The central respiratory chemoreceptor: where is it located?-Invited article.

We review previous reports on the localization of the central chemoreceptor focusing on our studies that used various experimental techniques including lesioning (brainstem transection and removal of pia mater), analyses of neuronal responses to CO(2) by electrophysiological and optical recording, mapping of CO(2)-excitable neurons by c-fos immunohistochemistry and local acidic stimulation. Among these experimental techniques, voltage imaging with calculation of cross correlation coefficients between the respiratory output activity and each pixel, i.e., correlation coefficient imaging technique, enabled us to effectively analyze imaging data without empirical signal processing. The reviewed studies have indicated that the most superficial layer of the rostral ventral medulla, i.e., the surface portions of the nucleus retrotrapezoideus/parafacial respiratory group, nucleus parapyramidal superficialis and nucleus raphe pallidus, is important in central chemoreception. We suggest that one of the major respiratory rhythm generators, i.e., the preBötzinger complex, is not chemosensitive in itself or rather inhibited by CO(2). Based on our detailed analysis of c-fos immunohistochemistry, we propose a cell-vessel architecture model for the central respiratory chemoreceptor. Primary chemoreceptor cells are mainly located beneath large surface vessels within the marginal glial layer of the ventral medulla, and surround fine penetrating vessels that branch from a large surface vessel. Respiratory neurons in the rostral portion of the ventral respiratory group could be intrinsically chemosensitive, but their role in chemoreception might be secondary. Definitive identification of chemosensitive sites and chemoreceptor cells needs further studies.