Subtle sex differences in vasopressin mRNA expression in the embryonic mouse brain

Abstract

Arginine vasopressin (AVP) is a neuropeptide which acts centrally to modulate numerous social behaviors. One receptor subtype through which these effects occur is the AVP 1a receptor (AVPR1A). The modulatory effects of Avp via the AVPR1A varies by species as well as sex, since both AVP and the AVPR1A tend to be expressed more prominently in males. Beyond these neuromodulatory effects there are also indications that the AVP system may play a role in early development to, in part, organize sex‐specific neural circuitry that is important to sexually dimorphic social behaviors in adulthood. However, to date, AVP's role in early development is poorly understood, particularly with respect to its differential effect on males and females. In order to determine the timing and distribution of the AVP system in early brain development, we examined the brains of male and female C57BL/6J mice between embryonic day (E) 12.5 and postnatal day (P) 2 and quantified Avp and Avpr1a mRNA using qPCR and AVPR1A protein using receptor autoradiography. The mRNA for Avp was measurable in males and females starting at E14.5, with males producing more than females, while Avpr1a mRNA was found as early as E12.5, with no difference in expression between sexes. AVPR1A binding was observed in both sexes starting at E16.5, and while there were no observed sex differences, binding density and the number of neuroanatomical areas did increase over time. These data are significant as they provide the first whole‐brain characterization of the vasopressin system in the embryonic mouse. Further, these findings are consistent with data from other species, that have documented a sex difference in the vasopressin system during early brain formation.

AVPR1A distribution in the whole C57BL/6J mouse neonate

“…Additionally, sampling availability may be reduced for certain tissues, such as the VNO, that are small and prone to damage during sectioning. As AVPR1A has previously been explored with autoradiography in the neonatal mouse brain 14,19,29 , the brain was not quantified in the autoradiography portion of our study. Receptor autoradiography with selective ligands remains the technical standard for robust and specific identification of tissues expressing functional G protein coupled receptors.…”

“…Additionally, sampling availability may be reduced for certain tissues, such as the VNO, that are small and prone to damage during sectioning. As AVPR1A has previously been explored with autoradiography in the neonatal mouse brain 14 , 19 , 29 , the brain was not quantified in the autoradiography portion of our study.…”

Sex differences in chronic pain-induced mental disorders: Mechanisms of cerebral circuitry

“…The past and current literature have indicated that neurotransmitters and neuromodulators systems such as norepinephrine (Joshi and Chandler, 2020 ), dopamine (Hasbi et al, 2020 ), serotonin (Zhang et al, 2017 ), GABA (Cerne et al, 2022 ), and oxytocin (Tamborski et al, 2016 ; Aulino and Caldwell, 2020 ) seemed to be strongly involved in pain-related sexually dimorphic mental disorders (Dazzi and Scicchitano, 2014 ). Differences in concentrations (Busch et al, 1997 ), receptors (Hasbi et al, 2020 ), and transporters (Zachry et al, 2021 ) of these neurotransmitters and neuromodulators sexual differences may be potential targets for explaining sex differences in pain-related mental disorders.…”

“…More than one study has suggested that activation of OTR in the VTA is critical for the expression of reward-like properties of social interactions (Song et al, 2016 ; Borland et al, 2018 ). However, there are clear sex differences in the embryonic development of Oxt /OTR, which may indicate sex differences in their involvement in pain/behavior (Tamborski et al, 2016 ; Aulino and Caldwell, 2020 ). In clinical studies, the expression of Oxt at rs4813625, a single nucleotide polymorphism linked to Oxt was found to correlate more with nociception, anxiety, and wellbeing in females, while no such correlation was found in males (Love et al, 2012 ).…”

Integrative single-cell characterization of hypothalamus sex-differential and obesity-associated genes and regulatory elements

“…Our findings are in line with previous studies. For example, AVP is more highly expressed in male GABAergic and glutamatergic neurons than in females and previous studies have shown that AVP, which regulates various social behaviors, including aggression and mating in males, has a higher expression in male hypothalamus than females 97,98 . We also found higher expression of VIP in female GABAergic neurons than males.…”