Disruption of cholinergic signaling is thought to be a major factor in many neurodegenerative disorders. However, design of drugs to combat these disruptions has been hampered by our lack of knowledge of how various brain systems are modulated by the cholinergic system. What is lacking is a systematic study of cholinergic system that synthesizes information at various levels to link cellular mechanisms to behavioral effects. Olfactory dysfunction is central to most forms of neurodegenerative disorders. Disruption of cholinergic signaling is thought to be a mechanism underlying olfactory dysfunction. The simplicity of the olfactory system where odor perception is only two synapses away from odor recognition, make this an ideal system to examine mechanisms underlying cholinergic modulation of olfactory signaling. Using the rat olfactory bulb as a starting point, in this proposal we will examine pathways transducing cholinergic signaling in the bulb their loci and their effects on the excitabiltiy of principals cells as well as on behavior will be examined. A fundamental transmitter system that is thought to shape processing of odorant information in the MOB is gamma-amino-butyric acid (GABA). In the first specific aim, we will examine, using electrophyiological and imaging studies, the location and mechanisms of signal transduction by muscarinic acetylcholine receptors (mAChRs) in the rat main olfactory bulb (MOB). We will focus on the regulation of GABA release by mAChRs, the locus of action and the effects of mAChRs on the firing of mitral cells the principal neurons of the MOB. In the second specific aim we will target the effects of nicotinic acetylcholine receptors (nAChRs) on GABAergic signaling in the MOB. We will examine the loci of these receptors, mechanisms employed by these receptors for calcium signaling and their role in mitral cell excitability. In the third specific aim we will extend our initial finding that there is a developmental switch in cholinergic signaling. Using electrophysiological studies we will characterize the mechanisms underlying this switch. We will then, using behavioral experimetns elucidate what this mechanistic switch implies for cholinergic modulation of olfaction during development. Information from these studies will form the bases for rational drug design aimed at combatting neurodegenerative diseases

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-K (02))
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Davis, Barry
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University of Colorado Denver
Schools of Medicine
United States
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Parsa, Pirooz Victor; D'Souza, Rinaldo David; Vijayaraghavan, Sukumar (2015) Signaling between periglomerular cells reveals a bimodal role for GABA in modulating glomerular microcircuitry in the olfactory bulb. Proc Natl Acad Sci U S A 112:9478-83
Vijayaraghavan, Sukumar; Sharma, Geeta (2015) Editorial: Brain cholinergic mechanisms. Front Synaptic Neurosci 7:14
D'Souza, Rinaldo D; Vijayaraghavan, Sukumar (2014) Paying attention to smell: cholinergic signaling in the olfactory bulb. Front Synaptic Neurosci 6:21
D'Souza, Rinaldo D; Parsa, Pirooz V; Vijayaraghavan, Sukumar (2013) Nicotinic receptors modulate olfactory bulb external tufted cells via an excitation-dependent inhibitory mechanism. J Neurophysiol 110:1544-53
D'Souza, Rinaldo D; Vijayaraghavan, Sukumar (2012) Nicotinic receptor-mediated filtering of mitral cell responses to olfactory nerve inputs involves the α3β4 subtype. J Neurosci 32:3261-6
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