Lost connections: Oxytocin and the neural, physiological, and behavioral consequences of disrupted relationships

Abstract

In humans and rodent animal models, the brain oxytocin system is paramount for facilitating social bonds, from the formation and consequences of early-life parent-infant bonds to adult pair bond relationships. In social species, oxytocin also mediates the positive effects of healthy social bonds on the partners' well-being. However, new evidence suggests that the negative consequences of early neglect or partner loss may be mediated by disruptions in the oxytocin system as well. With a focus on oxytocin and its receptor, we review studies from humans and animal models, i.e. mainly from the biparental, socially monogamous prairie vole (Microtus ochrogaster), on the beneficial effects of positive social relationships both between offspring and parents and in adult partners. The abundance of social bonds and benevolent social relationships, in general, are associated with protective effects against psycho- and physiopathology not only in the developing infant, but also during adulthood. Furthermore, we discuss the negative effects on well-being, emotionality and behavior, when these bonds are diminished in quality or are disrupted, for example through parental neglect of the young or the loss of the partner in adulthood. Strikingly, in prairie voles, oxytocinergic signaling plays an important developmental role in the ability to form bonds later in life in the face of early-life neglect, while disruption of oxytocin signaling following partner loss results in the emergence of depressive-like behavior and physiology. This review demonstrates the translational value of animal models for investigating the oxytocinergic mechanisms that underlie the detrimental effects of developmental parental neglect and pair bond disruption, encouraging future translationally relevant studies on this topic that is so central to our daily lives.

Figure 1. Local OT release within the NAcc shell of male prairie voles is affected by central CRFR2 manipulations

Blockade of CRFR2 by astressin-2B (CRFR2 antagonist) decreases the release of OT, whereas activation of CRFR2 by stresscopin (CRFR2 agonist) increases OT release. In continuation, such CRFR2-evoked (de-) activation of OT signalling in the NAcc shell has similar effects on passive-stress coping as local OTR manipulation in the NAcc shell. In detail, synthetic OT rescues the increased passive stress-coping after separation whereas the OTR antagonist increases passive stress-coping in non-separated males.

Figure 2. Scheme of the influence of CRFR2 on OT signalling from the PVN to the NAcc shell under paired conditions as well as following the loss of the partner

Separation from the pair bonded partner induces the release of CRFR ligands, which bind to CRFR2 on glutamatergic neurons, thereby inhibiting their activity. The resulting decreased excitability of OT neurons in the PVN causes decreased OT mRNA expression in neurones projecting to the NAcc shell. Subsequently, reduced OT mRNA expression may cause reduced OT-carrying large dense-core vesicles (LDCVs), thereby leading to impaired OT release within the NAcc shell. Furthermore, activation of CRFR2 on the terminals of OT neurons in the NAcc causes a decrease of OT release within the NAcc. In addition, OTR density within the NAcc shell is decreased following separation from the partner. Hence, loss of the partner results in impaired OT signalling from the PVN to the NAcc shell on multiple levels due to heightened brain CRFR2 activation.