Olfactory dysfunction is one of the earliest symptoms of neurodegenerative disorders like Alzheimer's disease and Parkinsonism. A dominant hypothesis is that these diseases have a primary cholinergic etiology. Understanding how this system modulates olfactory processing, therefore, sets the stage for early detection and intervention. Acetylcholine modulates olfactory perceptual learning and working memory. This modulation of olfaction results from the incoming cholinergic innervation from the basal forebrain and subsequent activation of two classes of cholinergic receptors - the muscarinic acetylcholine receptors and nicotinic acetylcholine receptors (nAChRs). In this proposal, we examine the role of nAChRs in modulating the excitability of mitral cells in the mouse main olfactory bulb. Using a synergistic approach incorporating olfactory slice electrophysiology and awake behaving recording we ask how interactions between various nAChR subtypes in the olfactory bulb result in the modulation of the glomerular output to incoming odor signals thereby affecting behavior. The proposal examines this question at multiple levels. In olfactory bulb slices we examine the nAChR modulation of the glomerular microcircuit using gene knockout mice, pharmacology, electrophysiology and calcium imaging. We test the model that nAChR modulation of glomerular output is due to efficient feedback inhibition from periglomerular (PG) cells. We also test a novel idea that effective inhibition of glomerular output is driven by amplification of GABA release due to PG-PG interactions. Using optogenetic approaches, we will examine how the glomerular circuit is modulated by ACh released from cholinergic fibers. Timing of transmitter release, relative to incoming odor input, will be examined both in slices, as well as with recordings from awake behaving animals. The research proposed here will greatly enhance our understanding of the principles governing cholinergic modulation in the brain to lay the foundation for rational drug design to treat neurodegenerative disorders.

Public Health Relevance

In humans, cholinergic signaling is thought to be involved in disorders of the sense of smell in diseases such as Parkinson's, Alzheimer's and schizophrenia. This grant will study cholinergic modulation of signal processing in the olfactory bulb, a fundamental process that plays an important role in modulating the sense of smell. Importantly, studying cholinergic modulation in the olfactory system will have important implications for the treatment of neurodegenerative disorders.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Sullivan, Susan L
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University of Colorado Denver
Schools of Medicine
United States
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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
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Salcedo, Ernesto; Tran, Tuan; Ly, Xuan et al. (2011) Activity-dependent changes in cholinergic innervation of the mouse olfactory bulb. PLoS One 6:e25441
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
Grybko, Michael; Sharma, Geeta; Vijayaraghavan, Sukumar (2010) Functional distribution of nicotinic receptors in CA3 region of the hippocampus. J Mol Neurosci 40:114-20
Hellier, Jennifer L; Arevalo, Nicole L; Blatner, Megan J et al. (2010) Olfactory discrimination varies in mice with different levels of ?7-nicotinic acetylcholine receptor expression. Brain Res 1358:140-50
Vijayaraghavan, Sukumar (2009) Glial-neuronal interactions--implications for plasticity and drug addiction. AAPS J 11:123-32
Sharma, G; Vijayaraghavan, S (2008) Nicotinic receptors containing the alpha7 subunit: a model for rational drug design. Curr Med Chem 15:2921-32

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