Peripheral oxytocin injection modulates vomeronasal sensory activity and reduces pup-directed aggression in male mice

Abstract

Behaviors are shaped by hormones, which may act either by changing brain circuits or by modifying sensory detection of relevant cues. Pup-directed behaviors have been previously shown to change via action of hormones at the brain level. Here, we investigated hormonal control of pup-induced activity in the vomeronasal organ, an olfactory sensory structure involved in the detection of non-volatile chemosignals. Vomeronasal activity decreases as males switch from a pup-aggressive state to a non-aggressive parenting state, after they socially contact a female. RNA sequencing, qPCR, and in situ hybridization were used to identify expression, in the vomeronasal sensory epithelium, of candidate GPCR hormone receptors chosen by in silico analyses and educated guesses. After identifying that oxytocin and vasopressin receptors are expressed in the vomeronasal organ, we injected the corresponding hormones in mice and showed that oxytocin administration reduced both pup-induced vomeronasal activity and aggressive behavior. Conversely, injection of an oxytocin receptor antagonist in female-primed male animals, which normally exhibit reduced vomeronasal activity, significantly increased the number of active vomeronasal neurons. These data link oxytocin to the modulation of olfactory sensory activity, providing a possible mechanism for changes in male behavior after social experience with females.

Sensory Detection by the Vomeronasal Organ Modulates Experience-Dependent Social Behaviors in Female Mice

“…We previously showed that Gαi2 is necessary for the detection of small organic pheromones by apical VSNs, and genetic ablation of these neurons severely impairs pup-directed aggression in virgin males ( Trouillet et al, 2019 ). This is consistent with published studies that show that pup cues preferentially activate neurons located in the apical VNO and the anterior AOB in virgin males ( Tachikawa et al, 2013 ; Nakahara et al, 2020 ). Our results show higher c-Fos activation in the anterior AOB after pup-exposure ( Figures 1C,D ), indicating that pups are also preferentially detected by Gαi2+ VSNs in virgin females.…”

“…Not only centrally controlled neural changes, but also sensory organ sensitivity to olfactory stimuli have been suggested to have an influence. In particular, previous studies report a decline in VNO activity induced by pup cues in virgin males after cohabitation with a pregnant female ( Tachikawa et al, 2013 ; Nakahara et al, 2020 ), suggesting the existence of a silencing mechanism at the level of VSNs. We can thus speculate that a similar process may occur in females after parturition, either induced by hormonal changes intrinsic to gestation, or by repeated exposure to pups.…”

“…Indeed, pup retrieval is improved in virgin females after co-housing with a dam and litter, even after ovariectomy ( Ehret et al, 1987 ; Koch and Ehret, 1989 ; Stolzenberg and Rissman, 2011 ; Elyada and Mizrahi, 2015 ), suggesting that pup signals modulate the behavioral response. In this scenario, hormones such as oxytocin may influence experience-dependent plasticity directly at the sensory processing level ( Fleming et al, 1979 ; Marlin et al, 2015 ; Nakahara et al, 2020 ).…”

Oxytocin via oxytocin receptor excites neurons in the endopiriform nucleus of juvenile mice

“…Oxytocin (OXT) is a nine amino acid neuropeptide that acts through the oxytocin receptor (OXTR) to generate physiological responses in adult mammals, such as facilitating milk let down for lactation, and labor and delivery. OXT also acts in the central nervous system to modulate social behavior by facilitating social learning and memory 1 , 2 , social recognition 3 – 5 , social reward 6 , 7 , pair-bond formation 8 , 9 , parental care 10 – 13 , sexual behavior 14 – 17 , and by reducing aggression 18 , 19 . Specifically, activation of OXT producing neurons in the paraventricular nucleus (PVN) of the hypothalamus and subsequent OXT release increases social behavior, while reduced activation of these neurons results in a decrease in social behavior 20 .…”

Oxytocin via oxytocin receptor excites neurons in the endopiriform nucleus of juvenile mice

“…Oxytocin (OXT) is a nine amino acid neuropeptide that acts through the oxytocin receptor (OXTR) to generate physiological responses in adult mammals, such as facilitating milk let down for lactation, and labor and delivery. OXT also acts in the central nervous system to modulate social behavior by facilitating social learning and memory 1,2 , social recognition [3][4][5] , social reward 6,7 , pair-bond formation 8,9 , parental care [10][11][12][13] , sexual behavior [14][15][16][17] , and by reducing aggression 18,19 . Specifically, activation of OXT producing neurons in the paraventricular nucleus (PVN) of the hypothalamus and subsequent OXT release increases social behavior, while reduced activation of these neurons results in a decrease in social behavior 20 .…”