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

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC008855-04
Application #
7851191
Study Section
Special Emphasis Panel (ZRG1-IFCN-K (02))
Program Officer
Davis, Barry
Project Start
2007-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$311,594
Indirect Cost
Name
University of Colorado Denver
Department
Physiology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Vijayaraghavan, Sukumar; Sharma, Geeta (2015) Editorial: Brain cholinergic mechanisms. Front Synaptic Neurosci 7:14
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
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 ?3?4 subtype. J Neurosci 32:3261-6
Hellier, Jennifer L; Arevalo, Nicole L; Smith, Lynelle et al. (2012) ýý7-Nicotinic acetylcholine receptor: role in early odor learning preference in mice. PLoS One 7:e35251
Doucette, Wilder; Gire, David H; Whitesell, Jennifer et al. (2011) Associative cortex features in the first olfactory brain relay station. Neuron 69:1176-87
Salcedo, Ernesto; Tran, Tuan; Ly, Xuan et al. (2011) Activity-dependent changes in cholinergic innervation of the mouse olfactory bulb. PLoS One 6:e25441
de Souza, Fabio M Simoes; Busquet, Nicolas; Blatner, Megan et al. (2011) Galantamine improves olfactory learning in the Ts65Dn mouse model of Down syndrome. Sci Rep 1:137
Grybko, Michael J; Hahm, Eu-Teum; Perrine, Wesley et al. (2011) A transgenic mouse model reveals fast nicotinic transmission in hippocampal pyramidal neurons. Eur J Neurosci 33:1786-98

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