The existence of a 'gut-brain axis' - reciprocal interaction between the central nervous system (CNS) and the gastrointestinal (GI) tract - has long been inferred from indirect evidence; recent work has shown that the gut-brain axis can be studied directly and that regulatory peptides which are common to both CNS and GI tract may modulate the transmission of neural information at either level. With the existence of the axis established by direct experimental evidence, specific information is now required on the peptides and pathways related to defined functions and on neuronal coding of relevant information. Satiety offers an appropriate model for further study, since two peptides, cholecystokinin-octapeptide (CCK-8) and bombesin have been implicated as 'satiety agents' in the rat; both peptides have been identified in the GI tract and CNS, and both have been shown to modulate neuronal firing rates in the nuclei of the tractus solitarius (NTS) and dorsal vagal nucleus (DVN) in the medulla of the anaesthetised rat. This project will use the established rat model for the study of the 'gut-brain axis', in which the firing activity of single units in the DVN and NTS of the anaesthetised rat is recorded in the absence and presence of gastric mechanoreceptor and duodenal gluco-receptor stimulation; previous studies have established that 40% of DVN and NTS neurons respond to such stimulation and preliminary work has established that both CCK-8 and bombesin have characteristic, but not identical, modulatory effects of such neurons. Two separate approaches to the problem will be used. First, neuronal responses will be subjected to real-time on-line computer analysis in order to identify specific patterns of neuronal firing related to the nature of the stimulus, and the modulatory effect of the peptide. Secondly, using standard immunohistochemical and morphological techniques, the distribution of responding neurons will be studied in order to determine whether there is a topographical distribution of responding DVN and NTS neurons related to specific GI stimuli as occurs, for example, within the somatosensory system; retrograde in vivo dye injection combined with subsequent specific immunostaining will be used to determine the distribution of specific peptides within the anatomical correlates of the 'gut-brain axis'.
The aim of these studies is to determine the role of CCK-8 and bombesin as peripheral or central agents, or merely as non-specific agents. A better understanding of satiety should surely lead to more effective modification of inappropriate feeding behaviour.
