Oxytocin Signaling in the Lateral Septum Prevents Social Fear during Lactation

Abstract

Oxytocin (OXT)-mediated behavioral responses to social and stressful cues have extensively been studied in male rodents. Here, we investigated the capacity of brain OXT receptor (OXTR) signaling in the lateral septum (LS) to prevent social fear expression in female mice using the social-fear-conditioning paradigm. Utilizing the activated OXT system during lactation, we show that lactating mice did not express fear 24 hr after social fear conditioning. Supporting the role of OXTR signaling in the LS in attenuation of social fear, synthetic OXT infusion or overexpression of OXTR in the LS diminished social fear expression, whereas constitutive OXTR knockout severely impaired social fear extinction in virgin mice. Subsequently, both pharmacological blockade of local OXTRs in the LS and chemogenetic silencing of supraoptic nucleus OXTergic afferents to the LS increased social fear expression in lactating mice. Hence, LS-projecting OXT neurons suppress social fear in female mice.

Tracking oxytocin functions in the rodent brain during the last 30 years: From push‐pull perfusion to chemogenetic silencing

“…The stylette was replaced with the push-cannula, and four consecutive 30-minute perfusates were sampled at 20 μL min -1 . 4,5,14,[29][30][31][32] Based on the finding that the activity of hypothalamic OXT neurones and OXT secretion into blood is under strong inhibition by endogenous opioids peripartum, 33,34 we hypothesised that the lack of a detectable rise in OXT release within the septum and dorsal hippocampus during birth is because of opioid restraint. Following sampling under basal conditions (ie, in the absence of the litter), the dam was reunited with the pups for 30 minutes, and both maternal behaviour and the occurrence of milk ejection reflexes were monitored during ongoing push-pull perfusion.…”

“…5 To date, our SFC study described above 5 provides the endpoint of our ongoing research, starting with the article in the first issue of the Journal of Neuroendocrinology and extending from a description of suckling-induced release of OXT in the septum using push-pull perfusion to the chemogenetic inhibition of such local release and then revealing its involvement in social fear extinction. 5 To date, our SFC study described above 5 provides the endpoint of our ongoing research, starting with the article in the first issue of the Journal of Neuroendocrinology and extending from a description of suckling-induced release of OXT in the septum using push-pull perfusion to the chemogenetic inhibition of such local release and then revealing its involvement in social fear extinction.…”

“…However, we could not detect an association between the specific rise in local OXT (or AVP) release during birth and the delivery of pups, indicating that such release within the limbic brain occurs independently of peripheral secretion of OXT into blood, and may rather prepare the maternal brain for substantial behavioural and physiological adaptations. 4,5,14,[29][30][31][32] Based on the finding that the activity of hypothalamic OXT neurones and OXT secretion into blood is under strong inhibition by endogenous opioids peripartum, 33,34 we hypothesised that the lack of a detectable rise in OXT release within the septum and dorsal hippocampus during birth is because of opioid restraint. Indeed, s.c.…”

“…The interest in the OXT system has especially been developed in the last 30 years by the discovery of a plethora of behavioural and physiological effects, both in animals and humans. 4,5 The nonapeptide OXT and the closely-related AVP are synthesised in defined nuclei of the hypothalamus, which substantially form the hypothalamic-neurohypophysial system (HNS) in mammals. 1,2 Here, in accordance with the focus of this special issue of the Journal of Neuroendocrinology celebrating its first volume in 1989, we give a very personal view and track our own lines of research, starting with the description of OXT release within limbic brain regions using the method of push-pull perfusion during suckling in the freely moving lactating rat, as published in this very first volume.…”

“…Thus, we will continue by describing the temporal and scientific bridge towards the use of state-of-the-art methodologies allowing the specific and sensitive identification of OXT pathways and their involvement in behavioural adaptations in lactation via a combination of behavioural models, neuronal tracing, and immunohistochemical, transgenic and pharmacogenetic approaches, some 30 years later. 4,5 The nonapeptide OXT and the closely-related AVP are synthesised in defined nuclei of the hypothalamus, which substantially form the hypothalamic-neurohypophysial system (HNS) in mammals.…”