A great deal of morbidity is caused by diseases of the gallbladder; nevertheless, the control of the motile and absorptive functions of the organ are incompletely understood. Although the musculature of the gallbladder responds to hormones, such as cholecystokinin (CCK), there is also a prominent ganglionated neural plexus in the gallbladder wall. The functions of this intrinsic nervous system, and its interaction with hormones re unknown. In order to gain a complete understanding of the physiology of the gallbladder, it is important to understand how the nervous system of the gallbladder is organized, to what extent it receives input form external sources (such as the CNS, sympathetic, and sensory ganglia), and whether or no the actions of hormones on the gallbladder are mediated in whole or in part through neurons. In the current proposal, therefore, the structure of the ganglionated plexus of the gallbladder is analogous to that of the gut (the enteric nervous system (ENS) has a unique structure and chemistry, which reflect an ability to mediate reflex activity independently of control by the CNS) or whether gallbladder ganglia instead are parasympathetic relay ganglia. These studies will include: (1). analysis of the organization of gallbladder ganglia (presence or absence of collagen, basal laminae, method of axonal ensheathment by supporting cells); (2). determination of whether the supporting cells f gallbladder ganglia are glial or Schwann cells; (3). determination of whether or not specialized capillary endothelia provide a blood-tissue barrier for gallbladder ganglia; (4). characterization of the unusual tyrosine hydroxylase-containing neurons of the gallbladder ganglia. The extrinsic sources of neural input to the gallbladder will be investigated through the use of retrograde tracers. This study will test the novel hypothesis that the gallbladder projects to and receives input from the ENS. The membrane properties and types of synaptic input to the intrinsic neurons of the gallbladder will be studied with intracellular microelectrodes.
An aim of this investigation will be to compare the physiological properties of gallbladder neurons to neurons of the ENS on the one hand, and to extraenteric autonomic ganglia on the other. Finally, the effects of CCK and putative neurotransmitters on gallbladder neurons will be analyzed electro-physiologically to attempt to determine the role that the neurons play in the action of these compounds on the gallbladder. Previous studies of the effects of drugs and hormones on neurons of the gallbladder and on gallbladder motility have involved application of the compounds while recording intraluminal pressure or contraction of gallbladder muscle strips; however, the contractile response to given substance is likely to be the net result of a complicated series of actions on a variety of the neurons that comprise the intrinsic circuits of the gallbladder's nervous system. It is therefore essential to study the effects of drugs, transmitter candidates, or hormones on individual neurons, as will be done in the current proposal.
| Lavoie, Brigitte; Balemba, Onesmo B; Godfrey, Cody et al. (2010) Hydrophobic bile salts inhibit gallbladder smooth muscle function via stimulation of GPBAR1 receptors and activation of KATP channels. J Physiol 588:3295-305 |
