This proposal presents a multidisciplinary approach to understanding a fundamental property of noradrenergic modulation in the mammalian brain: the non-linear action of the neuromodulator noradrenaline on cellular properties and the translation of these cellular effects into the modulation of sensory perception. The proposal addresses this question in the olfactory bulb of rats, using a combination of brain slice electrophysiology, behavioral pharmacology and computational modeling tools. The olfactory system represents an ideal system for such studies for several reasons, each of which is taken advantage of by the proposed studies. First, the mammalian olfactory system is anatomically relatively simple, and this simplicity has resulted in an extensive knowledge of synaptic connections and physiology and their regulation by neuromodulatory systems. Second, because olfactory bulb principal neurons are only a single synapse removed from primary olfactory sensory neurons, a relatively good understanding of the relationship between neural representations and perception of chemical signals has been developed. Third, this knowledge in turn has enabled the development of computational models which include the olfactory bulb and its neuromodulatory inputs. Finally, aided by the importance of olfaction to rats' survival, a variety of assays relying on these natural behaviors have been developed that can assess the effect of noradrenergic modulation on odor-guided behavior. It is specifically proposed to 1) determine the effects of increasing concentrations of the neuromodulator noradenaline on olfactory bulb mitral and granule cell properties, 2) test how the net concentration-dependence of noradrenergic effects is mediated by the different noradrenergic receptor subtypes and their binding affinities, 3) use a biophysical modeling approach to determine whether the cellular experimental data are sufficient to explain the overall network effects of noradrenaline, and 4) test functional predictions from these results using pharmacological manipulations during behavioral tests in rats. Taken together, the proposed experiments will elucidate how the nonlinear effects of noradrenergic modulation in sensory systems arise from the interaction with various receptor subtypes as well as how these nonlinear effects at the cellular level translate into perceptual modulation, and hence will have a broad impact on our understanding of sensory processing and neuromodulation. Neuromodulation is involved in many major degenerative diseases of brain function; a better understanding of the functions of these systems will have a high impact on public health. ? ? ?
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