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Genetic analysis of olfactory processing and function

Final Report Summary - ODORPROCESSING (Genetic analysis of olfactory processing and function)

Genetic analysis of olfactory processing and function

Our laboratory is interested in the functional properties of neural circuits underlying odor perception. We use a combination of molecular genetic, in vivo imaging and behavioral approaches in mice to understand the logic of odor coding at different stations of the olfactory neural circuit.
Odor perception involves the recognition of odorants in the periphery as well as central mechanisms in the brain that allow the discrimination of odors and appropriate behavioral responses. Odorants are recognized by odorant receptors (ORs), expressed in olfactory sensory neurons in the nose. Odors activate subsets of sensory neurons and elicit sparse and spatially invariant pattern of glomerular activity in the olfactory bulb. Mitral and tufted cells, the main principle neurons of the olfactory bulb, then transmit information encoded by glomerular activity to higher olfactory centers in the cortex, which are thought to link odor representations to appropriate behavioral responses.

Odorant receptor gene choice
OR gene choice is a paradigmatic example of transcriptional regulation in which each olfactory sensory neuron selects a single OR from a repertoire of over 1000 genes. Two mechanistic models of OR choice have been proposed. One postulates the existence of a specialized transcriptional machinery that selects just one OR allele, while a second, kinetic model proposes that OR chromatin is intrinsically non-permissive, such that inefficient activation during a critical window of time restricts expression to a single OR allele.
We used a transgenic approach in mice in which we inserted a conditionally regulated exogenous promoter into an OR locus by homologous recombination in embryonic stem cells. The resulting novel mouse lines allowed the functional interrogation of the OR locus in vivo during development of the olfactory epithelium, enabling us to directly test models of OR choice. Using this experimental strategy we found that OR loci are indeed slow to activate and that the subsequent phenomenon of spatial restriction of OR expression is accomplished by repression. We also observed a developmental shutdown of OR loci concomitant with expression of the OR repertoire. Together, these experiments provide evidence for a kinetic model of initiation of OR gene choice, coupled with repression of non-selected OR alleles.

Olfactory processing and behavior
Central to understanding the neural mechanisms of odor processing is the elucidation of the functional properties of the underlying neural circuits. In an effort to address this problem, we have altered the patterns of neural activity evoked by odors, by generating transgenic mice in which 95% of all sensory neurons express the same receptor. Imaging, electrophysiology, and behavioral analyses of these transgenic mice suggest that even massively degraded glomerular signals could be transformed to generate odor perception and behavior. We found that the massively perturbed patterns of glomerular activity in M71 transgenic mice can indeed be normalized to generate mitral cell responses that are largely indistinguishable from wild-type. In vivo imaging and electrophysiological recordings further revealed that this normalization was mediated by feed-forward inhibition. Interestingly, however, the normalization of perturbed glomerular inputs resulted in more variable patterns of mitral cell odor representations.
Our data show that glomerular activity can be transformed by olfactory bulb neural circuits, to extract meaningful odor information from highly degraded sensory input, thus providing an important link between olfactory processing and behavior.