

Research Interests: Neurophysiology/Neurogastroenterology



The general aim is to advance understanding of neurophysiologic control of mammalian gastrointestinal functions in health and disease states. Global function of the digestive tract emerges from coordinated activity of the musculature, mucosal epithelium and blood vasculature. Organized behavior of these effector systems is determined by the enteric nervous system in concert with the central nervous system. The enteric nervous system is situated within the walls of the gastrointestinal tract and esophagus where it is recognized as an independent integrative system that behaves like a minibrain with synaptic microcircuits distributed in close proximity to the effector systems it controls. Like the brain and spinal cord, the enteric nervous system consists of sensory neurons, interneurons and motor neurons. Interneuronal microcircuits process sensory information, contain a library of programs that determine gut behavior during different digestive states and control the outflow of information in motor neurons. These functions involve the same arrays of synaptic events and neurotransmitters as found in the brain and spinal cord. Current research investigates the electrical and synaptic behavior of enteric neurons in the various specialized regions of the gastrointestinal tract. The electrophysiologic work is combined with intraneuronal injection of markers that enable morphologic identification of neurons from which electrophysiologic data are obtained. Electrophysiologic results are obtained with intracellular recording with either sharp microelectrodes or with patch-clamp recording methods. Fluorescent immunohistochemical methods, RT-PCR and in situ hybridization for localization and expression of neurotransmitters and receptors are used in concert with the electrophysiology.



Apart from the minibrain-in-the-gut, the digestive tract is recognized as the organ system with the greatest concentration of immune cells in the body. In its position at one of the dirtiest of interfaces between the body and outside world, the intestinal mucosal immune system continuously encounters dietary antigens, bacteria, viruses and toxins. Physical and chemical barriers at the epithelial interface are insufficient to exclude fully the large antigen load thereby allowing chronic challenges to the mucosal immune system.



Current research with antigen sensitized animal models investigates direct communication between the mucosal immune system and the minibrain in the gut. The communication results in adaptive behavior of the bowel in response to circumstances within the lumen that are threatening to the functional integrity of the whole animal. Communication is chemical in nature (paracrine) and incorporates specialized sensing functions of the immune cells for specific antigens together with the capacity of the enteric nervous system for interpretation of the signals. Immuno-neural integration progresses sequentially beginning with immune detection followed by signal transfer to enteric neural microcircuits followed by neural interpretation and then selection of a specific neural program of coordinated mucosal secretion and motor propulsion that effectively clears the antigenic threat from the intestinal lumen. This occurs with the side effects of diarrhea and abdominal cramping pain that are reminiscent of the symptoms of the diarrhea predominant forms of the irritable bowel syndrome. Currently used experimental approaches in the study of immuno-neural interactions brings together the disciplines of mucosal immunology, enteric neurophysiology and clinical aspects of functional gastrointestinal disorders.



Research approaches include electrophysiologic recording with microelectrodes or patch clamp technology of electrical and synaptic behavior of neurons in the enteric nervous system in whole-mount preparations in vitro and in enteric neurons and glial cells in culture. Electrophysiology is integrated with intracellular marker techniques for morphologic assessment of enteric neurons and immunofluorescent, RT-PCR and in situ hybridization techniques for localization and expression of neurotransmitters and receptors. Physiologic genomics are used to expand insight into alterations in genes for neurotransmitters and receptors (eg., in inflammatory states) and cloning and expression of genes.



