The University of Michigan School of Dentistry
The long-term goal of this laboratory is to understand the sensory input and brainstem neural circuits involved in processing taste information.
In recent years gustatory research has made revolutionary advances at the level of transduction in taste receptor cells. However, the basic organization of the circuits responsible for processing this taste information at the brainstem gustatory relay nucleus has proved particularly difficult to analyze. The overall goal of this application is to better understand how the brainstem taste relay nucleus – the rostral nucleus of the solitary tract (rNST) - encodes, decodes and distributes the information it receives from the oral cavity. Specifically, differences in the morphology, neurophysiology, and synaptology of rNST neurons with known input and projection patterns will be determined. Such information is essential to understand sensory coding mechanisms in rNST because without knowledge of the underlying circuits it is problematic to make conclusions on how sensory information is processed. Most previous investigations of the rNST have relied on recordings from unidentified neurons with unknown roles in gustatory processing. However, there are reports that separate populations of rNST neurons project to either parabrachial or brainstem sites but not both. These separate groups of rNST neurons must have very different functional roles but since prior classifications of rNST neurons were based on whether they respond to lingual stimulation, they have all been uniformly classified as “taste neurons” and assumed to have similar functional roles in taste coding. Thus, the field is using a broad label of “taste neuron” for study of coding in rNST without in fact understanding the basic nature of the neurons and their connections. By specifically labeling rNST neurons with known projection patterns and known afferent input connections new information on rNST circuits will be determined. This approach is based on the hypothesis that different populations of rNST neurons that distribute chemosensory information to different brain areas have different neurobiological properties. The experiments described in this proposal will determine the degree to which the afferent information is transformed as it travels through the rNST and whether these different neuronal subsets have different synaptic characteristics. The results will provide necessary new knowledge for understanding how rNST neurons function in processing information derived from stimulating taste buds.
The rostral portion of the nucleus of the solitary tract (rNST) in the brainstem is the first central taste relay. The rNST receives primary afferent projections from facial and glossopharyngeal nerves, which innervate lingual taste buds and papillae and terminate centrally in a topography that reflects peripheral organization. The time course for and molecular factors involved in proliferation and differentiation of rNST cells are not well understood. Given the importance of an organized taste system for proper function, the long-term objective is to determine how the rNST is established in embryonic rat. The proposed research aims are to determine: the development of solitary tract (ST) projections; the developmental time course of proliferation and differentiation of cell components comprising the rNST; the development of biophysical properties and synapses of rNST neurons; specific molecular factors present in relation to rNST development; and, to manipulate the expression of these factors to determine effects on rNST development. Immunofluorescence will be used to identify the time course for development of neurons and glia that compose the rNST in staged embryos. An in vitrobrainstem slice preparation will be used to determine development of neuron function. Immunohistochemical and Western blot approaches will be used to identify the expression of Sonic hedgehog (Shh) signaling factors potentially important for proliferation and differentiation in the NST, and cell cycle regulators across developmental stages. Finally, an explant culture system will be used to isolate the brainstem and manipulate in vitro Shh signaling molecules localized to the rNST and surround. The working hypotheses are that during embryonic development, neural precursors migrate from the fourth ventricle and differentiate to form the earliest rNST, where neurons differentiate before glia; that rNST neurons are functional, but with changing properties, in the embryo; and, that Shh signaling regulates the timing of proliferation and differentiation of rNST neural precursors and emerging neurophysiological function in rNST. Results of these experiments will provide an understanding of the early establishment, organization and function of the rNST and will demonstrate possible molecular pathways involved in that development. This will provide an important foundation for understanding the formation of the primary afferent relay of the gustatory system and lay the groundwork for understanding the demonstrated plasticity that occurs in this relay when environmental manipulations take place during embryogenesis. Furthermore, the proposal addresses essential questions in the process of neural patterning in the CNS.
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Dr. Bradley has been at the University of Michigan since 1972 and has been a professor of dentistry since 1979. Dr. Bradley also became a professor in the Department of Physiology at the U-M Medical School in 1992.
He completed his undergraduate degrees from the Royal Dental Hospital at the University of London, England, in 1963; a master's degree in periodontics from the University of Washington in Seattle in 1966; and his doctorate from Florida State University in Tallahassee in 1970. In addition to his teaching activities, Dr. Bradley is principal investigator for two current research projects, is a reviewer for 13 scientific journals including the Journal of Dental Research, and has served on and chaired several NIH grant review committees.