Importance of olfactory and vomeronasal systems for male sexual function

Abstract

Chemosensory cues stimulate male sexual arousal and behavior. The main olfactory system has an important role in attracting males to estrous females, and the vomeronasal receptors are important for activating accessory olfactory pathways that engage mating behavior in a sexually dimorphic manner. The gonadotropin releasing hormone (GnRH) neurons like the vomeronasal organ (VNO) neurons take their origin in the olfactory placode and migrate to the basal forebrain along pathfinder axons that take their origin in the developing VNO. The maturation of both systems is synchronized in time such that the early postnatal testosterone surge masculinizes the VNO neural relay en route to the medio preoptic area (MPOA). Although VNO slices and VNO receptor neurons in culture respond to volatile odors, in vivo electrophysiological recordings at the first relay in the accessory olfactory bulb (AOB) are silent until the male makes active nuzzling investigations of the female. The VNO neurons may therefore respond to volatiles that are transported into the organ on carrier peptides that themselves may play a part in receptor activation. In the context of modern molecular phylogenetic studies, it is becoming less likely that pheromones acting via the VNO have any part to play in human sexual behavior, but the possibility exists for conserved VNO genes influencing human reproduction via fertilization.

Introduction

Vertebrates have evolved dual olfactory systems, which differ in their anatomy, central projections, and function [1]. The main olfactory system has receptors coded for by over 1000 genes [2], the largest mammalian family of G-protein-coupled receptors, which are capable of responding to an almost infinite variety of volatile odors derived from both the inanimate ecological and social environments. Receptors in the accessory (vomeronasal) olfactory pathway are divided into two distinct families (V1r, V2r) and are coded for by approximately 300 genes [3], [4], [5]. These are thought to be capable of responding to both volatile and nonvolatile odors. The vomeronasal pathway links directly with limbic brain structures that are important for both the development and expression of primary motivated behavior (sexual, aggressive and maternal behavior) and is required for the activation of neuroendocrine pathways involved with reproduction. Although the influence of olfactory cues on sexual behavior has been known for many years, it was not until 1975 [6] that the first paper appeared implicating the vomeronasal organ (VNO). It would seem from these early studies that the vomeronasal system is important for male sexual behavior in the hamster, but not essential for it, whereas lesions of the olfactory mucosa have little or no effect. Lesions of both systems completely eliminate male courtship and sexual activity.

Sexual experience is also important for male sexual behavior in a number of mammalian species (hamster, rat, mouse, ferret, sheep, monkey), and experienced males prefer the odors of estrous females over those from pregnant or lactating females. The cues important for hamster female attractiveness and male sexual behavior take their origins in vaginal secretions and include a volatile component, dimethyl disulfide, which actively promotes male investigative behavior [7]. A second component, aphrodisin, is a protein that probably acts as a carrier for ligands. Aphrodisin belongs to the lipocalin family [8], which is recognized as a transporter of low molecular weight hydrophobic molecules [9], and which facilitates their access to VNO receptors that are surrounded by a coating of watery mucous. Aphrodisin also stimulates male hamster copulatory behavior, and this effect is dependent on the vomeronasal pathway [10].

Likewise, in mice, urine contains major urinary proteins (MUPs), which also belong to the lipocalin family and bind ligands (e.g., brevicomin and thiazole) [11]. These proteins serve as a reservoir for the extended release of volatiles over time [12] and also gain entry to the vomeronasal organ [13], where they may deliver volatiles and be a part of the transduction process, since V2Rs have extended N-terminals thought to bind peptides [14], [15]. By analogy, lipocalins present in rat urine are themselves able to induce receptor-mediated G-protein activation of vomeronasal neurons even when deprived of natural ligands [14].

It is generally believed that recognition of the opposite sex involves the main olfactory pathway, and this has been demonstrated to be the case in ferrets, pig, monkeys, and rodents. There is a second component to mate recognition that is more specific to the individual, and this individual recognition is important in the context of inbreeding avoidance, pair bonding, and pregnancy block. It was also generally believed that the vomeronasal system, through its close connections with the reproductive hypothalamus, was the primary pathway for bringing about neuroendocrine changes of the kind involved in puberty acceleration, estrous induction, and pregnancy block, as well as the testosterone increases in males on exposure to estrous urine. However, these clear-cut demarcations of function for the main olfactory system (attraction, recognition) versus the vomeronasal system (use of peptides and neuroendocrine modulation) are not quite as distinct as we were once led to believe. Peptides are important as transporters of volatiles to the VNO, and mate recognition can involve the VNO, while in some species like the sheep, the neuroendocrine “male effect” involves the main olfactory system [16]. With the advent of molecular genetic studies, many of the functional distinctions in earlier studies can be viewed as part of an integrated response system between the dual olfactory systems.