Mutual influences between the main olfactory and vomeronasal systems in development and evolution

Abstract

The sense of smell plays a crucial role in the sensory world of animals. Two chemosensory systems have been traditionally thought to play-independent roles in mammalian olfaction. According to this, the main olfactory system (MOS) specializes in the detection of environmental odorants, while the vomeronasal system (VNS) senses pheromones and semiochemicals produced by individuals of the same or different species. Although both systems differ in their anatomy and function, recent evidence suggests they act synergistically in the perception of scents. These interactions include similar responses to some ligands, overlap of telencephalic connections and mutual influences in the regulation of olfactory-guided behavior. In the present work, we propose the idea that the relationships between systems observed at the organismic level result from a constant interaction during development and reflects a common history of ecological adaptations in evolution. We review the literature to illustrate examples of developmental and evolutionary processes that evidence these interactions and propose that future research integrating both systems may shed new light on the mechanisms of olfaction.

Keywords: axon guidance; cell migration; cerebral cortex; neuroethology; neurogenesis; odorant; pheromone.

Figure 1

Schematic representation of the main olfactory (MOS) and vomeronasal systems (VNS) in mice. (A) Sensory neurons of the MOS are located in the nasal cavity at the olfactory epithelium (OE), Grüneberg ganglion (GG), and septal organ (SO), from where they send projections to the OB. Neurons of the VNS are located in the vomeronasal organ (VNO) and send axonal projections to the accessory olfactory bulb (AOB). (B) Central projections of the OB (pink and orange) terminate at the anterior olfactory nucleus (AON), tenia tecta (TT), olfactory tubercule (OT), piriform cortex (Pir), nucleus of the lateral olfactory tract (NLOT), anterior cortical nucleus (ACN) and posterolateral cortical nucleus (PLCN) of the amygdala, and entorhinal cortex (ENT). Central projections of the VNS are shown in dark gray, the accessory olfactory bulb (AOB) projects to the bed nucleus of the stria terminalis (BNST), the bed nucleus of the accessory olfactory tract (BAOT), the medial amygdala anteroventral (MEAav), posterodorsal (MEApd), posteroventral (MEApv), and posteromedial cortical nucleus (PMCN).

Figure 2

Schematic representation of the spatio-temporal neurogenic pattern and its connections within the olfactory systems during embryonic development in the mouse. (A) At approximately embryonic day 9.5 (E9.5), the olfactory placode starts to form with the first signs of neurogenesis in the presumptive OE, while the first neurons are generated by E11 at the OB and by E10 at the OC. (B) The first axons emerging from the olfactory placode are identified before E10.5, and they form clear olfactory and vomeronasal nerves between E11 and E12, which form synapses in the OB and AOB around E13.5 (dotted lines suggest the first axons from the VNO arriving into the AOB). (A) First LOT axons (AOB) are observed between E11.5 and E12 and (B) LOT covers the OC surface by E13.5. (C) Axon collaterals emerge from the LOT in gross amount E15.5, colonizing the OC structures. (D) OSN axons, diffusely innervating the OB at E13.5, reorganize topographically innervating protoglomeruli by E17.5 in a process which extends until postnatal stages (not illustrated). The maturation of synapses between OSN and OB neurons occurs by E17–E18, while AOB synapses mature by the end of the first postnatal week (not illustrated). The definitive OB and AOB layering depends on the arrival of the prospective interneurons generated in their neurogenic niche at the forebrain SVZ (see text for details).

Figure 3

Transcription factors controlling generation and maturation of OSN and VSN. The OSN (top) and VSN (bottom) lineages are illustrated in parallel. Inhibitory feedback mechanisms are proposed to be acting on intermediate progenitor cells by mature neurons as well as regulation of stem cell pool by intermediate progenitors. See text and references therein for further explanations.

Figure 4

Molecules involved in the formation of the olfactory and vomeronasal nerves and the LOT. (A) Sagittal section of the rodent forebrain representing the olfactory structures. Panel (a1) represents the wiring between the OE and the OB, where each OSN expresses a single olfactory receptor gene and the axons from all cells expressing that particular receptor converge onto one or a few glomeruli (GL) in the OB. Molecules secreted from the OB form the olfactory nerve are represented as “+” when they attract/promote axon growth and as “−” when they repel/inhibit it. Spatial IGF-1, Sema 3A, Sema 3F, and Slit-1 gradients are crucial to address axons to their zonal targets within the OB. Panels (a2 and a3) show in detail the VNO and the AOB structures and their connections, with layer-specific representation of the cues involved in the process. (B) Schematics showing the spatial relationship of the centripetal projections from the OB (in green) and AOB (in blue) to their recipient structures in the cortex. Abbreviations: AOB, accessory olfactory bulb; AON, anterior olfactory nucleus; GL, glomerular layer; GrL, granule layer; LOT, lateral olfactory tract; ML, mitral cell layer; OB, olfactory bulb; OE, olfactory epithelium; OEG, olfactory ensheathing glia; ON, olfactory nerve; OSN, olfactory sensory neuron; RMS, rostral migratory stream; SVZ, subventricular zone; OT, olfactory tubercle; VNO, vomeronasal organ.

Figure 5

Schematic representation of SVZ and GnRH neuroblast migration within the olfactory system. (A) During development, neuroblasts originated in the lateral ganglionic eminences migrate toward the OB (red cells). GnRH-1 neuroblasts (green cells) generated in the OE follow the olfactory and vomeronasal axons on their way to the hypothalamus. (B) In the adult, the contingent of migrating SVZ neuroblasts (in red) forms the RMS toward the OB, whereas GnRH neurons (in green) are located in several areas comprising the preoptic area and the hypothalamus. The inset on the right illustrates the aspect of mature RMS, with the chains of migrating neuroblasts (in red) advancing among astrocytic channels (in yellow). Once they reach the OB, SVZ neuroblasts migrate radially to their final targets within the OB (left panel). Abbreviations: EP, external plexiform layer; GL, glomerular layer; GCL, granule layer; LOT, lateral olfactory tract; M, mitral cells; OB, olfactory bulb; OE, olfactory epithelium; OSN, olfactory sensory neuron; RMS, rostral migratory stream; SVZ, subventricular zone; VNO, vomeronasal organ.

Figure 6

Evolution of the vertebrate MOS and VNS. Cladogram showing the phylogenetic relationships of vertebrate species and relevant events related to the evolution of the MOS and VNS (A) according to the following numbers: 1, presence of a primitive olfactory system; 2, evolution of the classical vertebrate olfactory receptor (OR) genes; 3, evolution of the olfactory projections and origin of V1R and TRPC2 genes; 4, origin of V2R genes; 5, expression of ORs, V2R, and V1R in the OE; 6, origin of a distinctive VNS (VNO-AOB-MeA projection); 7, segregation of vomeronasal pathways; shift in receptor ratios associated to land colonization; 8, differential expression of G-proteins in aquatic vs. terrestrial species; 9, reduction of OR gene repertoire in aquatic species; 10, loss of the VNS in Archosauria; 11, expansion of vomeronasal structures in lepidosaurs; 12, evolution of bird-specific OR genes; 13, expansion of OR gene repertoire in terrestrial/nocturnal birds. (B) Evolution of the mammalian MOS and VNS. Cladogram showing the phylogenetic relationships of mammalian species and relevant events related to the evolution of the MOS and VNS. 1, Two-pathway segregated VNS, AOB dorsal to the OB; 2, amplification of V1R genes; 3, non-exclusive segregation of AOB glomeruli expressing Gα_i2 and Gα_o proteins; 4, loss of the V2R—Gα_o pathway; 5, pseudogenization of OR genes; 6, loss of the vomeronasal system; 7, loss of the OBs; 8, lateral AOB innervation and cell indentation between AOB subdomains.