Oxytocin structure and function in New World monkeys: from pharmacology to behavior

Abstract

Oxytocin (OT) is a hypothalamic nonapeptide that mediates a host of physiological and behavioral processes including reproductive physiology and social attachments. While the OT sequence structure is highly conserved among mammals, New World monkeys (NWMs) represent an unusual "hot spot" in OT structure variability among mammals. At least 6 distinct OT ligand variants among NWMs exist, yet it is currently unclear whether these evolved structural changes result in meaningful functional consequences. NWMs offer a new area to explore how these modifications to OT and its canonical G-protein coupled OT receptor (OTR) may mediate specific cellular, physiological and behavioral outcomes. In this review, we highlight relationships between OT ligand and OTR structural variability, specifically examining coevolution between OT ligands, OTRs, and physiological and behavioral phenotypes across NWMs. We consider whether these evolved modifications to the OT structure alter pharmacological profiles at human and marmoset OTRs, including changes to receptor binding, intracellular signaling and receptor internalization. Finally, we evaluate whether exogenous manipulation using OT variants in marmoset monkeys differentially enhance or impair behavioral processes involved in social relationships between pairmates, opposite-sex strangers, and parents and their offspring. Overall, it appears that changes to OT ligands in NWMs result in important changes ranging from cellular signaling to broad measures of social behavior.

Binding Characteristics of Two Oxytocin Variants and Vasopressin at Oxytocin Receptors from Four Primate Species with Different Social Behavior Patterns

“…Moreover, Pro 8 -OT increases the amount of social behavior that an OT-treated marmoset receives from its mate and reduces sociosexual behavior directed toward individuals other than the pairmate (Cavanaugh et al, 2014;Mustoe et al, 2015). Leu 8 -OT does affect some social behavior in marmosets, but Leu 8 -OT never enhances a social behavior that Pro 8 -OT does not also enhance (Mustoe et al, 2018). The binding and signaling data support these behavioral findings.…”

“…Other characteristics of these receptors, such as differential coupling to specific Ga subunits or bias for G proteins versus b-arrestin, are beyond the scope of this project but are nonetheless interesting future directions. The OTR is capable of coupling to a variety of Ga subunits resulting in a variety of cellular outcomes [see Gimpl and Fahrenholz (2001) and Mustoe et al (2018) for detailed reviews], and there is a need for and a value to the production and characterization of ligands that are functionally selective at the OTR as tools to target specific signaling cascades. Indeed, even relatively small modifications to the OT ligand can alter the functional selectivity at the OTR, causing it to couple to different Ga subunits (Busnelli et al, 2012), and it is already known that Pro 8 -OT is less efficacious than Leu 8 -OT at promoting b-arrestin recruitment and internalization at the human receptor (Parreiras-E-Silva et al, 2017).…”

“…Moreover, OXTR variation is associated with social monogamy among primates (Ren et al, 2015), and OT ligand variation at position 8 is associated with litter size within the family Cebidae (Vargas-Pinilla et al, 2015). Both native and non-native OT ligands modulate social behavior in NWMs expressing Pro 8 -OT (French et al, 2016), but the native Pro 8 -OT is more effective at modulating behavior than the ancestral Leu 8 -OT in the marmoset, a monogamous and biparental NWM (Cavanaugh et al, 2014;Mustoe et al, 2015Mustoe et al, , 2018. Together these findings indicate that both OT ligand variation and the corresponding variations in OTRs among NWMs contribute to functional outcomes.…”

Oxytocin regulates reunion affiliation with a pairmate following social separation in marmosets

“…Further, we tested OT ligand-specificity in modulating social behaviorby administering two unique OT ligands: Leu 8 -OT, the consensus mammalian ligand variant; Pro 8 -OT, the ligand variant present in marmosets (French, Taylor, Mustoe, & Cavanaugh, 2016; Mustoe, Taylor, & French, 2018; Ren et al, 2015). We monitored broad patterns of affiliative behavior immediately upon reunion, including initiated and received grooming behavior, and social proximity to the partner.…”

“…In this paper, we explore the role of the OT system in regulating initiated and received affiliative behavior during reunion following short and long social separation and social isolation in adult heterosexual pairs of marmosets via pharmacological manipulation of the OT system. Further, we tested OT ligand-specificity in modulating social behaviorby administering two unique OT ligands: Leu 8 -OT, the consensus mammalian ligand variant; Pro 8 -OT, the ligand variant present in marmosets (French, Taylor, Mustoe, & Cavanaugh, 2016; Mustoe, Taylor, & French, 2018; Ren et al, 2015). We monitored broad patterns of affiliative behavior immediately upon reunion, including initiated and received grooming behavior, and social proximity to the partner.…”