The precise regulation of digestive and other physiological processes in the gastrointestinal tract in accordance with the food ingested requires continuous monitoring of the luminal content by chemosensory cells. With regard to the detection of chemical compounds in the lumen of the gastrointestinal tract, G-protein-coupled receptors (GPCRs) are interesting signaling proteins, since some of them are well known to bind to macronutrients, including sugars, amino acids and lipids. We report that Olfr78, a member of the odorant receptor (OR) class of GPCRs, is expressed in the murine gut. Our results support the concept that Olfr78 is activated by propionate, an important nutrient generated in the colon by microbiota. In situ hybridization and immunohistochemical approaches show that Olfr78 is expressed in the colon but is absent from other gastrointestinal compartments, such as the stomach and small intestine. In the colon, Olfr78 is expressed by a subset of epithelial cells lining the crypts; these cells are endowed with an apical process protruding towards the crypt lumen. The Olfr78-positive cells in the colon co-express the hormonal peptide YY (PYY), a marker for given enteroendocrine cells. The expression of the propionate receptor Olfr78 in epithelial enteroendocrine cells of the colon suggests that Olfr78 is involved in the regulation of hormone secretion from such cells, as evoked by nutritional compounds.

Within the main olfactory system of mammals, a unique subsystem exists that is comprised of sensory neurons expressing odorant receptors (ORs) of the OR37 subfamily. These receptors are exclusive for mammals and are highly conserved across species. The mouse OR37 receptor subtypes A, B and C were shown to be activated by the long-chain aliphatic aldehydes pentadecanal, hexadecanal and heptadecanal, respectively. The search for biological sources of these compounds showed that bodily secretions from conspecifics activated the OR37A, B and C glomerulus. At the same time, the activity of cells in a target region of projection neurons from OR37 glomeruli, the paraventricular nucleus of the hypothalamus (PVN), was reduced compared with controls (clean test box). A large number of the activated cells in the PVN of mice that were placed into a clean test box were corticotropin-releasing hormone cells, indicating an induction of the stress axis due to the novel environment. The much lower number of activated cells of mice in a box enriched with bodily secretions from conspecifics indicated a reduced stress response. As bodily secretions from conspecifics activated the OR37 system and simultaneously reduced stress-induced activation of the PVN, it was tested whether the ligands for OR37 receptors could induce this effect. Indeed, a similarly reduced activity in the PVN was found in mice kept in a clean test box and exposed to a mixture of the OR37 ligands delivered via an air stream. These data indicate that the OR37 system may play a role in mediating a phenomenon called social buffering.

The capacity of the mammalian olfactory system to detect an enormous collection of different chemical compounds is based on a large repertoire of odorant receptors (ORs). A small group of these ORs, the OR37 family, is unique due to a variety of special features. Members of this subfamily are exclusively found in mammals, they share a high degree of sequence homology and are highly conserved during evolution. It is still elusive which odorants may activate these atypical receptors. We have reasoned that compounds from skin, hairs, or skin glands might be potential candidates. We have exposed mice to such compounds and monitored activation of glomeruli through the expression of the activity marker c-fos in juxtaglomerular cells surrounding ventrally positioned glomeruli in the olfactory bulb (OB). Employing this methodology it was found that stimulation with long-chain alkanes elicits activation in the ventral part of the OB, however, none of the OR37 glomeruli. Analyses of long-chain hydrocarbon compounds with different functional groups revealed that long-chain aliphatic aldehydes elicited an activation of defined OR37 glomeruli, each of them responding preferentially to an aldehyde with different chain lengths. These results indicate that OR37 receptors may be tuned to distinct fatty aldehydes with a significant degree of ligand specificity.

In search for biological sources of the long-chain fatty aldehydes (penta-, hexa-, and heptadecanal), which we recently identified as ligands for members of the mouse odorant receptor subfamily OR37, the headspace of secretions and excretions from mice was analyzed by gas chromatography and mass spectrometry. In urine, skin swabs, and saliva, these components were not detectable. However, in fecal pellets, a substantial amount of hexadecanal, the OR37B ligand, was found. Accordingly, exposure of mice to feces induced an activation of the OR37B glomerulus, whereas the OR37A and the OR37C glomerulus were not responsive. The amount of hexadecanal deposited with feces varied significantly; however, it was independent of the amount of feed. In many species, feces is covered with secretion from anal glands. Due to the size and the inaccessibility of these glands in mice, the headspace of anal gland secretion from dog was analyzed by gas chromatography-mass spectrometry, which resulted in a prominent peak for hexadecanal. Exposure of mice to anal gland secretion from dog activated the OR37B glomerulus. Altogether, these data suggest that hexadecanal, a ligand for the receptor OR37B, is produced in anal glands and deposited with feces into the environment.

The subventricular zone (SVZ) provides a constant supply of new neurons to the olfactory bulb (OB). Different studies have investigated the role of olfactory sensory input to neural precursor cell (NPC) turnover in the SVZ but it was not addressed if a reduced demand specifically for periglomerular neurons impacts on NPC-traits in the rostral migratory stream (RMS). We here report that membrane type-1 matrix metalloproteinase (MT1-MMP) deficient mice have reduced complexity of the nasal turbinates, decreased sensory innervation of the OB, reduced numbers of olfactory glomeruli and reduced OB-size without alterations in SVZ neurogenesis. Large parts of the RMS were fully preserved in MT1-MMP-deficient mice, but we detected an increase in cell death-levels and a decrease in SVZ-derived neuroblasts in the distal RMS, as compared to controls. BrdU-tracking experiments showed that homing of NPCs specifically to the glomerular layer was reduced in MT1-MMP-deficient mice in contrast to controls while numbers of tracked cells remained equal in other OB-layers throughout all experimental groups. Altogether, our data show the demand for olfactory interneurons in the glomerular layer modulates cell turnover in the RMS, but has no impact on subventricular neurogenesis.

Olfactory sensory neurons (OSNs) which express distinct odorant receptor (OR) genes are spatially arranged within the mouse olfactory epithelium. Towards an understanding of the mechanisms which determine these patterns, representative OR genes which are typically expressed in the unique central patch of the epithelium were investigated. Inside the patch, numerous OSNs which initially selected a representative gene from this OR group finally expressed another gene from the group, indicating that OSNs inside the patch 'switch' between these genes. If an OSN successively chose genes from the same OR gene cluster, these originated from the same parental chromosome. A deletion of the olfactory cyclic nucleotide-gated ion channel altered the distribution pattern of distinct OSN populations; they were no longer located exclusively inside the patch. Together, the results indicate that OSNs inside the patch initially sample several OR genes for expression; for their correct patterning in the OE, odor-induced activity appears to play a critical role.