Genetic dissection of pheromone processing reveals main olfactory system-mediated social behaviors in mice

Abstract

Most mammals have two major olfactory subsystems: the main olfactory system (MOS) and vomeronasal system (VNS). It is now widely accepted that the range of pheromones that control social behaviors are processed by both the VNS and the MOS. However, the functional contributions of each subsystem in social behavior remain unclear. To genetically dissociate the MOS and VNS functions, we established two conditional knockout mouse lines that led to either loss-of-function in the entire MOS or in the dorsal MOS. Mice with whole-MOS loss-of-function displayed severe defects in active sniffing and poor survival through the neonatal period. In contrast, when loss-of-function was confined to the dorsal MOB, sniffing behavior, pheromone recognition, and VNS activity were maintained. However, defects in a wide spectrum of social behaviors were observed: attraction to female urine and the accompanying ultrasonic vocalizations, chemoinvestigatory preference, aggression, maternal behaviors, and risk-assessment behaviors in response to an alarm pheromone. Functional dissociation of pheromone detection and pheromonal induction of behaviors showed the anterior olfactory nucleus (AON)-regulated social behaviors downstream from the MOS. Lesion analysis and neural activation mapping showed pheromonal activation in multiple amygdaloid and hypothalamic nuclei, important regions for the expression of social behavior, was dependent on MOS and AON functions. Identification of the MOS-AON-mediated pheromone pathway may provide insights into pheromone signaling in animals that do not possess a functional VNS, including humans.social behavior | pheromone processing | main olfactory system | vomeronasal system M ost mammals have two major olfactory subsystems-the main olfactory system (MOS) and vomeronasal system (VNS). The MOS comprises the main olfactory epithelium (MOE), in which olfactory sensory neurons detect odorants, and their projection target, the main olfactory bulb (MOB) (Fig. S1A). Although the MOS is thought to detect volatile odorants and the VNS is thought to be important for the detection of nonvolatile pheromones, evidence shows that the MOS is also involved in pheromone detection (1-8). Surgical blocking of odorant access to the MOE, but not surgical ablation of the vomeronasal epithelium (VNE), eliminates preference to odors from the opposite sex in ferrets (9, 10). In mice, chemical ablation of the MOE impairs male and female sexual behaviors (11,12). In these experiments in which the MOE was ablated, the function of the VNS is not directly disrupted, because the VNS is activated by direct application of urine to the nostril. Thus, these results indicate that the MOS also contributes to pheromone processing and related behaviors.Nonconditional disruption of genes encoding signal transduction proteins that are required for activation of olfactory neurons, such as cyclic nucleotide-gated channel (Cnga2) or adenylyl cyclase 3, impairs several social behaviors (11,(13)(14)(15). However, complete loss of MOS function causes a...

Importance of the GluN2B carboxy-terminal domain for enhancement of social memories

“…The main olfactory system detects mainly volatile odorants and MHC molecules (Spehr et al 2006) via the main olfactory epithelium which projects to the main olfactory bulb and the anterior olfactory nucleus. The vomeronasal system is important for the detection of nonvolatile pheromones and major histocompatibility complex (MHC) molecules (Leinders-Zufall et al 2004) by activation of the vomeronasal epithelium which projects to the accessory olfactory bulb (Matsuo et al 2015). The two subsystems provide complementary information when the animal is confronted by another animal.…”

Activating transcription factor 5 (ATF5) is essential for the maturation and survival of mouse basal vomeronasal sensory neurons

“…The involvement of the main olfactory system (MOS) in vomeronasal phenotypes is evident from studies with MOS loss-of-function mouse models (Mandiyan et al 2005;Wang et al 2006;Matsuo et al 2015). We therefore could not rule out the possibility that the defect of maturation and survival of VSNs might be due to the indirect effect of the global ATF5 deficiency, since at least MOS in ATF5 −/− mice also have abnormal phenotypes (Wang et al 2012;Umemura et al 2015).…”

“…Actually, the size of the olfactory bulb is reduced in ATF5 −/− mice compared with that in the wild-type (Umemura et al 2015), and olfactory sensory neurons (OSNs) in the ATF5 −/− MOE remain immature and frequently undergo apoptosis (Wang et al 2012;Umemura et al 2015). In addition, ATF5 −/− mice display reduced inter-male aggression (Umemura et al 2015), and this behavior is regulated by the vomeronasal sensory system (Stowers et al 2002;Chamero et al 2011;Prince et al 2013), but also by the main olfactory sensory system (Mandiyan et al 2005;Wang et al 2006;Matsuo et al 2015). In this study, we investigated the effect of deficiency of ATF5 in VSNs using ATF5 −/− mice.…”

The neural circuits of mating and fighting in male mice

“…Unconditional disruption of genes that encode signal transduction proteins that are required for activating olfactory neurons resulted in the impairment of several social behaviors [61–63]. More recently, Mastuo et al selectively deleted the dorsal part of the MOB and found that the manipulation reduced aggression towards males and also ultrasonic vocalization towards females, whereas copulatory behavior remained relatively unchanged [64]. However, these mutant mice lacking the dorsal MOB showed mostly normal investigation towards a conspecific and the activity in the AOB was unchanged.…”