Sex differences in vasopressin and oxytocin innervation of the brain
Introduction
An impressive number of studies have implicated vasopressin (AVP) and oxytocin (OXT) in centrally regulated functions and behaviours. Initially, such studies focused on functions such as learning and memory (De Wied, 1969), cardiovascular functions (Versteeg et al., 1983), thermoregulation (Cooper et al., 1979; Kasting, 1989), territorial (Ferris et al., 1984) and reproductive behaviours including parental behaviour (Bohus, 1977; Pedersen et al., 1982; Södersten et al., 1985; Wang et al., 1994a). More recently, the focus has shifted to prosocial behaviours. A Medline search using ‘vasopressin’, ‘vasotocin’, ‘oxytocin’ and ‘social behaviour’ as keywords currently reveals over 500 papers, most of which published in the last decade. For example, these neuropeptides have been linked to social recognition memory and to parental, affiliative and aggressive behaviours (Carter et al., 1995; Albers and Bamshad, 1998; Engelmann et al., 2000; Young and Wang, 2004).
The neural substrate underlying vasopressin (AVP) and OXT's behavioural effects is less clear. For example, OXT is widely known to stimulate maternal behaviour (Lim and Young, 2006), but which OXT projections contribute to these effects is unclear. Knowing which cell groups synthesize and which terminals release AVP and OXT to modulate specific functions is crucial to understand how the brain uses these peptides to influence behaviour. Sex differences in AVP and OXT pathways offer a unique opportunity to address this question.
We found sex differences in AVP projections from the bed nucleus of the stria terminalis (BNST) and medial amygdaloid nucleus (MeA) by chance, while studying the development of what we thought were projections from the suprachiasmatic nucleus (SCN) to the lateral septum in rats. After finding a large variability among subjects, we repeated the study, now separating subjects by sex. This revealed a much higher AVP fibre density in males than in females from the second postnatal week onward (De Vries et al., 1981). Later, we and others traced the origin of these fibres to the BNST (De Vries and Buijs, 1983) and MeA (Caffé et al., 1987), where males showed about two to three times more AVP cells than females (Van Leeuwen et al., 1985; Miller et al., 1989b; Szot and Dorsa, 1993; Wang and De Vries, 1995).
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Causes of sex differences in AVP projections
In mammals, differences in gonadal hormone levels are a main cause of neural sex differences (Becker et al., 2005). Early in life, gonadal hormones direct the differentiation of neural circuitry that will, in adulthood, generate male or female-typical functions and behaviours. These developmental effects are permanent and therefore called ‘organizational effects’. For example, testosterone exposure during development increases the likelihood that animals show male sexual behaviour as adults.
Effects of circulating hormones in adulthood
In rats, circulating gonadal steroids drive AVP expression in BNST and MeA projections. Gonadectomy eliminates AVP expression whereas treatment with gonadal steroids reverses these changes (De Vries et al., 1984, 1985; Van Leeuwen et al., 1985; Miller et al., 1989a). These changes are relatively slow. In males, AVP immunoreactivity disappears from BNST and MeA projections in about 2–3 months (De Vries et al., 1984); mice show an equally slow decline (Mayes et al., 1988). AVP mRNA levels per
Oestrogen versus androgen effects
Testosterone influences AVP production by androgen as well as oestrogen receptor-mediated mechanisms. In castrated male rats, estradiol, an oestrogenic metabolite of testosterone, partially restores AVP expression, whereas dihydrotestosterone, an androgenic metabolite of testosterone, does not by itself restore AVP expression. However, in combination with estradiol, it enhances AVP expression to control male levels (De Vries et al., 1986, De Vries et al., 1994; Wang and De Vries, 1995).
Hormones and sex differences in AVP expression
The activational effects of gonadal hormones on AVP expression suggest that differences in circulating gonadal hormones contribute to differences in BNST and MeA projections. However, such differences cannot fully explain all sex differences, because treating gonadectomized males and females with similar amounts of testosterone does not eliminate differences in AVP cell number and the density of their projections (De Vries and Al Shamma, 1990; Wang et al., 1993; De Vries et al., 1994).
Sex chromosomes in sex differences in AVP expression
We tested this possibility using a model system that can distinguish between differences caused by sex chromosomal complement (XX vs. XY) or different gonads (testes vs. ovaries) (De Vries et al., 2002). In this model, female mice with an XX genotype were crossed with males with an XY−Sry genotype. The Y chromosome of XY−Sry mice lack the Sry gene, which normally directs the differentiation of the primordial gonad into a testis (Koopman et al., 1991). XY−Sry mice develop a male phenotype
Cellular mechanisms underlying differentiation of AVP expression
Two fundamentally different sets of processes could cause differences in AVP cell number: processes such as cell birth, cell death, or cell migration, or processes that influence the phenotype of existing cells. Differential cell birth and migration are unlikely, because AVP cells are born at least a week before hormones trigger their sexual differentiation (Wang et al., 1993; Al-Shamma and De Vries, 1996). Differential cell death can probably be ruled out as well, because the sex difference
The origin of sexually dimorphic AVP innervation
Steroid responsiveness has been helpful in differentiating projections from the most conspicuous sources of AVP innervation in the brain, i.e. the SCN, paraventricular nucleus (PVN), BNST and MeA (Fig. 1B) (De Vries and Miller, 1998). For example, our proposal that the BNST and MeA are the sources of sexually dimorphic AVP innervation (DeVries et al., 1985) has been widely accepted. This proposal, however, was based on a rather limited set of experiments performed primarily to locate the source
Sex differences in other AVP systems
Although PVN and SCN AVP projections do not show sex differences as global as those shown by BNST and MeA projections, partial sex differences have been found. For example, AVP innervation of the medial preoptic nucleus and periventricular nucleus of the hypothalamus likely originates in the SCN (Kriegsfeld et al., 2004). In gerbils, projections to the former nucleus are denser in males whereas the latter do not differ (Crenshaw et al., 1992). This discrepancy may be related to sex differences
Function of sex differences in AVP expression
The widespread occurrence of the sex differences in BNST and MeA projections suggests that they serve a function important enough to be conserved through evolution. Figuring out this function is intimately connected to determining the role of AVP in the brain. This task is made easier by the large amount of research devoted to this peptide. Ever since De Wied introduced the neuropeptide concept inspired by AVP's (and ACTH's) effects on learning and memory (De Wied, 1969), many studies have
Lessons from spotted hyenas and prairie voles
Spotted hyenas show unusual sexual differentiation. For example, female hyenas develop a phallus as large as that of a male (Matthews, 1939; Watson, 1877). They also show a reversal of typical sex difference in behaviour, with female hyenas being socially dominant and more aggressive than males (Matthews, 1939; Hamilton et al., 1986). Although the lack of sexual differentiation in peripheral tissue is not well understood, unusually high androstenedione levels in females during development and
Dual function for sex differences in the brain
Inspired by these findings we proposed that sex differences can cause or prevent sex differences in specific behaviours or centrally regulated functions (De Vries and Boyle, 1998). This hypothesis is perfectly testable. One would predict that, in the former case, blocking AVP neurotransmission would blunt or eliminate sex differences and that, in the latter case, blocking would cause a sex difference that was not there before. In fact, such tests have already been done. For example, AVP
Clinical implications
A more complete understanding of the development and function of sex differences in AVP and OXT innervation may also provide novel clues as to the origin of behavioural disorders such as depression, autism and schizophrenia (De Vries, 2004; Ring, 2005; Landgraf, 2006; Carter, 2007). Each of these disorders shows sex differences in occurrence (Altemus, 2006; Goldstein, 2006; Knickmeyer and Baron-Cohen, 2006), and, in case of AVP, can be linked to variability in AVP signalling, such as elevated
Abbreviations
- AVP
vasopressin
- AVT
vasotocin
- BNST
bed nucleus of the stria terminalis
- MeA
medial nucleus of the amygdala
- OXT
oxytocin
- SCN
suprachiasmatic nucleus
Acknowledgement
This paper was written while the author was funded by NIH grants MH47538 and MH01497.
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