Brainstem circuits controlling gastrointestinal function
Project Director: R. Alberto Travagli

Functional gastrointestinal (GI) motility disorders, including functional dyspepsia, are very common, often chronic and disabling, conditions that account for a large proportion of consultations with primary care and specialist physicians. The pathophysiology of these disorders remains incompletely understood, but several lines of evidence point toward impairment of the vagal sensory-motor loop connecting the gut to the central nervous system (CNS) and back. Visceral sensory information is conveyed to the CNS via vagal afferent nerve fibers, which terminate within the brainstem in the nucleus tractus solitarius (NTS). Neurons of the NTS assimilate this sensory information and project to integrative CNS centers involved in metabolic homeostasis, as well as to the adjacent dorsal motor nucleus of the vagus, which provides the preganglionic vagal motor output and, ultimately, coordinates GI vago-vagal reflexes.

An extraordinary degree of adaptive plasticity is required to ensure that vagally-regulated GI functions respond properly to a variety of intrinsic and extrinsic (taste, stress, food, environmental conditions etc) factors, but the neural mechanisms responsible for this remodeling are not well understood. Our recent data indicate that the levels of cAMP in vagal brainstem circuits play a critical role in their adaptive plasticity. While these adaptive responses are essential to adjust to ever-changing physiological conditions, mal-adaptation or untimely deviations may lie behind the vagally-mediated exacerbation of meal- and/or stress-induced f unctional dyspepsia . Indeed, our preliminary data demonstrate that meal- and stress-related peptides induce radical modifications of vago-vagal reflex activities.

We will combine electrophysiological (patch clamp recordings), in vivo functional (gastric tone and motility measurements) and molecular (single cell RT-PCR) approaches with the aim of defining the neural and cellular mechanisms controlling the plasticity of vagal brainstem circuits. Our overarching hypothesis is that selective activation of different groups of metabotropic glutamate receptors (mGluR) by vagal afferent inputs controls the plastic response of GI brainstem circuits to stress- and feeding-related hormones.

Our overarching hypothesis predicts that inhibitory brainstem vago-vagal circuits are normally quiescent. This dormancy is determined by the low basal release of glutamate from subsets of vagal afferent fibers interacting with G i/o -coupled mGluRs on NTS neurons. Following a meal, however, hormones or neuromodulators that increase cAMP levels overcome the dampening effects of mGluR activation, induce receptor trafficking on discrete neuronal circuits and dictate the appropriate vagal motor output. In physiological conditions, these plastic changes are essential to fulfill the digestive processes, however, derangements or untimely deviations may have pathophysiological consequences such as the vagally-mediated meal- and/or stress-induced f unctional dyspepsia . We anticipate that the results generated in this funding cycle will provide the background information necessary to develop novel therapeutic approaches to the treatment of those functional gastrointestinal motility disorders exacerbated by stress or digestive malfunctions.

Title: Cellular determinants of vagal pancreatic control
Project Director: R. Alberto Travagli

Until recently it was assumed that the response of brainstem autonomic circuits to environmental inputs was pre-determined, resulting in a stereotyped and predictable outcome, i.e. circuits are simple relay stations with no “personality”. The challenge to this existing dogma proposes that brainstem circuits are pathway specific at multiple levels, from a neuron's membrane properties, to its local network connections, its distant network associations as well as to its target effector. This diversity in neuronal organization, although confusing, may represent specialization or segregation into specific functional lines – each brainstem circuit (i.e., a neuron, its inputs and its target) 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 brainstem signaling. This type of cellular organization implies a “task matching” capability where subsets of parasympathetic and sympathetic brainstem neurons integrate vital cardiac, respiratory and gastrointestinal (GI) functions. The requirements of each system vary greatly, in response type, timing and duration. Our long-term goal is to investigate the organization of these autonomic circuits with the intention of uncovering the distinctions emerging between the neural control of different visceral functions and the role these differences play in responses to ever-changing environmental conditions. Surprisingly, our recent data have shown that even within a relatively restricted group of brainstem neurons, such as those controlling GI functions, fundamental differences exist between gastric- and pancreatic-projecting motoneurons.

Previous studies suggest that pancreatic exocrine and endocrine secretion are regulated not only by nutritional factors but also by distinct neuronal inputs, some of which are supplied by parasympathetic fibers originating from brainstem neurons of the dorsal motor nucleus of the vagus (DMV). While it is now clear that the efferent vagus controls pancreatic secretory functions, the peculiar anatomical relationship between the vagus, the intrinsic pancreatic plexus and the pancreatic secretory elements have made the details of this circuitry difficult to define. A major obstacle has been the inability to identify unambiguously those efferent neurons that control any singular aspect of pancreatic function. In the previous funding cycle, we developed a technique that allowed us to identify and study pancreas-projecting DMV neurons.

We will use state of the art anatomical, molecular and electrophysiological (in vitro and in vivo) techniques to test the overarching hypothesis of specificity in the vagal circuits that modulate pancreatic functions , i.e., pancreatic acini and islets, are controlled selectively by specific intrapancreatic ganglion neurons, and these ganglion neurons receive inputs from distinct groups of preganglionic DMV neurons . Thus, neuronal groups comprise specific vagal circuits that are devoted to the single function of controlling either exo- or endocrine secretion . By providing evidence of specificity in communication between the CNS and the pancreas, we will contribute to the newly emerging concept of uniqueness in CNS-to-target organ connections. To further test our hypothesis of specificity in vagal circuitry, we will examine whether the involution of pancreatic acinar tissue resulting from nutritional copper deficiency precipitates a selective rearrangement of anatomical and functional inputs to the pancreas, thus identifying selective patterns of vagal innervation targeting specifically the exocrine pancreas.

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