In the brain, a subset of neuromodulatory GPCRs localize to the primary cilia of neurons, altough their function remains unclear. To investigate a role for primary cilia in modulating neuronal function in the olfactory bulb (OB) we characterized the expression and localization of several known ciliary GPCRs. Using in situ hybridization and immunofluorescence labelling we analyzed the expression of SSTR3, MCHR1, DRD1, DRD2, HTR6, CHRM2, CHRM3, CHRM5, and GPR161. Of these, DRD1, HTR6, SSTR3, and MCHR1 localized to cilia of neurons in the OB. MCHR1, the only melanin-concentrating hormone (MCH) receptor in the mouse genome, localized to inhibitory granule cells and glomerular interneurons, but not excitatory mitral and tufted cells. The localization of MCHR1 suggests a mechanism by which interneurons can be modulated by the hypothalamic neuropeptide MCH. To further support this connection, we labelled hypothalamic MCH neurons using cre-dependent AAVs expressing fluorescent reporters. Fibers from MCH neurons were detected in both the glomerular and granule cell layers of the OB, and could be seen in close proximity to cilia. To determine if MCHR1 signaling influences odor coding we perfromed calcium imaging of the OB. Using anesthetized Thy1-GCaMP6 mice we find that application of MCH to the OB reduces glomerular responses to odors (t(99) = 10.98, p <0.0001). Conversely, application of the MCHR1 antagonist SNAP-94847 increases responses (t(157) = 5.425, p <0.0001). To test specificity, we crossed Thy1-GCaMP6 mice with a novel MCHR1 knockout model we created. In contrast to wildtype littermates, MCHR1 knockout mice do no show increased glomerular responses when the MCHR1 antagonist is applied. Combined these data higlight both a role for ciliary signaling in the modulation of neuronal activity, and identify a specific hypothalamic peptide capable of modulating odor responses in the OB.

This project is supported by NIH NIDCD R01DC019379