Oxytocin: the great facilitator of life

Abstract

Oxytocin (Oxt) is a nonapeptide hormone best known for its role in lactation and parturition. Since 1906 when its uterine-contracting properties were described until 50 years later when its sequence was elucidated, research has focused on its peripheral roles in reproduction. Only over the past several decades have researchers focused on what functions Oxt might have in the brain, the subject of this review. Immunohistochemical studies revealed that magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei are the neurons of origin for the Oxt released from the posterior pituitary. Smaller cells in various parts of the brain, as well as release from magnocellular dendrites, provide the Oxt responsible for modulating various behaviors at its only identified receptor. Although Oxt is implicated in a variety of "non-social" behaviors, such as learning, anxiety, feeding and pain perception, it is Oxt's roles in various social behaviors that have come to the fore recently. Oxt is important for social memory and attachment, sexual and maternal behavior, and aggression. Recent work implicates Oxt in human bonding and trust as well. Human disorders characterized by aberrant social interactions, such as autism and schizophrenia, may also involve Oxt expression. Many, if not most, of Oxt's functions, from social interactions (affiliation, aggression) and sexual behavior to eventual parturition, lactation and maternal behavior, may be viewed as specifically facilitating species propagation.

Fig. 1

Schematic diagram of the oxytocin and vasopressin genes (large arrows), preprohormones (boxes), and neuropeptides (bottom). Their human chromosomal location is shown at the top. Both genes are composed of three exons shown as small blue arrows and separated by two introns (shown as dotted lines between the exons). The genes are located on the same chromosome but are transcribed in opposite directions and separated by an intergenic region (IGR). The IGR length varies across species. The preprohormones each contain a signal peptide (SP), a neuropeptide (Avp or Oxt), and a neurophysin (NP). In the case of Avp, a glycopeptide (GP) as well. Protein processing signals are represented by thick lines. Cysteine residues form a disulfide bond to create a cyclic six amino acid ring for both neuropeptides. Seven out of the nine amino acids are identical in the neuropeptides and two are different (red). Adapted and modified from (Caldwell et al., 2008).

Fig. 2

Disruption of the Oxtr in mouse forebrain by Camk2a-driven Cre recombinase expression. Oxtr levels were examined by receptor binding in coronal sections from adult WT (A B, C), Oxtr^FB/FB (D, E, F), and Oxtr^−/− (G, H, I) mice. Most areas in the forebrain of Oxtr^FB/FB mice show decreased levels of binding, with the notable exception of the medial amygdala (MA). Oxtr^−/− mice show only background levels. Exposure was for 3 weeks to X-ray film (C). Abbreviations: Am, amygdala; AON, anterior olfactory nucleus; CP, caudate-putamen; Ctx, cerebral cortex; Hi, hippocampal formation; LS, lateral septum; MA, medial amygdala; OB, olfactory bulb; PC, piriform cortex; VP, ventral pallidum. Scale bar equals 0.5 cm. From (Lee et al., 2008).

Fig. 3

Social recognition by Oxtr WT and KO males, as examined with the two-trial social recognition task. Investigation times of stimulus females during Trial 1 were equal across genotypes, indicating no motivational or olfactory differences. During Trial 2, Oxtr WT males display remember the previous stimulus females, represented by significantly less time investigating those female from Trial 1 (“familiar”) as compared to new females (“novel”); *p < 0.05 by t-test between familiar and novel. In contrast, Oxtr KO males spend equal times investigating the “familiar” and “novel” females, indicating a reduced ability to remember the familiar female and impaired social recognition. Adapted from (Lee et al., 2008).

Fig. 4

The effects of treatment with saline, 10 mg/kg of amphetamine, 10 mg/kg of apomorphine, or 6 mg/kg of phencyclidine on the prepulse inhibition of the startle reflex (PPI) percentage in Oxt WT (A) and KO (B) mice. Data were analyzed using a repeated measures analysis of variance. There were main effects of drug treatment, but not genotype. Compared to saline, treatment with amphetamine, apomorphine, and phencyclidine all had an effect on PPI percentage and there was a prepulse intensity-dependent increase in PPI percentage across all groups. There was an interaction between drug and genotype. Specifically, in Oxt KO mice, treatment with phencyclidine resulted in impaired PPI compared to saline treatment in Oxt WT mice. From (Caldwell et al., 2009).

Fig. 5

A simple cycle of life illustrates numerous points at which Oxt may affect behaviors and physiology to facilitate the propagation of the species.