Genetic dissection of olfactory inputs that mediate aversive responses.
Final Report Abstract
A fundamental question in neurobiology is whether specific behaviors are innate or learned, and how sensory inputs and neuronal circuits give rise to innate behaviors. In olfaction, an important issue is whether specific odors have an innate valence and whether separate pathways exist for processing innate and learned odor-guided behaviors. In the main olfactory epithelium, odorants are detected by three different classes of olfactory receptors (ORs): class I ORs, class II ORs and trace amine-associated receptors (TAARs). While ventral projections to the olfactory bulb almost exclusively consist of class II ORs, dorsal projections are made by all three classes of ORs which systematically map to sub-regions of the dorsal olfactory bulb. The functional significance of this remarkable organization is unknown. One possibility is that these domains may relate to innate and learned odor responses by feeding into distinct hard-wired downstream circuits. For this project, we focused on the TAARs, which project to the DIII domain in the dorsal bulb and are selectively activated by structurally diverse amines. We examined if specific activation of dorsal TAAR glomeruli is sufficient to drive aversive behavior. Using optogenetic activation during a place preference assay, we show that specific activation of a TAAR glomerulus elicits behavioral aversion. In contrast, optogenetic activation of another dorsal control glomerulus fails to induce aversive responses even though another behavioral test indicates that mice can detect the stimulus. Together, these data show that specifically activating a TAAR glomerulus, and not other glomeruli, is sufficient to elicit aversion. This is the first demonstration that activation of a specific region of the dorsal olfactory bulb is sufficient to trigger an aversive behavior indicating that the DIII domain may represent a labeled-line for aversion. Next, we examined whether moving TAAR glomeruli to an ectopic position in another dorsal domain abolishes aversive behavior to amines. We generated two different gene-targeted strains that express a TAAR coding sequence from the locus of another dorsal OR resulting in ectopically formed TAAR glomeruli outside of the DIII domain. In the first strain, all OSNs expressing the swapped TAAR are labelled with a red fluorescent protein. This strain is used to investigate if shifting TAAR glomeruli to an ectopic position abolishes amine aversion in a place preference assay. These mice are now actively breeding and we expect to have the results shortly. In the second strain, all OSNs expressing the swapped TAAR co-express channelrhodopsin as well as a yellow fluorescent protein. Using optogenetic activation during a place preference assay, we demonstrate that light stimulation of an ectopically formed TAAR glomerulus outside of the DIII domain fails to induce behavioral aversion. Together, these findings indicate that the location of the olfactory input is important to elicit aversion. All experimental outcomes support the idea that the TAARs normally feed into a hard-wired neuronal circuit from a particular bulb location (domain) that mediates aversion. This intriguing finding suggests that the dorsal domain organization of the olfactory bulb may relate to valence - a novel finding.
