Raphe serotonin neuron‐specific oxytocin receptor knockout reduces aggression without affecting anxiety‐like behavior in male mice only

Abstract

Serotonin and oxytocin influence aggressive and anxiety-like behaviors, though it is unclear how the two may interact. That the oxytocin receptor is expressed in the serotonergic raphe nuclei suggests a mechanism by which the two neurotransmitters may cooperatively influence behavior. We hypothesized that oxytocin acts on raphe neurons to influence serotonergically-mediated anxiety-like, aggressive and parental care behaviors. We eliminated expression of the oxytocin receptor in raphe neurons by crossing mice expressing Cre recombinase under control of the serotonin transporter promoter (Slc6a4) with our conditional oxytocin receptor knockout line. The knockout mice generated by this cross are normal across a range of behavioral measures: there are no effects for either sex on locomotion in an open-field, olfactory habituation/dishabituation or, surprisingly, anxiety-like behaviors in the elevated O and plus mazes. There was a profound deficit in male aggression: only one of 11 raphe oxytocin receptor knockouts showed any aggressive behavior, compared to eight of 11 wildtypes. In contrast, female knockouts displayed no deficits in maternal behavior or aggression. Our results show that oxytocin, via its effects on raphe neurons, is a key regulator of resident-intruder aggression in males but not maternal aggression. Furthermore, this reduction in male aggression is quite different from the effects reported previously after forebrain or total elimination of oxytocin receptors. Finally, we conclude that when constitutively eliminated, oxytocin receptors expressed by serotonin cells do not contribute to baseline anxiety-like behaviors or maternal care.

Honing in On Hormone-Sensitive Neural Targets for Therapeutic Intervention: Mission Impossible?

“…Approximately, a fourth of serotonergic neurons in the dorsal raphe express OTR and, conversely, a third of OTR expressing neurons in the raphe are serotonergic. These neuroanatomical results are consistent with the observation that although OT acts in the raphe to reduce anxiety [22], this may not be due to OT action directly on serotonergic neurons because knocking out OTR from serotonergic cells had no effect on anxiety-like behavior [23]. These data suggest that OT's anxiolytic effects in the raphe may instead be coordinated by nonserotonergic neurons.…”

The serotonin system in autism spectrum disorder: From biomarker to animal models

“…They found that presynaptic OT receptors on dorsal raphe projections within the accumbens induce release of 5-HT and, further, that the activation of the post-synaptic 5-HT 1B receptors is necessary to establish social preference (Dölen et al, 2013). Another study used conditional knockout mice to demonstrate that male mice lacking the OT receptor on 5-HT neurons showed lower frequency of aggression than wild type mice; whereas female mice did not exhibit genotype effects on behavior (Pagani et al, 2015). This sex difference is important, but few other studies in mice have included female animals in their analyses.…”

Distribution of oxytocin and co-localization with arginine vasopressin in the brain of mice

“…In women, OT increases the VTA activation to salient sexual and infant stimuli (Gregory et al 2015) in nulliparous and postpartum women, respectively. Finally, the raphe magnus shows a specific OT-ir innervation, from which OT can act on serotoninergic neurons (Eaton et al 2012;Mottolese et al 2014) modulating anxiety (Yoshida et al 2009) and aggression (Pagani et al 2015).…”