We propose an interdisciplinary study of the behavioral consequences and the cellular and synaptic basis for the modulation of olfactory bulb function by centrifugal noradrenergic innervation. The proposal is based on behavioral experiments where we show that microinfusion of both 1 and 2 adrenergic antagonists confined to the olfactory bulb interferes with the ability of mice to discriminate between structurally related odors. In addition, we present patch clamp experiments in olfactory bulb slices that show both acute and long term effects of noradrenaline on mitral cell function that likely underlie the effect of the adrenergic antagonists in vivo. We hypothesize that noradrenaline modulates odor responsiveness and mitral cell action potential firing and that these changes in mitral cell function contribute to the behavioral discrimination of closely related odors. In order to test this hypothesis, we will utilize the powerful techniques of assessment of olfactory ability through computer-assisted operant conditioning and adrenergic receptor pharmacology with patch clamp studies of modulation of mitral cell function in olfactory bulb slices. ? ? Two aims are proposed.
Aim 1. Test the hypothesis that centrifugal noradrenergic modulation of olfactory bulb function is necessary for discrimination of closely related odors. ? ? Aim 2. Test the hypothesis that noradrenaline modulates cellular properties and mitral cell spike activity in mouse olfactory bulb slices. This interdisciplinary approach will allow us to critically assess the cellular and synaptic basis of modulation of olfactory behavior by noradrenergic modification of olfactory bulb function.7. Project Narrative. In humans, disorders of the sense of smell are encountered in diseases such as Alzheimer's (Doty, 1991;Rawson, 2000), bipolar depression (Hahn et al., 2005) and schizophrenia (Turetsky et al., 2003). This grant will study noradrenergic modulation of olfactory bulb function. The study of noradrenergic modulation is relevant to schizophrenia (Yamamoto and Hornykiewicz, 2004) whose etiology we study in the Restrepo laboratory. ? ? ?
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