Until recently it was assumed that the responses of brain areas devoted to the control of environmental reflexes (such as food ingestion and digestion) were pre-determined, resulting in stereotyped and predictable outcomes. That is to say, autonomic reflexes were composed of simple nerve cells acting as relay stations with no "personality". This project challenges this existing dogma and proposes that autonomic reflex circuits are highly integrated, with pathways defined uniquely at multiple specific levels and organized into specific functional lines. This type of cellular organization also implies that separate subsets of brainstem neurons display "task matching" capabilities and integrate vital cardiac, gastrointestinal and respiratory functions. The requirements of each system vary greatly in response type, timing and duration. The long-term goal of the present project is to investigate the organization of these reflex circuits with the intention of uncovering distinctions in the neural control of visceral functions and the role these variations play in allowing different responses to ever-changing environmental conditions. The recent data from this team of researchers show that fundamental differences exist even with the relatively restricted group of neurons controlling the stomach or the pancreas. The present project will combine state of the art anatomical, molecular and electrophysiological techniques to provide evidence of specificity in communication between the brain and the pancreas. This combination of experimental approaches will allow the unveiling of a coherent broader picture discriminating reflex circuits involved in specific metabolic and homeostatic functions. By providing training in this unique combination of techniques, the researcher leading this project will continue to foster the career of junior faculty, postdoctoral fellows and students within, as well as outside, the laboratory.
During this period of NSF funding we aimed to describe the neural connectivities within the medulla oblongata, with a particular emphasis on the neural circuits controlling gastrointestinal and pancreatic functions. The overall idea behind these studies was to test the hypothesis that some reflexive circuits are pathway specific at multiple levels, from the single properties of a brain nerve cell, to its local network connections, its distant network associations as well as to the target organ of its response. This diversity in neuronal organization, although complex, may represent specialization or segregation into specific functional lines – each element of the reflexive circuit may be "recognized" by adjacent neurons allowing reinforcement of each other’s common pathways and goals, hence offering a level of potential redundancy, and safety, in signaling. This type of cellular organization implies a "task matching" capability where subsets of neural brain cells integrate vital cardiac, respiratory and gastrointestinal functions. Since the requirements of each system vary greatly, in response type, timing and duration, we focused our studies to a description of the neural circuits controlling gastrointestinal functions, including the pancreas. We wanted, among others goals, to test the hypothesis that the selective degeneration of pancreatic acinar tissue induced by dietary copper deficiency induces a selective degeneration of the neurons within the intrapancreatic ganglia that project to the acinar cells. The degeneration of the intrapancreatic neurons would then induce a degeneration of their selective vagal inputs and, by a process of elimination, would have revealed the specificity in the vagal circuits that modulate pancreatic exocrine function. The data we have generated support this hypothesis strongly, resulting in the publication of a number of manuscripts, book chapters and invited reviews. Additional articles have been submitted or will be submitted in the near future. Thanks to these NSF funds, we have trained one graduate student (Mr. Michael Snyder, who unfortunately left the program due to medical issues) and three undergraduate students (Mr. Scott Hoffman, Mr. Michael Skolka and Mrs. Edie Pettiford. Mrs. Pettiford’s work in the lab was accepted for presentation at the AMBRCS symposium). In addition, manuscript #6 (below) is set for a press release or a Penn State Hershey Newswire story (will submit to the appropriate NSF officer when available). Manuscripts, Reviews, Book Chapter and website: 1) Browning KN, Travagli RA. Plasticity of vagal brainstem circuits in the control of gastric function. Neurogastroenterol. Motil. 22(11): 1154-63; 2010. 2) Babic T, Browning KN, Travagli RA. Differential organization of excitatory and inhibitory synapses within the rat dorsal vagal complex. Am. J. Physiol. 300 (1): G21-32; 2011. 3) Browning KN, Travagli RA. Plasticity of vagal brainstem circuits in the control of gastrointestinal function. Autonomic Neuroscience: Basic and Clinical. 161 (1-2): 6-13; 2011. 4) Travagli R.A., Browning K.N. Central Autonomic Control of the Pancreas. In: Central Regulation of the Autonomic Function, 2nd edition. (I. Llewellyn-Smith and A.J.M. Verberne, eds). Chapter 15, 2011. 5) Travagli R.A and Browning K.N.: www.lib.umich.edu/spo/panc/pathways/neural-control-of-pancreatic-function 6) Babic T., Browning KN, Kawaguchi Y., Tang X, Travagli RA. Pancreatic insulin and exocrine secretion are under the modulatory control of distinct subpopulations of vagal motoneurones in the rat. J. Physiology. 590: 3611-22; 2012. Submitted: 1) Browning K.N., Babic T., Holmes G.M., Swartz E. and R. A. Travagli. "A critical re-evaluation of the specificity of action of perivagal capsaicin". 2) "Role of the vagus in the reduced pancreatic exocrine function in copper deficient rats" Babic T., Bhagat R., Wan S., Browning KN, Snyder M., Fortna SR & Travagli RA Abstracts: 1) Selective lesion of the exocrine pancreas induces neural plasticity in distinct autonomic vagal circuits. Browning K.N and Travagli R.A. Society for the Neuroscience (SFN) Meeting2009 2) Acute pancreatitis increases the excitability of brainstem vagal circuits. Travagli R.A and Browning K.N. SFN2009 3) Interaction of GABA and glutamate inputs in the dorsal motor nucleus of the vagus. Babic T., Browning K.N., Travagli R.A. Experimental Biology (EB) Meeting 2010 4) Organization of Metabotropic Glutamate Receptors on Pancreas-Projecting DMV Neurons. Babic T., Browning K.N., Travagli R.A. EB2011 5) Metabotropic glutamate receptors (mGluRs) Modulate Synaptic Transmission to identified Pancreas-Projecting DMV Neurons. Babic T., Browning K.N., Travagli R.A. Digestive Disease Week (DDW)2011 6) Perivagal capsaicin alters the response of vagal motoneurons to Thyrotropin Releasing Hormone (TRH). Holmes, Swartz & Travagli DDW2012 7) Group III metabotropic glutamate receptors activate selectively pancreas-projecting neurons in the dorsal motor nucleus of the vagus that control insulin secretion Babic and Travagli DDW2012 8) Acute pancreatitis alters the sensitivity of dorsal motor nucleus of the vagus (DMV) neurons to group II metabotropic glutamate receptors Babic and Travagli. DDW2012 9) Group III metabotropic glutamate receptors activate selectively pancreas-projecting neurons in the dorsal motor nucleus of the vagus that control endocrine secretions Babic and Travagli EB2012 10) Perivagal capsaicin alters the response of vagal motoneurons to Thyrotropin Releasing Hormone (TRH) Holmes, Swartz & Travagli EB2012
