and intermediate chemosensitive areas. The RTN has singular importance in the control of breathing for in anesthetized animals unilateral RTN destruction abolishes chemosensitivity and depresses respiration often to apnea. This project will evaluate the function and importance of the RTN region. It will describe the sources of afferents to the RTN using retrograde anatomical tracers and evaluate the role of the RTN in responses to stimulation of central and peripheral chemoreceptors and to upper airway receptors with superior laryngeal afferents. Using multi-barrelled pipettes for recording and injecting we will determine the RTN unit types affected by each afferent and the neurotransmitter involved. The efferent effects of RTN stimulation on the three major groups of respiratory related brainstem neurons will be evaluated as well as its role in long term facilitation, the prolonged increase of phrenic activity seen with certain forms of stimulation. How unilateral RTN alterations are so effective will be examined as will its role in conscious animals. Further knowledge of central chemoreception and this small region, the destruction of which can abolish chemoreception and result in apnea, is important for having a complete understanding of the normal physiology of the control of breathing. It may be important in situations like chronic obstructive lung disease where the respiratory control system often determines the adaptive response and the Sudden Infant Death Syndrome where abnormalities in chemosensitivity are one etiological hypothesis and recent work has shown, in two human victims, neuronal hypoplasia in a medullary region analogous to the RTN region in rat and cat.