Oxytocin: The great facilitator of life

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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.

Introduction

Oxytocin (Oxt) is a nonapeptide hormone best known for its role in lactation and parturition. The word “oxytocin” was coined from the Greek words (ωκνξ, τoκoxξ) meaning “quick birth” after its uterine-contracting properties were discovered by Dale (1906). Shortly thereafter, the milk ejection property of Oxt was described (Ott and Scott, 1910, Schafer and Mackenzie, 1911). The nine amino acid sequence of Oxt was elucidated in 1953 (du Vigneaud et al., 1953b, Tuppy, 1953) and synthesized soon after (du Vigneaud et al., 1953a, du Vigneaud et al., 1954). Prior to the determination of the structure of the preprohormone from the cloned gene for Oxt (Ivell and Richter, 1984), oxytocin was shown to be cleaved from a precursor containing a neurophysin polypeptide during axonal transport to the posterior pituitary (Brownstein et al., 1980). Its sole known receptor (Oxtr) was cloned in 1992 (Kimura et al., 1992). These landmark studies have paved the way for a large body of work, covering not only on the roles of Oxt in the periphery, but as we will review, in the central nervous system control of behavior.

Oxt is composed of nine amino acids (Cys–Tyr–Ile–Gln–Asn–Cys–Pro–Leu–GlyNH2) with a sulfur bridge between the two cysteines (Fig. 1). The structure of Oxt is very similar to another nonapeptide, vasopressin (Avp), which differs from Oxt by two amino acids. Oxt and Avp are neuropeptides that are evolutionarily well conserved across phyla (Acher et al., 1995, Caldwell and Young, 2006). As a result of gene duplication, the Oxt gene is located on the same chromosome (chromosome 2 in mice and 20 in humans) as Avp but is oriented in opposite transcriptional direction in mammals. Both Oxt and Avp contain three exons and two introns and are highly homologous. The two genes are separated by an intergenic region (IGR) that varies in length across species (e.g., 11 kb in rat and human, and 3.6 kb in mouse). The IGR harbors regulatory DNA sequences within conserved portions for both Oxt and Avp (Gainer et al., 2001, Young and Gainer, 2003, Young and Gainer, 2009). The preprohormone consists, in order, of the signal peptide, the nanopeptide (Oxt), and the neurophysin (Fig. 1).

Oxytocin is currently known to have only one receptor (Oxtr), unlike Avp which has at least three different subtypes (Caldwell et al., 2008). Oxtr belongs to the rhodopsin-type (class I) G protein-coupled receptor (GPCR) family and is coupled to phospholipase C through Gαq11 (Gimpl and Fahrenholz, 2001, Young and Gainer, 2003). Much work has gone into creating agonists and antagonists (both peptides and small molecules) with specificity for the Oxtr and little if any activity at the Avp receptors (Manning et al., 2008). Two well known Oxt antagonists are Atosiban (deamino-[D-Tyr2–(O-ethyl)–Thr4–Orn8]vasotocin) (Akerlund et al., 1985), and OVTA (Elands et al., 1988). Atosiban is clinically used to delay premature delivery (Zingg and Laporte, 2003). However, both antagonists have an affinity for the vasopressin receptor (Avpr) 1a (Akerlund et al., 1999, Manning et al., 1995). Non-peptide Oxtr antagonists such as SSR126768 (Serradeil-Le Gal et al., 2004) and GSK2211149A (McCafferty et al., 2007) have higher specificity and may eventually find clinical use. Synthetic Oxt (known as Pitocin) is used to induce labor and to help milk production (Hayes and Weinstein, 2008). Non-peptide agonists are also under development (Manning et al., 2008). As central Oxt is involved in many behaviors, the use of agonists and antagonists for peripheral indications will need close scrutiny to assess unintended behavioral effects due to passage of the agents through the blood brain barrier. Excellent reviews are available (Gimpl, 2008, Manning et al., 2008).

Oxytocin is primarily synthesized in magnocellular neurons of the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. The bulk of the peptide is transported to the posterior pituitary where it is released to regulate parturition and lactation. However, some of the Oxt is transported into the dendrites where regulation of its release is critical for controlling the firing patterns of the Oxt neurons (Rossoni et al., 2008). Lesser amounts of Oxt are generated by smaller, parvocellular neurons of the PVN and, depending on species, the bed nucleus of the stria terminalis (BNST), medial preoptic area, and lateral amygdala for release within the brain (Young and Gainer, 2003, Young and Gainer, 2009).

The distribution of Oxtr expression within the central nervous system (CNS) of numerous species has been examined using in situ hybridization histochemistry (Ostrowski, 1998, Yoshimura et al., 1993), a transgenic mouse model (Gould and Zingg, 2003), and receptor autoradiography. A number of species, including rat (De Kloet et al., 1985a, Freund-Mercier et al., 1987, Kremarik et al., 1993, van Leeuwen et al., 1985, Veinante and Freund-Mercier, 1997), mouse (Insel et al., 1991), vole (Insel and Shapiro, 1992), and human (Loup et al., 1989, Loup et al., 1991), have been studied by receptor autoradiography, a technique that indicates where the receptor is transported after synthesis. Sexual and species differences exist in the distributions of the Oxtr, even within the same genus, and these differences are believed to explain certain variations in behavior (see Section 2). In general, however, Oxtr is widely distributed throughout the brain. In rodents, it is often especially prominent in the olfactory bulb (OB) and tubercle, neocortex, endopiriform cortex, hippocampal formation (especially subiculum), central and lateral amygdala, BNST, nucleus accumbens (NAcc), and ventromedial hypothalamus (VMH) (Insel et al., 1991, Veinante and Freund-Mercier, 1997) (Fig. 2). In humans, expression is prominent in the basal nucleus of Meynert, the nucleus of the vertical limb of the diagonal band of Broca, the ventral part of the lateral septal nucleus, the preoptic/anterior hypothalamic area, the posterior hypothalamic area, the substantia nigra pars compacta, and the substantia gelatinosae of the caudal spinal trigeminal nucleus and of the dorsal horn of the upper spinal cord, as well as in the medio-dorsal region of the nucleus of the solitary tract (Loup et al., 1989, Loup et al., 1991).

It should be emphasized, as Leng and colleagues discuss (Leng et al., 2008b), that there is not always a match between Oxt immunoreactive terminals and receptor concentrations. Their work shows that dendritic release from magnocellular PVN and SON neurons can influence behavior (Ludwig and Leng, 2006). They suggest, for example, that the lordotic response (see below), shown to rely on VMH Oxtr, may reflect action of Oxt that diffused to the VMH from the PVN and SON after dendritic release (Sabatier et al., 2007).

Oxt and Oxtr expression is usually higher in females (Carter, 2007, Zingg and Laporte, 2003). The central roles of Oxt on behaviors and physiology are strongly dependent on steroid hormones (discussed below) and gender, and Oxt and Oxtr distributions between brains of different sexes have been reported (Carter, 2007, Insel et al., 1991, Tribollet et al., 1992, Tribollet et al., 1997). For example, the numbers of Oxt-immunostained cells and the amounts of Oxt found in females far exceed the numbers and amounts found in males along with greater numbers of oxytocin-immunostained axons (Haussler et al., 1990). In female but not male, rats Oxt binding is increased by high levels of maternal stimulation during infancy, suggesting that epigenetic influence can alter the Oxtr expression in a sex-specific manner (Francis et al., 2002). Sexually dimorphic expression of Oxt binding is observed in some brain regions where Oxt is known to have behavioral effects, such as the VMH, while other areas such as the central nucleus of the amygdala, do not show sexual dimorphism (Uhl-Bronner et al., 2005).

Estrogen receptor (ER) β is present in magnocellular neurons of the PVN and SON (Forsling et al., 2003, Hrabovszky et al., 2004). The ERβ mRNA expression there is negatively regulated by basal glucocorticoid secretion and by hyperosmotic stimulation (Somponpun et al., 2004). The rat and human Oxt gene promoters contain estrogen-response elements (ERE) and are stimulated by estrogen (E) and thyroid hormones (Mohr and Schmitz, 1991, Richard and Zingg, 1990). A recent in vivo study suggests that E action on the Oxt gene is more likely to involve a DNA-independent mechanism than direct regulation by ERs (Stedronsky et al., 2002). Interestingly, the poly(A) tail, which is important for mRNA stability, is increased by osmotic stimulation (Carter and Murphy, 1989) and blocked by gonadectomy (Crowley and Amico, 1993).

It is well known that E stimulates expression of Oxtr in the uterus (see Richter et al. (2004) and references therein) and greatly increases the expression in the kidney (Breton et al., 1996, Ostrowski et al., 1995). Oxtr expression increases in the myoepithelial cells of the breast during pregnancy and lactation (Soloff, 1982). In rats, Oxtr binding and mRNA levels in the brain are increased with E and testosterone treatment and decreased by castration (Breton and Zingg, 1997, Larcher et al., 1995, Stevenson et al., 1994, Tribollet et al., 1990). However, this effect may depend on the species studied (Insel et al., 1993). Oxtr expression also increases in a number of brain areas just prior to parturition (Meddle et al., 2007), accompanied by a concomitant increase in gonadal hormones, particularly E (Rosenblatt et al., 1988).

The VMH is an important nucleus for the regulation of sex behavior and the role of Oxtr within the VMH has been the focus of intense study. Within the VMH of males and females, Oxtr is particularly sensitive to gonadal steroids (Bale and Dorsa, 1995, Bale et al., 1995, Coirini et al., 1989, De Kloet et al., 1985b, De Kloet et al., 1986, Johnson et al., 1991, Quinones-Jenab et al., 1997).

There are complete palindromic EREs in the promoters of the Oxtr genes of mice and rats (Bale and Dorsa, 1997, Kubota et al., 1996), as well as half-palindromic EREs in those of mice, rats and humans (Inoue et al., 1994, Kubota et al., 1996, Rozen et al., 1995). It is likely that E can act on the half palindromic EREs, albeit with lower affinity (Sanchez et al., 2002). A recent study suggests that a membrane bound receptor for E may also regulate expression within the PVN and SON (Sakamoto et al., 2007). The Oxtr gene has several other response elements in its promoter, including an interleukin response element, a cAMP response element, and AP-1, AP-2, AP-3, and AP-4 sites (Bale and Dorsa, 1998, Gimpl and Fahrenholz, 2001, Rozen et al., 1995). E-induced Oxtr binding in the brain is abolished in ER-α knockout (KO) mice, whereas the basal Oxtr expression in the brain of the KO mice is similar to controls (Young et al., 1998).

A large number of studies have utilized KO mouse models. Oxt KO mice were first introduced in 1996 by two groups (Nishimori et al., 1996, Young et al., 1996b). Oxt KO mice display normal parturition even though female KO do not show milk ejection (Nishimori et al., 1996, Young et al., 1996b). These two groups later independently generated Oxtr KO mice (Lee et al., 2008, Takayanagi et al., 2005) with one line showing late-onset obesity (Takayanagi et al., 2008). The other line is a conditional KO that allows temporal and spatial Oxtr elimination (Lee et al., 2008). Detailed descriptions of the behavioral deficits in these Oxt and Oxtr KOs are presented in Section 2.

Other eliminated genes have significant effects on Oxt expression or effectiveness. For example, absence of the basic helix–loop–helix-PAS Sim1 (Michaud et al., 1998) or the POU protein Brn-2 (Nakai et al., 1995, Schonemann et al., 1995) genes lead to elimination of magnocellular neurons of the PVN and SON. As absence of Sim1 also leads to lack of Brn-2, it would seem that Sim1 functions upstream of Brn-2 (Michaud et al., 1998). Knockout mice lacking CD38, a protein that aids in release of Oxt show decreased release of Oxt accompanied by defects in maternal and social behaviors (Jin et al., 2007).

Section snippets

Behavior

Oxt is involved in the regulation of a wide variety of behaviors; many times, these behaviors are intertwined (e.g., more social species tend to have monogamous relationships and to be biparental). To better elucidate the role Oxt has in each of these behaviors, we have separated this review into two broad categories: social behaviors and non-social behaviors. Within each category we will separately discuss various behaviors affected by Oxt, with a concerted effort to draw out the similarities

Love, bonding, and Trust

While many studies indicate Oxt as a facilitator to pair bonding and parental care in animal studies (see Section 2.1.2), data from human studies is inconclusive. Generally, it is believed that Oxt facilitates social interactions and feelings of attachment in humans. Heterosexual couples receiving intranasal Oxt prior to a videotaped “conflict discussion” display significantly increased positive communication behaviors (such as eye contact, self-disclosure, and positive body language) than

Concluding remarks

In the current review, we have detailed the role of Oxt in a variety of behaviors, including recognition of previously met conspecifics, affiliation, sexual behavior, and reduction of anxiety. In light of the prominent role in parturition and essential role in lactation, we are drawn to the view that Oxt serves the continued propagation of a species. As indicated in Fig. 5, the cycle of life has numerous points at which Oxt intercedes. In ancient species such as earthworms, leeches, and

Acknowledgement

This work was supported by the NIMH Intramural Research Program (Z01-MH-002498-20).

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    These authors contributed equally (in alphabetical order).

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