Department of Cell and Developmental Biology (CDB)

A Systems Approach to Olfaction: Areas of Research in the Restrepo Lab

The olfactory system performs the complex task of detecting and quantifying the concentration of volatile molecules present in the air we breathe. Olfactory receptor neurons are sophisticated detectors whose sensitivity, even in the presence of complex mixtures of volatile molecules, rivals that of modern analytical equipment. We use this fascinating model system to study basic questions of sensory signal processing. Our approach is multidisciplinary, involving mouse genetic, behavioral, molecular biological, biophysical and electrophysiological techniques. We have also developed a mapping techique to map the glomerular layer of the olfactory bulb.

The image shows three representative olfactory bulb pseudocolor maps of the density of glomeruli innervated by olfactory sensory neurons that express TRPM5. The background spots are immunofluorescence emitted by ciliary microdomains of average size 70 nm labeled with TRPM5 antibody (imaged by STED microscopy). See article by Lin and co-workers in PNAS 2007 showing the TRPM5 glomeruli respond to semiochemicals.

A major focus of the laboratory is the understanding of the mechanisms underlying the recognition of semiochemicals (odors involved in animal communication) including the process of individual recognition by smell analogous to face recognition in humans. We use a systems-level strategy: incorporating molecular, mouse genetic, biophysical, engineering and behavioral approaches. Our laboratory has shown that individual body odors -- determined by the major histocompatibility complex (MHC) -- elicit characteristic patterns of activity in the glomerular layer in the main olfactory bulb (the first olfactory relay station in the brain). Recent findings indicate that glomeruli involved in recognition of semiochemicals are targeted by olfactory sensory neurons (OSNs) expressing an effector of the phospholipase C (PLC) pathway, the transient receptor potential channel M5, in the cilia where olfactory transduction takes place. This indicates that, in addition to the canonical cAMP pathway, OSNs involved in detection of semiochemicals utilize elements of the PLC pathway. Our work constitutes the beginning of a systems-level understanding of processing of semiochemicals by the olfactory system.

While olfactory behavior is evidently dependent on olfactory input such as the presence of semiochemicals in the environment, it is also clear that the ability of individuals to detect and discriminate odors is highly dependent on context. Centrifugal innervation of olfactory structures in the brain is massive. In mice, for example, 40% of the adrenergic innervation converges on the olfactory bulb; this structure also receives massive innervation from the cholinergic and serotonergic systems. In addition, the olfactory bulb has an interesting intrinsic, sensory-history-dependent, dopaminergic modulatory system. Our laboratory is actively pursuing the understanding of how centrifugal innervation and the history of odor exposure affect olfaction. We perform behavioral measurements and awake-behaving multielectrode recordings in genetically altered mice to study this question. In addition, along with a group of engineers at CU Boulder, we target improvement in hybrid brain machine interfaces used for measurement of neural activity and context-dependent modification of behavior. Our findings indicate that centrifugal adrenergic innervation of the olfactory bulb plays a role in allowing the animal to differentiate between closely related odors in a context where it is essential for the animal to discriminate between these odors. Currently we use awake behaving recordings to study whether context affects the processing of olfactory signals in olfactory bulb, piriform cortex and orbitofrontal cortex.

Finally, the olfactory system is endowed with features that impart a unique advantage in the study of olfactory and neural dysfunction. In the past we have shown that human olfactory sensory neurons (the only central neurons readily available for biopsy in adult humans) can be used to study the functional basis of olfactory dysfunction. Currently, we are studying the involvement of deficits in cholinergic innervation in the etiology of Schizophrenia and Down’s syndrome. The work on Schizophrenia is performed under the aegis of the UCD Conte Center and work on Down’s syndrome is undertaken as part of an effort funded by the SIE foundation.

Lin,W., Arellano,J., Slotnick,B., and Restrepo,D. (2004). Odors Detected by Mice Deficient in Olfactory Cyclic Nucleotide-Gated Channel Subunit A2 Stimulate the Main Olfactory System. J.Neurosci. 24, 3703-3710.

Hahn,C.-Y., Gomez,G., Restrepo,D., Friedman,E., Jossiasen,R., Pribitkin,E.A., Lowry,L.D., Gallop,R.J., and Rawson,N.E. (2005). Anomalous regulation of intracellular calcium in olfactory neurons from bipolar patients. Am.J.Psych. 162:616-618.

Salcedo,E., Zhang,C., Kronberg,E., and Restrepo,D. (2005). Analysis of training-induced changes in ethyl acetate odor maps using a new computational tool to map the glomerular layer of the olfactory bulb. Chem.Senses 30, 615-626.

Clevenger,A.C. and Restrepo,D. (2006). Evaluation of the validity of a maximum likelihood adaptive staircase procedure for measurement of olfactory detection threshold in mice. Chem.Senses 31, 9-26.

Restrepo,D., Lin,W., Salcedo,E., Yamazaki,K., and Beauchamp,G. (2006). Odortypes and MHC peptides: complementary chemosignals of MHC haplotype? Trends Neurosci. 29:604-9.

Sharp,A.A., Panchawagh,H.V., Ortega,A., Artale,R., Richardson-Burns,S., Finch,D.S., Gall,K., Mahajan,R.L., and Restrepo,D. (2006). Toward a self-deploying shape memory polymer neuronal electrode. J. Neural Eng 3, L23-L30.

Lin,W., Margolskee,R., Donnert,G., Hell,S.W., and Restrepo,D. (2007). Olfactory neurons expressing TRPM5 project to the ventral olfactory bulb and are involved in sensing semiochemicals. Proc. Natl. Acad. Sci. USA 104(7):2471-6.

Doucette,W., Schutzman,J. and Restrepo,D. (2007). Adrenergic modulation of olfactory bulb circuitry affects odor discrimination. Leraning and Memory. 14:539-47.

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