Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior

“The right column depicts representative rat brain images adapted from The Rat Brain Atlas (Paxinos & Watson, 1998).”

“The first studies to report intranasal OT effects in humans were done in males only, showing a role for OT in trust and in the processing of socially relevant information (Kosfeld et al., 2005; Zak et al., 2007; Domes et al., 2007; Guastella et al., 2008a; Guastella et al., 2008b; Di Simplicio et al., 2009).”

“…neurons in the PVN, SON, and accessory nucleus of the hypothalamus (Ross et al., 2009, Knobloch et al., 2012) project centrally, where OT can modulate the activity of many brain regions via binding to the widely distributed OT receptor (OTR; Jard et al., 1987; Gimpl and Fahrenholz, 2001).”

“…Fliers et al., 1985; Weirda et al., 1991; Meynen et al., 2007) or LH, AH, and MPOA (hamsters, gerbils, voles, naked mole rats: Brownstein et al., 1980; Dierickx, 1980; Rhodes et al., 1981; Swanson and Sawchenko, 1983; Wang et al., 1996; Rosen et al., 2008; Xu et al., 2010; Wang et al., 2013).”

“…potential of the OT system to restore social dysfunction in sex-biased psychiatric disorders (Guastella et al., 2010a; Meyer-Lindenberg et al., 2011; Cochran et al., 2013), and recent initiatives from the NIH requiring the inclusion of both sexes in preclinical research (Clayton & Collins, 2014).”

“This may further gain momentum because of the potential of the OT system to restore social dysfunction in sex-biased psychiatric disorders (Guastella et al., 2010a; Meyer-Lindenberg et al., 2011; Cochran et al., 2013), and recent initiatives from the NIH requiring the inclusion of both sexes in preclinical research (C…”

“Furthermore, intranasal VP administration in humans was associated with an increase in VP concentration in cerebrospinal fluid (Born et al., 2002).”

“…studies to report intranasal OT effects in humans were done in males only, showing a role for OT in trust and in the processing of socially relevant information (Kosfeld et al., 2005; Zak et al., 2007; Domes et al., 2007; Guastella et al., 2008a; Guastella et al., 2008b; Di Simplicio et al., 2009).”

“Here, impaired social recognition was found in male OTR KO mice (Takayanagi et al., 2005; Lee et al., 2008; Macbeth et al., 2009), male OT KO mice (Ferguson et al., 2000; Macbeth et al., 2009), and female OT KO mice (Choleris et al., 2003; Choleris et al, 2006).”

“Moreover, OT synthesized in parvocellular neurons of the PVN (Buijs, 1978; Buijs and Swaab, 1979; Sofroniew, 1980; Sofroniew, 1983) and magnocellular neurons in the PVN, SON, and accessory nucleus of the hypothalamus (Ross et al., 2009; Knobloch et al., 2012) project centrally,where OT canmodulate the activity ofmany…”

“Studies in non-human primates have also reported an absence of sex differences in OT-immunoreactive neurons in macaques (PVN, SON: Caffé et al., 1989) and marmosets (PVN, SON, BNST, MeA: Wang et al., 1997).”

“This suggests that social behaviors may be regulated by a synchrony of activity of OT and VP acting at distinct brain regions, and that a balance of OT and VP activity is necessary for the modulation of a wide range of social behaviors (Neumann & Landgraf, 2012).”

“In detail, intracerebroventricular (ICV) V1aR antagonist impaired partner preference formation in males (Winslow et al., 1993), but there was no effect in females (Insel & Hulihan, 1995).”

“…neuropeptides vasopressin (VP) and oxytocin (OT) are involved in the regulation of diverse social behaviors such as social recognition, pair-bonding, and social cognition in mammals, including humans (Veenema & Neumann, 2008; Ross & Young, 2009; MeyerLindenberg et al., 2011; Albers, 2014).”

“VP-producing magnocellular neurons of the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus project to the posterior pituitary, where VP is released into the general circulation as a hormone (Brownstein et al., 1980; Young and Gainer, 2003).”

“The first studies to report intranasal OT effects in humans were done in males only, showing a role for OT in trust and in the processing of socially relevant information (Kosfeld et al., 2005; Zak et al., 2007; Domes et al., 2007; Guastella et al., 2008a; Guastella et al., 2008b; Di Simplicio et al., 2009).”

“Interestingly, estrogens may directly regulate OTR gene expression through binding to the estrogen receptor alpha, which is a transcription factor that modulates gene transcription via interaction with estrogen response elements located on the promotor region of the OTR gene (Carson-Jurica et al., 1990; Young et al.,…”

“For example, men and women carrying one or two copies of the A allele in the most common SNP, rs53576, show reduced empathy (Rodrigues et al., 2009; Uzefovsky et al., 2015), and have lower levels of optimism, mastery, and self-esteem (Saphire-Bernstein et al., 2011), whereas reduced positive affect…”

“Here, impaired social recognition was found in male OTR KO mice (Takayanagi et al., 2005; Lee et al., 2008; Macbeth et al., 2009), male OT KO mice (Ferguson et al., 2000; Macbeth et al., 2009), and female OT KO mice (Choleris et al., 2003; Choleris et al, 2006).”

“Together, these studies demonstrate that intranasal OT can induce different behavioral responses, but even when behavioral responses are the same (Ditzen et al., 2009), the neuronal mechanisms through which OT is mediating these behavioral responses seems to be consistently different in males versus females.”

“V1aR binding densities were analyzed in non-estrus and estrus Wistar ristics defined by Goldman et al. (2007). Rats were categorized as being in proestrus/ her levels of estradiol and progesterone) or in non-estrus (n = 15; cells characteristic of V1aR binding densities were also analyzed in virgin (nulliparous, n = 1…”

“The first studies to report intranasal OT effects in humans were done in males only, showing a role for OT in trust and in the processing of socially relevant information (Kosfeld et al., 2005; Zak et al., 2007; Domes et al., 2007; Guastella et al., 2008a; Guastella et al., 2008b; Di Simplicio et al., 2009).”

“For a more comprehensive read on sex differences in brain VP and vasotocin, the reader is referred to several excellent reviews (Goodson & Bass, 2001; De Vries & Panzica, 2006; Albers, 2014).”

“Male prairie voles additionally show more VP-immunoreactive fibers in the ventral pallidum compared to females (Lim et al., 2004a).”

“For example, partner preference formation in prairie voles is modulated by the VP system acting in the LS and ventral pallidum (Liu et al., 2001; Pitkow et al., 2001; Lim & Young, 2004) and by the OT system acting in the NAc and prefrontal cortex (Young et al., 2001; Liu and Wang, 2003).”

“VP and OT systems have been implicated in sex-biased psychiatric disorders of social dysfunction, such as autism spectrum disorder and schizophrenia(Green et al., 2001; Wu et al., 2005; Jacob et al., 2007; Campbell et al., 2011; Miller et al., 2013; Di Napoli et al., 2014; Golimbet et al., 2014; Jobst et al., 2014).”

“…SNP, rs53576, show reduced empathy (Rodrigues et al., 2009; Uzefovsky et al., 2015), and have lower levels of optimism, mastery, and self-esteem (Saphire-Bernstein et al., 2011), whereas reduced positive affect (Lucht et al., 2009) and reward dependence (Tost et al., 2010) were found in men only.”

“…Fliers et al., 1985; Weirda et al., 1991; Meynen et al., 2007) or LH, AH, and MPOA (hamsters, gerbils, voles, naked mole rats: Brownstein et al., 1980; Dierickx, 1980; Rhodes et al., 1981; Swanson and Sawchenko, 1983; Wang et al., 1996; Rosen et al., 2008; Xu et al., 2010; Wang et al., 2013).”

“For example, V1aR knockout male mice show deficits in social recognition (Bielsky et al., 2004; however, see Wersinger et al., 2007).”

“…in rats, social play in rats, and aggression in hamsters has been found (Dantzer et al., 1987; Bluthe & Dantzer, 1990; Winslow et al., 1993; Insel & Hulihan, 1995; Ferris et al., 1997; Cho et al., 1999; Caldwell and Albers, 2004a; Gutzler et al., 2010; Veenema et al., 2012; Bredewold et al., 2014).”

“Here, ICV V1aR antagonist administration impaired partner preference in male voles only (Winslow et al., 1993; Insel and Hulihan, 1995) and OT administration into the LS altered social play in female juvenile rats only (Bredewold et al.”

“, 2001; Lim & Young, 2004) and by the OT system acting in the NAc and prefrontal cortex (Young et al., 2001; Liu and Wang, 2003).”

“, 1991; Ishunina and Swaab, 1999), and most human studies report a lack of sex differences in plasma OT (Zhong et al., 2012; Taylor et al., 2010; Grewen et al., 2005; Gordon et al., 2008; Gordon et al., 2010; Graugaard-Jensen et al., 2014; however see van Londen et al., 1997; Miller et al., 2013; Weisman et al., 2013).”

“(2013) Golden hamsters PVN Delville et al. (1994) Macaques BNSN, MeA, PVN, SCN, SON, dorsomedial hypothalamus, LC, NTS, diagonal band Caffé et al.”

“Specifically, V1aR antagonist injection into the AH decreased intermale aggression, while VP increased intermale aggression (Ferris et al., 1997; Caldwell and Albers, 2004a).”

“, 2012), and OT plays a stronger role in partner preference in female prairie voles compared to males (Winslow et al., 1993; Williams et al., 1994; Insel and Hulihan, 1995; Liu et al., 2001).”

“…Swaab, 1999), and most human studies report a lack of sex differences in plasma OT (Zhong et al., 2012; Taylor et al., 2010; Grewen et al., 2005; Gordon et al., 2008; Gordon et al., 2010; Graugaard-Jensen et al., 2014; however see van Londen et al., 1997; Miller et al., 2013; Weisman et al., 2013).”

“In males only, those who carried the 334 pb allele for the AVPR1A RS3, opposed to men who did not carry the 334 pb allele, had lower scores on a partner bonding scale, reported more marital problems, were more likely to be unmarried, and had lower scores of marital quality as perceived by their spouse (Walum et al., 2…”

“…necessarily related to social behavior, per se, but deficits in prepulse inhibition are observed in a variety of neuropsychiatric disorders of social dysfunction (Geyer et al., 1990; Perry et al., 2007), as well as in animal models of social dysfunction (Dieckmann et al., 2007; Koh et al., 2008).”

“Notably, distinct and non-overlapping receptor distribution profiles in rats were already reported by Tribollet et al (1988), and Veinante and Freund-Mercier (1997).”

“Even so, these studies overall suggest a correlation between OTR SNPs and differences in social processing, social behaviors, and social functioning in both sexes, with some important sex differences that perhaps may be informative in understanding the potential role of the OTR in mediating sex differences in the susc…”

“Upon its central release, VP can modulate the activation of many brain regions via binding to vasopressin receptors (discussed further in section 3.a.), thereby regulating social, emotional, and cognitive behaviors (Veenema & Neumann, 2008; Koshimizu et al., 2012; Albers, 2014).”

“VP and OT systems have been implicated in sex-biased psychiatric disorders of social dysfunction, such as autism spectrum disorder and schizophrenia(Green et al., 2001; Wu et al., 2005; Jacob et al., 2007; Campbell et al., 2011; Miller et al., 2013; Di Napoli et al., 2014; Golimbet et al., 2014; Jobst et al., 2014).”

“However, this study used [3H] OT and, like [3H] VP, [3H] OT may not exclusively bind OTR (Mouillac et al., 1995; Manning et al., 2012), and thus possibly may mask potential sex differences in OTR binding.”

“For example, while subcutaneous injections of VP enhanced social recognition in male (Dantzer et al., 1987) and female (Bluthe & Dantzer, 1990) rats, a subcutaneous injection of the VP antagonist, dPTyr(Me)AVP, blocked social recognition in male rats only (Dantzer et al., 1987; Bluthe & Dantzer,…”

“VP and OT systems have been implicated in sex-biased psychiatric disorders of social dysfunction, such as autism spectrum disorder and schizophrenia(Green et al., 2001; Wu et al., 2005; Jacob et al., 2007; Campbell et al., 2011; Miller et al., 2013; Di Napoli et al., 2014; Golimbet et al., 2014; Jobst et al., 2014).”

“Local VP release in the brain has been measured in male (Veenema et al., 2010; Lukas et al., 2011a) and female (Bosch & Neumann, 2010; Bosch et al., 2010) rats during the expression of social behavior; however, to our knowledge, there are no studies which have compared brain VP release in males and…”

“, 2009), and female OT KO mice (Choleris et al., 2003; Choleris et al., 2006).”

“Although VP and OT do not pass the blood brain barrier, it has been suggested that intranasal VP and OT may reach the brain given the fast behavioral and cognitive effects of intranasal administration (Guastella & MacLeod, 2012).”

“Likewise, there were no sex differences in V1R binding in several brain regions analyzed in humans (Loup et al., 1991), but this also remains inconclusive because 3H VP was used and the number of women was very low (n=4).. V1aR binding was also found throughout the brain of male and female…”

“…nucleus of the hypothalamus (SCN), bed nucleus of the stria terminalis (BNST) and medial amygdala (MeA) project centrally to multiple areas in the brain (Buijs, 1978; Sofroniew & Weindl, 1978; Buijs & Swaab, 1979; Buijs, 1980; Sofroniew, 1980; Sofroniew, 1983; Rood & De Vries, 2011).”

“Re-expression of V1aR in the LS of V1aR KO mice restored social recognition (Bielsky et al., 2005a), thereby confirming studies in rats showing the importance of the LS-VP system in social recognition.”

“…studies to report intranasal OT effects in humans were done in males only, showing a role for OT in trust and in the processing of socially relevant information (Kosfeld et al., 2005; Zak et al., 2007; Domes et al., 2007; Guastella et al., 2008a; Guastella et al., 2008b; Di Simplicio et al., 2009).”

“…necessarily related to social behavior, per se, but deficits in prepulse inhibition are observed in a variety of neuropsychiatric disorders of social dysfunction (Geyer et al., 1990; Perry et al., 2007), as well as in animal models of social dysfunction (Dieckmann et al., 2007; Koh et al., 2008).”

“…been implicated in the etiology of psychiatric disorders, such as schizophrenia (Jobst et al., 2014), autism (Yang et al., 2010; Xu et al., 2013; LoParo and Waldman, 2014), depression (Yuen et al., 2014), and borderline personality disorder (Bertsch et al., 2013), disorders which show sex…”

“Intranasal VP increased activity in areas such as the striatum, basal forebrain, insula, amygdala, and hippocampus in men, but decreased or had no effect in women (Rilling et al., 2012; 2014).”

“Further, men and women homozygous for the A allele reported seeking less emotional social support (Kim et al., 2010).”

“…neuropeptides vasopressin (VP) and oxytocin (OT) are involved in the regulation of diverse social behaviors such as social recognition, pair-bonding, and social cognition in mammals, including humans (Veenema & Neumann, 2008; Ross & Young, 2009; MeyerLindenberg et al., 2011; Albers, 2014).”

“…expression in the olfactory bulb, hippocampus, caudate putamen, septum, amygdala, hypothalamus, cortex, and cerebellum in male Sprague Dawley rats (Lolait et al., 1995; Vaccari et al., 1998) and V1bR-immunoreactivity in the olfactory system, cortex, BNST, diagonal band of Broca, amygdala, NAc,…”

“Similar to VP, there is little research on potential sex differences in brain OT release, because investigation into brain region-specific OT release patterns in rats have been performed in one sex only (males: Engelmann et al., 1999; Ebner et al., 2000; Waldherr and Neumann, 2007; or females: Nyuyki et al., 2011; Neu…”

“These inconsistencies may be due to methodological differences across studies, as commercially available methods to quantify plasma OT concentrations are in need of improvement (Szeto et al., 2011).”

“For example, partner preference formation in prairie voles is modulated by the VP system acting in the LS and ventral pallidum (Liu et al., 2001; Pitkow et al., 2001; Lim & Young, 2004) and by the OT system acting in the NAc and prefrontal cortex (Young et al., 2001; Liu and Wang, 2003).”

“De Vries et al. (1981) were the first to discover the sexually dimorphic nature of VP in the rat brain, and reported that there were more VPimmunoreactive fibers in the lateral septum (LS) and lateral habenular nucleus in males compared to females (De Vries et al., 1981).”

“…nucleus of the hypothalamus (SCN), bed nucleus of the stria terminalis (BNST) and medial amygdala (MeA) project centrally to multiple areas in the brain (Buijs, 1978; Sofroniew & Weindl, 1978; Buijs & Swaab, 1979; Buijs, 1980; Sofroniew, 1980; Sofroniew, 1983; Rood & De Vries, 2011).”

“…nucleus of the hypothalamus (SCN), bed nucleus of the stria terminalis (BNST) and medial amygdala (MeA) project centrally to multiple areas in the brain (Buijs, 1978; Sofroniew & Weindl, 1978; Buijs & Swaab, 1979; Buijs, 1980; Sofroniew, 1980; Sofroniew, 1983; Rood & De Vries, 2011).”

“In humans, intranasal VP had sex-specific effects during social communication and cooperation interactions (Thompson et al., 2006; Rilling et al., 2014; Feng et al., 2014), while AVP1A gene variants had sex-specific effects on pair-bondng and prepulse inhibition (Walum et al.”

“…1978; Buijs and Swaab, 1979; Sofroniew, 1980; Sofroniew, 1983) and magnocellular neurons in the PVN, SON, and accessory nucleus of the hypothalamus (Ross et al., 2009, Knobloch et al., 2012) project centrally, where OT can modulate the activity of many brain regions via binding to the widely…”

“General Discussion We discussed above that various rodent species show consistent sex differences in VPimmunoreactive neurons and fiber density in the brain (rats: De Vries et al., 1983; Van Leeuwen et al., 1985; Miller et al., 1989; Wang & De Vries; mice: De Vries et al., 2002; Bakker et al., 2006; Gatewood et al., 2…”

“Intranasal VP increased activity in areas such as the striatum, basal forebrain, insula, amygdala, and hippocampus in men, but decreased or had no effect in women (Rilling et al., 2012; 2014).”

“For example, carriers of long allele versions (327–343 bp) of the AVP1AR RS3 polymorphism, compared to carriers of the short allele versions (308–325 bp), showed higher levels of altruism as assessed by money donations in a computer game and by self-reported scales (Knafo et al., 2008).”

“For example, partner preference formation in prairie voles is modulated by the VP system acting in the LS and ventral pallidum (Liu et al., 2001; Pitkow et al., 2001; Lim & Young, 2004) and by the OT system acting in the NAc and prefrontal cortex (Young et al., 2001; Liu and Wang, 2003).”

“VP-ir fibers Macaques Medial septum, BNST, amygdala, hippocampus VTA, peraquaductal gray, raphe, LC, NTS, parabrachial nuclei, diagonal band Caffé et al. (1989)”

“…a discussion of recent evidence for the sex-specific involvement of the human V1aR gene (AVPR1A) in various social behaviors, as variations in this gene have given some insight into the role of the V1aR in human social behavior (for reviews see Meyer-Lindenberg et al., 2011; Ebstein et al., 2012).”

“Furthermore, individuals homozygous for the G allele for the SNPS rs53576 and rs2254298 exhibited higher scores on Attachment Style Questionnaire factors that are associated with depression and adult separation anxiety (Costa et al., 2009).”

“Additional studies implicated a role for the LS (Liu et al., 2001) and ventral pallidum (Pitkow et al.”

“…cortex, and cerebellum in male Sprague Dawley rats (Lolait et al., 1995; Vaccari et al., 1998) and V1bR-immunoreactivity in the olfactory system, cortex, BNST, diagonal band of Broca, amygdala, NAc, hippocampus, thalamus, hypothalamus, and cerebellum in male Wistar rats (Hernando et al., 2001).”

“For example, V1aR has been implicated in pair bonding, maternal care, aggression, social recognition, and social play (Bielsky et al., 2004; Egashira et al., 2004; Lim et al., 2004b; Bosch and Neumann, 2008; Veenema and Neumann, 2008; Veenema et al., 2013; Albers, 2014).”

“Interestingly, it was found that carriers of one or two A alleles of the same SNP were judged to be less prosocial than carriers of two G alleles, and that this was due to variations in expression of affiliative cues by these individuals (Kogan et al., 2011).”

“…SNP, rs53576, show reduced empathy (Rodrigues et al., 2009; Uzefovsky et al., 2015), and have lower levels of optimism, mastery, and self-esteem (Saphire-Bernstein et al., 2011), whereas reduced positive affect (Lucht et al., 2009) and reward dependence (Tost et al., 2010) were found in men only.”

“Here, impaired social recognition was found in male OTR KO mice (Takayanagi et al., 2005; Lee et al., 2008; Macbeth et al., 2009), male OT KO mice (Ferguson et al., 2000; Macbeth et al., 2009), and female OT KO mice (Choleris et al., 2003; Choleris et al, 2006).”

“This may further gain momentum because of the potential of the OT system to restore social dysfunction in sex-biased psychiatric disorders (Guastella et al., 2010a; Meyer-Lindenberg et al., 2011; Cochran et al., 2013), and recent initiatives from the NIH requiring the inclusion of both sexes in preclinical research (C…”

“Moreover, OT synthesized in parvocellular neurons of the PVN (Buijs, 1978; Buijs and Swaab, 1979; Sofroniew, 1980; Sofroniew, 1983) and magnocellular neurons in the PVN, SON, and accessory nucleus of the hypothalamus (Ross et al.”

“, 2015), and have lower levels of optimism, mastery, and self-esteem (Saphire-Bernstein et al., 2011), whereas reduced positive affect (Lucht et al.”

“Plasma VP Sprague Dawley rats n/a Share et al. (1988) Humans n/a Share et al.”

“…release, because investigation into brain region-specific OT release patterns in rats have been performed in one sex only (males: Engelmann et al., 1999; Ebner et al., 2000; Waldherr and Neumann, 2007; or females: Nyuyki et al., 2011; Neumann et al., 1993; Bosch et al., 2010; Bosch et al., 2004).”

“, 1991; Ishunina and Swaab, 1999), and most human studies report a lack of sex differences in plasma OT (Zhong et al., 2012; Taylor et al., 2010; Grewen et al., 2005; Gordon et al., 2008; Gordon et al., 2010; Graugaard-Jensen et al., 2014; however see van Londen et al., 1997; Miller et al., 2013; Weisman et al., 2013).”

“We discussed above that various rodent species show consistent sex differences in VPimmunoreactive neurons and fiber density in the brain (rats: De Vries et al., 1983; Van Leeuwen et al., 1985; Miller et al., 1989; Wang & De Vries; mice: De Vries et al., 2002; Bakker et al., 2006; Gatewood et al., 2006; Rood & De Vrie…”

“General Discussion We discussed above that various rodent species show consistent sex differences in VPimmunoreactive neurons and fiber density in the brain (rats: De Vries et al., 1983; Van Leeuwen et al., 1985; Miller et al., 1989; Wang & De Vries; mice: De Vries et al., 2002; Bakker et al., 2006; Gatewood et al., 2…”

“This finding seems consistent with studies showing sex differences in plasma VP concentrations with higher plasma VP concentrations in preadolescent and adolescent boys (Miller et al., 2013), adult men (Share et al., 1988; Van Londen et al., 1997) but also in elderly men (Asplund & Aberg, 1991).”

“, 1991; Ishunina and Swaab, 1999), and most human studies report a lack of sex differences in plasma OT (Zhong et al., 2012; Taylor et al., 2010; Grewen et al., 2005; Gordon et al., 2008; Gordon et al., 2010; Graugaard-Jensen et al., 2014; however see van Londen et al., 1997; Miller et al., 2013; Weisman et al., 2013).”

“…were a bit surprising, given the typically pro-social behavior effects of OT, although recent studies suggest a role for the OTR in the LS in reducing pro-social behaviors and enhancing anxiety in rodents (Olazábal and Young, 2006; Beery et al., 2008; Beery and Zucker, 2010; Guzman et al., 2013).”

“…studies to report intranasal OT effects in humans were done in males only, showing a role for OT in trust and in the processing of socially relevant information (Kosfeld et al., 2005; Zak et al., 2007; Domes et al., 2007; Guastella et al., 2008a; Guastella et al., 2008b; Di Simplicio et al., 2009).”

“…studies implicated a role of the VP system in the LS and olfactory bulb in the regulation of social recognition (Le Moal et al., 1987; Dantzer, 1998; Engelmann & Landgraf, 1994; Everts & Koolhaas, 1999; Landgraf et al., 2003; Tobin et al., 2010), but these studies were conducted in males only.”

“In C57BL/6mice, V1bR mRNA expression was predominantly found in the CA2 field of the hippocampus, with lower expression levels in the PC, caudate putamen, septum, midbrain, pons, cerebellum and medulla (Young et al., 2006).”

“…per sex, which might explain the limited brain regions in which sex differences in V1aR binding were found (C57B6 mice: Dubois Dauphin et al., 1996; Siberian hamsters: Dubois-Dauphlin et al., 1991; golden hamsters: Delville & Ferris, 1995; voles: Bales et al., 2007a; Smeltzer et al., 2006).”

“Men and women with the 334 bp (long version) allele for the RS3 also showed higher activation of the left amygdala compared to 20 other alleles analyzed (Meyer-Lindenberg et al., 2009).”

“Finally, AVPR1A gene variants have also been associated with dance and musical aptitude (Bachner-Melman et al., 2005; Ukkola et al., 2009).”

“These findings were a bit surprising, given the typically pro-social behavior effects of OT, although recent studies suggest a role for the OTR in the LS in reducing pro-social behaviors and enhancing anxiety in rodents (Olazábal and Young, 2006; Beery et al., 2008; Beery and Zucker, 2010; Guzman et al., 2013).”

“…studies implicated a role of the VP system in the LS and olfactory bulb in the regulation of social recognition (Le Moal et al., 1987; Dantzer, 1998; Engelmann & Landgraf, 1994; Everts & Koolhaas, 1999; Landgraf et al., 2003; Tobin et al., 2010), but these studies were conducted in males only.”

“Indeed, the OT system in the olfactory bulb, septum (Popik et al., 1992), and MPOA (Popik and Van Ree, 1991) plays a role in social recognition.”

“For example, women, but not men, carrying rs7632287A scored lower on a partner bonding scale and on a relationship quality survey (Walum et al., 2012).”

“However, ICV administration of an OTR antagonist impaired social recognition in both male (Lukas et al., 2013) and female (Engelmann et al., 1998) rats.”

“Similar to V1aR, sex differences in OTR binding were found in multiple brain regions in those rodent studies that used a more comprehensive analysis (deer mice: 8 out of 20 brain regions; Insel et al., 1991; rats: 9 out of 15 forebrain regions; Dumais et al., 2013).”

“In further support, we found sex differences in areas that may not be sensitive to gonadal steroids (Tribollet et al., 1990), such as the cortex, caudate putamen and hippocampal CA1 (Dumais et al., 2013).”

“In further support, we found sex differences in areas that may not be sensitive to gonadal steroids (Tribollet et al., 1990), such as the cortex, caudate putamen and hippocampal CA1 (Dumais et al., 2013).”

“…neuropeptides vasopressin (VP) and oxytocin (OT) are involved in the regulation of diverse social behaviors such as social recognition, pair-bonding, and social cognition in mammals, including humans (Veenema & Neumann, 2008; Ross & Young, 2009; MeyerLindenberg et al., 2011; Albers, 2014).”

“Interestingly, estrogens may directly regulate OTR gene expression through binding to the estrogen receptor alpha, which is a transcription factor that modulates gene transcription via interaction with estrogen response elements located on the promotor region of the OTR gene (Carson-Jurica et al., 1990; Young et al.,…”

“Here, a single neonatal intraperitoneal (i.p.) injection of OT on postnatal day 1 facilitated partner preference in both male and female adult prairie voles, but required a high (12μg) or low (3μg) dose in males and an intermediate dose (6μ) in females (Bales & Carter, 2003a; Bales et al. 2007b).”

“…per sex, which might explain the limited brain regions in which sex differences in V1aR binding were found (C57B6 mice: Dubois Dauphin et al., 1996; Siberian hamsters: Dubois-Dauphlin et al., 1991; golden hamsters: Delville & Ferris, 1995; voles: Bales et al., 2007a; Smeltzer et al., 2006).”

“…in VP neurons and plasma VP concentrations have also been found in humans (Share et al., 1988; Asplund & Aberg, 1991; Van Londen et al., 1997; Ishinina et al., 1999; Miller et al., 2013; Graugaard-Jensen et al., 2014; however, see Fliers et al., 1985; Swaab et al., 2001; Gouin et al., 2012).”

“Interestingly, pregnancy and parturition induce long-lasting enhancements in maternal behaviors during subsequent maternal experiences (Bridges, 1975, 1977; Nephew et al., 2009; Macbeth & Luine, 2010).”

“…such as schizophrenia (Jobst et al., 2014), autism (Yang et al., 2010; Xu et al., 2013; LoParo and Waldman, 2014), depression (Yuen et al., 2014), and borderline personality disorder (Bertsch et al., 2013), disorders which show sex biases in prevalence, symptom severity, and treatment responses.”

“Indeed, intranasal OT administration also leads to increases in OT in plasma and saliva in humans (Gossen et al., 2012; van Ijzendoorn et al., 2012) and rhesus macaques (Modi et al., 2014).”

“Although OTR is present early in development in various species (Hammock, 2015), sex differences in the OTR system early in life are still to be determined.”

“, 2011), the perception of neutral facial expressions as being angry (Thompson et al., 2004), and in musical working memory (Granot et al.”

“, 2009), and female OT KO mice (Choleris et al., 2003; Choleris et al., 2006).”

“Local VP release in the brain has been measured in male (Veenema et al., 2010; Lukas et al., 2011a) and female (Bosch & Neumann, 2010; Bosch et al.”

“Interestingly, pregnancy and parturition induce long-lasting enhancements in maternal behaviors during subsequent maternal experiences (Bridges, 1975, 1977; Nephew et al., 2009; Macbeth & Luine, 2010).”

“…Swaab, 1999), and most human studies report a lack of sex differences in plasma OT (Zhong et al., 2012; Taylor et al., 2010; Grewen et al., 2005; Gordon et al., 2008; Gordon et al., 2010; Graugaard-Jensen et al., 2014; however see van Londen et al., 1997; Miller et al., 2013; Weisman et al., 2013).”

“…in brain OT release, because investigation into brain region-specific OT release patterns in rats have been performed in one sex only (males: Engelmann et al., 1999; Ebner et al., 2000; Waldherr and Neumann, 2007; or females: Nyuyki et al., 2011; Neumann et al., 1993; Bosch et al., 2010;…”

“VP and OT systems have been implicated in sex-biased psychiatric disorders of social dysfunction, such as autism spectrum disorder and schizophrenia(Green et al., 2001; Wu et al., 2005; Jacob et al., 2007; Campbell et al., 2011; Miller et al., 2013; Di Napoli et al., 2014; Golimbet et al., 2014; Jobst et al., 2014).”

“…studies implicated a role of the VP system in the LS and olfactory bulb in the regulation of social recognition (Le Moal et al., 1987; Dantzer, 1998; Engelmann & Landgraf, 1994; Everts & Koolhaas, 1999; Landgraf et al., 2003; Tobin et al., 2010), but these studies were conducted in males only.”

“For example, VP system manipulations in the LS produced opposite effects on social play behavior in juvenile rats (Veenema et al., 2013; Bredewold et al., 2014), intranasal VP produced opposite effects on facial perception in humans (Thompson et al.”

“…neurons in the PVN, SON, and accessory nucleus of the hypothalamus (Ross et al., 2009, Knobloch et al., 2012) project centrally, where OT can modulate the activity of many brain regions via binding to the widely distributed OT receptor (OTR; Jard et al., 1987; Gimpl and Fahrenholz, 2001).”

“Participants with an A allele for SNP rs2254298 also had greater amygdala volumes compared to those homogyzous for the G allele in adolescent girls (Furman et al., 2011) and adult men and women (Inoue et al., 2010).”

“Here, ICV V1aR antagonist administration impaired partner preference in male voles only (Winslow et al., 1993; Insel & Hulihan, 1995) and OT administration into the LS altered social play in female juvenile rats only (Bredewold et al., 2014).”

“Male prairie voles additionally show more VP-immunoreactive fibers in the ventral pallidum compared to females (Lim et al., 2004a).”

“Also during reciprocated cooperation, VP increased activation in the bilateral insula and right supramarginal gyrus in males, but decreased this response in females (Feng et al., 2014).”

“However, ICV administration of an OTR antagonist impaired social recognition in both male (Lukas et al., 2013) and female (Engelmann et al., 1998) rats.”

“Specifically, in females, but not males, neonatal OT and OTR antagonist both increased OTimmunoreactivity in the PVN (Yamamoto et al., 2004).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript investigated OTR binding in the coppery titi monkey in males and females, however an analysis of sex was not performed (Freeman et al., 2014).”

“Participants with an A allele for SNP rs2254298 also had greater amygdala volumes compared to those homogyzous for the G allele in adolescent girls (Furman et al., 2011) and adult men and women (Inoue et al., 2010).”

“…in VP neurons and plasma VP concentrations have also been found in humans (Share et al., 1988; Asplund & Aberg, 1991; Van Londen et al., 1997; Ishinina et al., 1999; Miller et al., 2013; Graugaard-Jensen et al., 2014; however, see Fliers et al., 1985; Swaab et al., 2001; Gouin et al., 2012).”

“…per sex, which might explain the limited brain regions in which sex differences in V1aR binding were found (C57B6 mice: Dubois Dauphin et al., 1996; Siberian hamsters: Dubois-Dauphlin et al., 1991; golden hamsters: Delville & Ferris, 1995; voles: Bales et al., 2007a; Smeltzer et al., 2006).”

“…studies implicated a role of the VP system in the LS and olfactory bulb in the regulation of social recognition (Le Moal et al., 1987; Dantzer, 1998; Engelmann & Landgraf, 1994; Everts & Koolhaas, 1999; Landgraf et al., 2003; Tobin et al., 2010), but these studies were conducted in males only.”

“For example, while subcutaneous injections of VP enhanced social recognition in male (Dantzer et al., 1987) and female (Bluthe & Dantzer, 1990) rats, a subcutaneous injection of the VP antagonist, dPTyr(Me)AVP, blocked social recognition in male rats only (Dantzer et al., 1987; Bluthe & Dantzer,…”

“Sex differences in vasopressin and oxytocin receptors in the brain 3.a. VP receptors VP receptors are G protein coupled receptors consisting of two major subtypes, the V1 receptor (V1R) and the V2 receptor (V2R; Jard, 1983).”

“For example, V1aR knockout male mice show deficits in social recognition (Bielsky et al., 2004; however, see Wersinger et al., 2007).”

“Indeed, later studies consistently found higher OTR mRNA expression (Bale and Dorsa, 1995) and higher OTR binding density ([using the specific OTR antagonist d(CH2)5[Tyr(Me)2,Thr4,Orn8,[125I]Tyr9-NH2]-OVTA; Uhl-Bronner et al., 2005) in males compared to females in the VMH of Long-Evans and Sprague-Dawley rats, respect…”

“Similarly, women given intranasal OT reported more distress and anger in response to a social stress test, while men given OT reported less negative affect (Kubzansky et al., 2012).”

“…discussed above that various rodent species show consistent sex differences in VPimmunoreactive neurons and fiber density in the brain (rats: De Vries et al., 1983; Van Leeuwen et al., 1985; Miller et al., 1989; Wang & De Vries; mice: De Vries et al., 2002; Bakker et al., 2006; Gatewood et…”

“, 2008), and rhesus monkeys (Young et al., 1999), albeit the number of male (n=2) and female (n=3; 1 gonadally intact, 1 overiectomized, 1 lactating) rhesus monkeys was too low to be conclusive.”

“Local VP release in the brain has been measured in male (Veenema et al., 2010; Lukas et al., 2011a) and female (Bosch & Neumann, 2010; Bosch et al., 2010) rats during the expression of social behavior; however, to our knowledge, there are no studies which have compared brain VP release in males and…”

“Finally, AVPR1A gene variants have also been associated with dance and musical aptitude (Bachner-Melman et al., 2005; Ukkola et al., 2009).”

“As such, VP is part of the hypothalamic-pituitaryadrenal (HPA) axis, a system involved in the neuroendocrine stress response (Herman, 1995; Volpi et al., 2004).”

“Males of several fish species show more vasotocin neurons in the preoptic area (homologous to PVN and SON in mammals; Moore and Lowry, 1998) than females (reviewed in Goodson and Bass, 2001).”

“For example, in men, intranasal VP altered activation and connectivity in a medial prefrontal cortex-amygdala circuit during processing of facial emotions (Zink et al., 2010) and when viewing pictures illustrating socially threatening scenes (Brunnlieb et al.”

“Similar to VP, there is little research on potential sex differences in brain OT release, because investigation into brain region-specific OT release patterns in rats have been performed in one sex only (males: Engelmann et al., 1999; Ebner et al., 2000; Waldherr and Neumann, 2007; or females: Nyuyki et al., 2011; Neu…”

“xerampelinus singing mice had higher OTR binding in the MeA and hippocampal CA1 compared to females (Campbell et al., 2009).”

“, 2013), and facilitated kinship recognition in women, but not men (Fischer-Shofty et al., 2013).”

“There is also a lack of sex differences in OT neuron size and number in humans (Fliers et al., 1985; Wierda et al., 1991; Ishunina and Swaab, 1999), and most human studies report a lack of sex differences in plasma OT (Zhong et al., 2012; Taylor et al., 2010; Grewen et al., 2005; Gordon et al.,…”

“Additional studies implicated a role of the VP system in the LS and olfactory bulb in the regulation of social recognition (Le Moal et al., 1987; Dantzer, 1998; Engelmann & Landgraf, 1994; Everts & Koolhaas, 1999; Landgraf et al., 2003; Tobin et al., 2010), but these studies were conducted in males…”

“For example, men and women carrying one or two copies of the A allele in the most common SNP, rs53576, show reduced empathy (Rodrigues et al., 2009; Uzefovsky et al., 2015), and have lower levels of optimism, mastery, and self-esteem (Saphire-Bernstein et al., 2011), whereas reduced positive affect…”

“Local VP release in the brain has been measured in male (Veenema et al., 2010; Lukas et al., 2011a) and female (Bosch & Neumann, 2010; Bosch et al., 2010) rats during the expression of social behavior; however, to our knowledge, there are no studies which have compared brain VP release in males and…”

“This may further gain momentum because of the potential of the OT system to restore social dysfunction in sex-biased psychiatric disorders (Guastella et al., 2010a; Meyer-Lindenberg et al., 2011; Cochran et al., 2013), and recent initiatives from the NIH requiring the inclusion of both sexes in…”

“We further found that V1aR blockade in the LS of juvenile rats did not impair social recognition in male and female juvenile rats, but rather increased social investigation of the familiar over the novel stimulus rat (Veenema et al., 2012).”

“As such, VP is part of the hypothalamic–pituitary–adrenal (HPA) axis, a system involved in the neuroendocrine stress response (Herman, 1995; Volpi et al., 2004).”

“Indeed, intranasal OT administration also leads to increases in OT in plasma and saliva in humans (Gossen et al., 2012; van Ijzendoorn et al., 2012) and rhesus macaques (Modi et al., 2014).”