The nasal cavity in mammals houses distinct chemosensory epithelia including the main olfactory epithelium, the vomeronasal epithelium and the trigeminally innervated respiratory epithelium (so-called "non- sensory" epithelium) (Finger et al., 2000). Each of these receptive epithelia is implicated in detection of diverse compounds and evokes different behaviors. Traditionally, the vomeronasal epithelium was thought to detect pheromones - chemicals released by a conspecific that elicit a physiological or behavioral response in the recipient - while the main olfactory epithelium was thought to mediate conscious perception of general odorants. In addition, the trigeminal system is thought to detect potentially noxious substances, which can elicit aversive responses such as a decrease in respiratory rate, sneezing or coughing. However, recent experiments - including those published by us in the current period of support - indicate that the traditional view on the role of these chemosensory systems needs to be revised because the main olfactory epithelium also appears to be involved in detecting pheromones and other semiochemicals - odors involved in animal communication (Baxi et al., 2006;Buck, 2005;Lin et al., 2007;Lin et al., 2004). This novel aspect of chemoreception by the main olfactory system will be studied in this proposal. We will focus our proposal on our finding that the transient receptor channel M5 (TRPM5), an effector in the phospholipase C (PLC) pathway, is expressed in a subset of olfactory sensory neurons in the main olfactory epithelium whose axons project to semiochemical-responsive glomeruli (Lin et al., 2007). We propose three specific aims:
Aim 1. Test whether the PLC pathway participates in olfactory transduction by opening the TRPM5 channel in response to the increase in calcium elicited by odors.
Aim 2. Test the hypothesis that sensory input to the nose during the postnatal period affects TRPM5 expression in OSNs Aim 3. Test whether TRPM5 OSNs transmit information about semiochemicals to restricted areas of the MOB which project in turn to the medial amygdala - an area associated with reproductive and defensive behaviors. 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 the basic mechanisms of olfactory transduction in olfactory sensory neurons as well as central projections of the olfactory system. This basic science study is performed within the context of the Rocky Mountain Taste and Smell Center (RMTSC), an entity dedicated to basic and clinically-relevant research on olfaction and taste. Drs. Restrepo and Finger are Co-Directors of the RMTSC. Clinically relevant work within the center includes work on schizophrenia, Downs syndrome and brain inflammation. The clinical studies benefit greatly from solid basic science research, and because of this we expect our current proposal to strengthen the clinically relevant work carried out by the RMTSC. Reference List Doty,R.L. (1991). Olfactory dysfunction in neurodegenerative diseases. In Smell and taste in health and disease, T.V. Getchell, R.L. Doty, L.M. Bartoshuk, and J.B. Snow, Jr., eds. (New York: Raven Press), pp. 735-752. Hahn,C.G., Gomez,G., Restrepo,D., Friedman,E., Josiassen,R., Pribitkin,E.A., Lowry,L.D., Gallop,R.J., and Rawson,N.E. (2005). Aberrant intracellular calcium signaling in olfactory neurons from patients with bipolar disorder. Am. J. Psychiatry 162, 616-618. Rawson,N.E. (2000). Human olfaction. In The neurobiology of taste and smell, T.E. Finger, W.L. Silver, and D. Restrepo, eds. (New York: Wiley-Liss), pp. 257-284. Turetsky,B.I., Moberg,P.J., Owzar,K., Johnson,S.C., Doty,R.L., and Gur,R.E. (2003). Physiologic impairment of olfactory stimulus processing in schizophrenia. Biol. Psychiatry 53, 403-411.

Public Health Relevance

. 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 the basic mechanisms of olfactory transduction in olfactory sensory neurons as well as central projections of the olfactory system. This basic science study is performed within the context of the Rocky Mountain Taste and Smell Center (RMTSC), an entity dedicated to basic and clinically-relevant research on olfaction and taste. Drs. Restrepo and Finger are Co-Directors of the RMTSC. Clinically relevant work within the center includes work on schizophrenia, Downs syndrome and brain inflammation. The clinical studies benefit greatly from solid basic science research, and because of this we expect our current proposal to strengthen the clinically relevant work carried out by the RMTSC. Reference List Doty,R.L. (1991). Olfactory dysfunction in neurodegenerative diseases. In Smell and taste in health and disease, T.V. Getchell, R.L. Doty, L.M. Bartoshuk, and J.B. Snow, Jr., eds. (New York: Raven Press), pp. 735-752. Hahn,C.G., Gomez,G., Restrepo,D., Friedman,E., Josiassen,R., Pribitkin,E.A., Lowry,L.D., Gallop,R.J., and Rawson,N.E. (2005). Aberrant intracellular calcium signaling in olfactory neurons from patients with bipolar disorder. Am. J. Psychiatry 162, 616-618. Rawson,N.E. (2000). Human olfaction. In The neurobiology of taste and smell, T.E. Finger, W.L. Silver, and D. Restrepo, eds. (New York: Wiley-Liss), pp. 257-284. Turetsky,B.I., Moberg,P.J., Owzar,K., Johnson,S.C., Doty,R.L., and Gur,R.E. (2003). Physiologic impairment of olfactory stimulus processing in schizophrenia. Biol. Psychiatry 53, 403-411.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC006070-10
Application #
8305634
Study Section
Special Emphasis Panel (ZRG1-IFCN-E (03))
Program Officer
Sullivan, Susan L
Project Start
2003-04-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2012
Total Cost
$369,239
Indirect Cost
$119,192
Name
University of Colorado Denver
Department
Biology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Frenz, Christopher T; Hansen, Anne; Dupuis, Nicholas D et al. (2014) NaV1.5 sodium channel window currents contribute to spontaneous firing in olfactory sensory neurons. J Neurophysiol 112:1091-104
Rolen, S H; Salcedo, E; Restrepo, D et al. (2014) Differential localization of NT-3 and TrpM5 in glomeruli of the olfactory bulb of mice. J Comp Neurol 522:1929-40
Restrepo, Diego; Hellier, Jennifer L; Salcedo, Ernesto (2014) Complex metabolically demanding sensory processing in the olfactory system: implications for epilepsy. Epilepsy Behav 38:37-42
Gonzalez-Silva, Carolina; Vera, Jorge; Bono, Maria Rosa et al. (2013) Ca2+-activated Cl- channels of the ClCa family express in the cilia of a subset of rat olfactory sensory neurons. PLoS One 8:e69295
Keydar, Ifat; Ben-Asher, Edna; Feldmesser, Ester et al. (2013) General olfactory sensitivity database (GOSdb): candidate genes and their genomic variations. Hum Mutat 34:32-41
Thompson, John A; Salcedo, Ernesto; Restrepo, Diego et al. (2012) Second-order input to the medial amygdala from olfactory sensory neurons expressing the transduction channel TRPM5. J Comp Neurol 520:1819-30
Tizzano, Marco; Cristofoletti, Mirko; Sbarbati, Andrea et al. (2011) Expression of taste receptors in solitary chemosensory cells of rodent airways. BMC Pulm Med 11:3
Stratford, Jennifer M; Finger, Thomas E (2011) Central representation of postingestive chemosensory cues in mice that lack the ability to taste. J Neurosci 31:9101-10
Todrank, Josephine; Heth, Giora; Restrepo, Diego (2011) Effects of in utero odorant exposure on neuroanatomical development of the olfactory bulb and odour preferences. Proc Biol Sci 278:1949-55
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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