Version of Record: https://www.sciencedirect.

com/science/article/pii/S2352154617302085
Manuscript_131b622d30a17867de7541a00ce40a50

Oxytocin and sex differences in behavior

Heather K. Caldwell, PhD

Laboratory of Neuroendocrinology and Behavior, Department of Biological Sciences and School
of Biomedical Sciences, Kent State University, Kent, Ohio, USA.

253C Cunningham Hall

Department of Biological Sciences
Kent State University
Kent, OH 44240
hcaldwel@kent.edu

Highlights:
• There are quantifiable oxytocin-dependent sex differences in behavior
• Sex differences in behavior are often not associated with structural changes in the
oxytocin system
• Oxytocin-dependent sex differences in behavior vary greatly by species

Abstract
Oxytocin is an evolutionarily ancient neuropeptide that is implicated in the neural modulation
of behavior in vertebrates. While this system is well known for its species-specific effects, there
is a lack of consensus regarding oxytocin’s sex-specific effects  due in part to shortcomings in
the way that studies have traditionally been designed. Sex differences in the neuroanatomy of
the oxytocin system are not abundant and are generally not predictive of sex differences in
behavior. Rather, it seems likely that the differential evolution of these systems in males and
females has resulted in sex differences in the sensitivity to oxytocin as well as sex differences in
the function of the neural circuitry important for behavioral displays. This hypothesis is
supported by work which suggests that sex differences in behavior are likely due to sex-specific
patterns of activity between brain regions that have been implicated in the regulation of social
behavior. It is also important to consider how oxytocin’s sex-specific behavioral effects are
shaped by social context, species evolution, and an animal’s behavioral ecology.

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Introduction
One of the most fascinating aspects of the neurohomone oxytocin and its homologues are their
fairly conserved role in the neural regulation of social behaviors. From C. elegans to H. sapiens,
oxytocin-related peptides act to modulate behavior, primarily promoting plasticity in innate
behaviors [8, 11, 12, 26•, 49•, 55, 61]. However, the nuances of how oxytocin acts to affect
behavior are highly varied. This is particularly true in the context of oxytocin’s sex-specific
effects, which, due in part to oxytocin’s species-specific actions, makes it difficult to determine
the ‘when’ and ‘where’ of oxytocin’s action. In fact, definitive statements about oxytocin’s
effects with regards to the modulation of female versus male behavior are very difficult to
make. Therefore, rather than attempt to provide a comprehensive review of oxytocin’s effects
on social behavior, which can be found elsewhere [8, 11, 12, 26•], this review will focus on
where scientific consensus exists in terms of oxytocin’s effects on sex differences in mammalian
behavior, with particular attention to social behaviors. To start this discussion though, where in
the brain oxytocin may function in sex-specific ways must first be considered, with the following
major caveat: sex differences in neuroanatomy are often not clearly related to sex differences
in behavior [17, 62• •]. It is also important to note that there has not been a lot of direct testing
of sex differences in oxytocin’s behavioral effects, largely due to the fact that each sex is often
studied in isolation, rather than at the same time with the same tests.

There are not many sex differences in oxytocin and oxytocin receptor distribution
There are very few sex differences in the sites of oxytocin synthesis. In all mammalian species in
which oxytocin has been localized it is primarily produced in the paraventricular nucleus (PVN)
and the supraoptic nucleus (SON) of the hypothalamus. In some species, there are also
additional sites of synthesis, including the bed nucleus of the stria terminalis (BNST), the medial
preoptic area (MPOA), the lateral hypothalamus (LH), and the medial amygdala (MeA) (please
see [26•] for a comprehensive review). In rodents, there are no reported sex differences in
oxytocin mRNA expression in the PVN and SON of any species [for review see 26•] and a recent
report in Wistar rats found no sex differences in oxytocin immunoreactivity in either the
number of cell bodies or the density of fibers in brain areas outside of than the PVN and SON
[18•]. In primates there are no reports of sex differences in oxytocin immunoreactive fibers in
macaques [10], marmosets [86], or humans [35, 45, 88]. Essentially, the only reported sex
differences in oxytocin are in the number of immunoreactive fibers in rodents and these
findings are species- and brain-region specific. When sex differences are detected, females are
reported as having more oxytocin immunoreactive fibers than males [41, 73, 85, 92]. These
studies may indicate that sex differences in oxytocin function are due to its rate of axonal
transport or secretion in response to physiological challenges, rather than to absolute amounts.

Oxytocin receptor expression, on the other hand, varies widely in its distribution and density
between species. Two brain regions in which sex differences in the oxytocin receptor are
regularly reported are the BNST and the MeA, with males typically having more oxytocin
receptors in these brain regions than females [41, 73, 74•, 85, 92]. Though, there are studies
which have found sex differences in the other direction (female > male) within different brain

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regions [5, 13, 24, 43, 82]. Generally speaking, what is lacking, is scientific agreement on where
there are consistently observed sex differences in oxytocin receptors. In almost all of the
aforementioned studies, oxytocin receptor binding only differs in a few brain areas and there is
considerable species variation.

Based on these data, most species do not appear to have any obvious sex-differences in the
oxytocin system that can easily be correlated with sex differences in behavior. However, it must
be stated that structure and function do not always associate with one another [17]. Therefore,
it is likely that sex-specific development of the neural circuitry and differences in the patterns of
activation across brain regions underlie oxytocin’s sex-specific effects on behavior. This
hypothesis is supported by a recent fMRI study in rats, which found that oxytocin administered
centrally or peripherally results in sex differences in brain activation, both in terms of pattern
and magnitude [25].

While the studies mentioned above were conducted in adults, and in some instances in
juveniles, earlier in development there are some marked sex differences in the oxytocin system.
In C56BL/6J female mice oxytocin mRNA, as measured by quantitative PCR performed on whole
heads, is detectable as early as embryonic day (ED) 16.5. In males, oxytocin mRNA is not
detectable until postnatal day (PND) 2. Females also have more oxytocin on PND2 than males
and across embryonic development females have more Oxtr mRNA than males, specifically on
E14.5, E16.5, E18.5, and PND2 [78•] (Figure 1). In the postnatal period, these sex differences
disappear with no observable sex differences Oxtr density [39]. What these sex differences in
the developing oxytocin system may or may not mean to behavior is unknown, as well as
largely unexplored in other species. Though, it is known that manipulation of the oxytocin
system in early postnatal life, at least in some rodents, can have sex-specific effects on
behavior. This suggests that the oxytocin system may play a role in the sexual differentiation of
the brain [65].

Sex differences in oxytocin’s behavioral effects can be found across the lifespan
Uncovering oxytocin’s contributions to sex differences in behavior is a challenge, possibly due
to differential evolution of this system in the two sexes [36]. Although, new scientific tools
continue to emerge and further refine our understanding of oxytocin’s contributions to
behavior. That said, the vast majority of studies that have examined oxytocin’s contributions to
sex differences in behavior have taken a pharmacological approach. As would be expected, with
these data sets there is often a disconnect between what is observed following treatment with
an oxytocin receptor antagonist, which blocks endogenous oxytocin signaling through its native
receptor, versus treatment with oxytocin or an oxytocin receptor agonist, which competes with
endogenous oxytocin; researchers are quite limited in their ability to manipulate the amount of
endogenous oxytocin released. Genetic studies have gotten around some of the issues
associated with pharmacological treatments, but they too have their limitations. More recently
there have been studies that have quantified endogenous oxytocin release using microdialysis
followed by radioimmunoassay, but these studies are still relatively few in number [7, 27, 28,

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69, 71, 83]. Nonetheless, combining these data sets have increased our understanding of the
role of oxytocin in sex-specific behaviors.
Early Life
Some sex-specific behavioral effects are observed following postnatal manipulation of the
oxytocin system in socially monogamous prairie voles (Microtus ochrogaster) and mandarin
voles (Lasiopodomys mandarinus). These manipulations are in the form of single injections of
oxytocin or oxytocin receptor antagonists during early postnatal life followed by behavioral
testing in adulthood. In female prairie and mandarin voles, an intraperitoneal injection of
oxytocin on PND1 increases female-directed aggression, but does not affect male-directed
aggression in males [2, 47]. However, in male prairie voles, oxytocin on PND1 does facilitate
pair bond formation [1], but the same effect is not observed in females unless a higher dose is
used [4]. In mandarin voles, the effects of PND1 oxytocin treatment on pair bonding are
opposite that observed in prairie voles, with PND1 oxytocin treatment in females facilitating
partner preference within 24 hours of cohabitation, but suppressing the maintenance of
partner preference, with no effects on male partner preference formation or maintenance.
Rather, male mandarin voles increase their mounting behavior, though it should be noted that
females did not display sexual behavior because they were tested on diestrous, so there may
have been undetected effects on female sexual behavior [46]. In terms of alloparental care, in
male prairie voles, PND1 injections of an oxytocin receptor antagonist increases pup-directed
aggression and decreases paternal care; similar effects are not observed in females [3]. Thus,
the sex-specific effects of oxytocin in these two species of voles seems to be that female mate-
guarding may be sensitive to oxytocin injections in early life.

Sociability and alloparenting were also tested in a non-monogamous species, i.e. ICR mice (Mus
musculus), using a similar protocol as that described above, with male and female mice treated
with either oxytocin or an oxytocin receptor antagonist on PND0. In these experiments, the
results differed significantly from what was observed in prairie and mandarin voles. Specifically,
in female mice, treatment with an oxytocin receptor antagonist at a 3µg/20µl dose decreases
sociability, and has no effect in males. In measures of alloparenting in females, oxytocin
increased pup retrievals and time spent retrieving pups, but did not change the latency to
retrieve pups. As expected, females treated with an oxytocin receptor antagonist showed
decreases in pup retrievals and spent less time retrieving pups. While oxytocin treatment had
no effect in the males, males treated with the oxytocin receptor antagonist had longer latencies
to retrieve pups [67]. The authors of this work suggested that the species differences might be
due to oxytocin’s effects during the neonatal development on the organization of sex
differences in alloparental responsiveness in these species. Perhaps this makes sense given the
differences in behavioral ecology between the aforementioned vole species and ICR mice,
which have quite different mating systems. The behavioral data demonstrating that neonatal
oxytocin system manipulation can affect adult behavior, so far does not appear to extend to
juvenile behaviors. In recent study in monogamous Mongolian gerbils (Meriones unguiculatus),
play behavior, which is largely restricted to juveniles, was not affected by treatment with an
oxytocin or an oxytocin receptor antagonist on PND1 in either sex [79].

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In the context of these neonatal manipulations it is important to consider the possibility that
there are sex-dependent differences in the sensitivity of the brain to oxytocin, which further
complicates these types of studies and makes it even more difficult to parse out what
endogenous oxytocin does within specific brain regions with regards to these behaviors. It is
also important to mention that neonatal perturbations/manipulations of oxytocin signaling
have quantifiable effects on subsequent brain neurochemistry, this is reviewed elsewhere [65].

Puberty
In juvenile Wistar rats, there are sex differences in how oxytocin signaling in the amygdala
modulates social interest which run counter to a structure-function relationship between
oxytocin and sex-specific behavior in this strain. The MeA is one of the brain regions in which
males have more oxytocin receptor binding than females, with the central amygdala (CeA)
having no sex differences in oxytocin receptor binding [24]. Surprisingly, oxytocin or an oxytocin
receptor antagonist injected into the MeA has no effect on social investigation times in either
sex. However, in males, an oxytocin receptor antagonist injected into the CeA decreases social
investigation times, but has no effect in females and no effect of oxytocin in either sex.
Interestingly, when endogenous oxytocin release in measured in the CeA, there are no sex
differences at baseline or during the social interest test. Though, in females there is positive
correlation between oxytocin release during the social interest test and social investigation
time, which the authors propose is a consequence of the social stimulus exposure. These data
suggest that something other than local oxytocin release is important for oxytocin receptor-
mediated social interest in the males [22].

There are also reported sex differences in oxytocin’s modulation of juvenile social play
behavior. When tested in their home cage, but not in a novel cage, an oxytocin receptor
antagonist injected into the lateral septum (LS) reduces social play behavior in females but has
no effect in males [9]. Interestingly, the LS may play a role in social memory in male rats, as
they have increased endogenous oxytocin release during the memory retrieval phase of a social
memory task [57]. This is particularly interesting given that male rats have been shown to have
more oxytocin receptor binding in the LS than females [24]. These behavioral effects also
reinforce an important theme that is common in the oxytocin-behavior literature, that
oxytocin’s effects are often context specific [12, 38, 40, 48, 58, 76].

Adulthood
There do appear to be brain region-specific sex differences in oxytocin’s effects on social
memory in the BNST. In rats, there is a sex difference in oxytocin receptor binding density in the
posterior BNST (pBNST), with males having three-fold more binding in this region compared to
females [24]. In both males and females, microinjection of an oxytocin receptor antagonist into
the pBNST impairs social recognition, but only in males does oxytocin improve social
recognition memory. Consistent with these findings, oxytocin release during social recognition
is higher in males than females. Thus, the authors of this work speculate that in males the
increase in the number of oxytocin receptors coupled the increases in oxytocin release are
likely responsible for oxytocin’s sex-specific effects on social memory in this brain region [23• •].

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There are also studies that have examined oxytocin’s effects on social memory in other brain
areas as well as in mice. However, these studies did not evaluate males and females at the
same time [6, 16, 20, 29, 32, 33, 52, 57, 60, 72, 77, 87]. Nonetheless, the consensus from these
studies is that oxytocin appears to be important for social recognition in both males and
females, and that there may be some site-specific differences in the sensitivity to exogenous
oxytocin, with less sensitivity in females [26•]. Some of the observed effects in males are likely
mediated by oxytocin receptor signaling in aromatase-positive neurons of the MeA [93]. These
data also fit with a recent study demonstrating that the neuronal representation of social
information within the amygdala differs between males and females. Essentially, there are sex
differences in the neural representations of different social contexts within the MeA and in
males, sexual experience results in long lasting changes in the activity of the MeA that can be
altered with intraperitoneal treatment with an oxytocin receptor antagonist [53•]. There are
also data which suggest that oxytocin receptor expressing interneurons in the medial prefrontal
cortex are important for shaping social preference in females, but not males [68]. Thus, there
are likely significant differences about where in the brain oxytocin may signal within each sex to
shape how an animal processes social information.

It is important to keep in mind that numerous studies have elegantly examined the effects of
oxytocin on aspects of social behavior [8, 11, 12]. Unfortunately, very few have directly
compared female to male behavior. For instance, there is evidence that oxytocin is important
for pair bond formation in prairie voles, with females possibly being more sensitive to
exogenous oxytocin than males. Specifically, numerous studies have found that ICV
administration of oxytocin facilitates partner preference in females, but not males [44, 89-91],
likely via its action in the nucleus accumbens [50, 54, 94]. That said, there are studies
demonstrating, directly or indirectly, the involvement of the oxytocin system in pair bonding in
male prairie voles [15, 51, 66]. The lack of comparative studies between males and females, as
well as the murkiness of the data, has made the development and refinement of any theories
regarding sex differences in oxytocin’s actions very difficult.

There is, of course, great interest in understanding the implications of sex differences in this
system with regards to human behavior, particularly in the context of neuropsychiatric
disorders that have a sex bias. While beyond the scope of this review, there is evidence which
suggests that intranasal oxytocin may differentially affect male and female behavior [14, 19, 21,
30, 34, 42, 59, 75, 81]. There is also evidence that genetic differences in the oxytocin system in
women and men may be of functional significance [e.g. 31, 64, 84]. However, it is the preclinical
work that can shed light on the neural mechanisms that underlie these observed differences.

Conclusions
One goal of this review was to highlight the complexity of oxytocin’s actions with regards to sex
differences in behavior. While the oxytocin system appears to contribute to meaningful and
measureable differences in female versus male behavior, the magnitude of these effects
appears to be somewhat small relative to oxytocin’s brain region and species-specific actions.

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Further, much of our understanding of oxytocin’s contributions to sex differences in behavior
has been drawn from studies whose foci were not necessarily on sex differences in behavior.
Thus, if there is real scientific interest in how female and male behaviors are modulated by
oxytocin then, as much as possible, studies should include both sexes. Sex differences in the
sensitivity to oxytocin, the relationship between structure and function, social context, and
species evolution and behavioral ecology should also be considered.
It is also important to put our fixation on specific brain regions in its proper context. While
there is no doubt that a single brain region can be very important, it is only one part of a larger
neural network. In the context of social behavior, there are numerous neural networks that are
known to be important for behavioral output. These include the social behavior neural network
[70], the motivated behavior neural network [56], and the social salience neural network [48].
These networks are not mutually exclusive, but rather are integrated in such a fashion as to
help modulate aspects of social behavior. Due in part because to its wide distribution
throughout the brain and within these networks, the oxytocin system that is in a unique
position to contribute to behavioral plasticity. Thus, perhaps one of the reasons we have
struggled to pin down where oxytocin acts to shape sex-specific behavior across species, is that
it is the sex-specific patterns of activity within these networks that are particularly important,
rather than the individual brain regions [37, 63, 80]. Fortunately, many researchers are already
thoughtfully exploring these complexities. Further, the commitment of the scientific field to
understanding oxytocin’s contributions to many types of behaviors in many different species
has resulted in scientific richness that continues to be used to inform hypotheses about how
oxytocin contributes to sex differences in behavior.

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:
•
of special interest
••
of outstanding interest
Acknowledgements
The author wishes to thank Dr. Wilson Chung and Dr. Colleen Novak for their comments on a
previous version of this manuscript. The author is supported by the National Science
Foundation (IOS353859).

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 References

[1] K.L. Bales, C.S. Carter, Developmental exposure to oxytocin facilitates partner preferences in
male prarie voles (Microtus ochrogaster), Behavioral Neuroscience, 117 (2003) 854-859.
[2] K.L. Bales, C.S. Carter, Sex differences and developmental effects of oxytocin on aggression
and social behavior in prairie voles ( Microtus ochrogaster ), Horm Behav, 44 (2003) 178-184.
[3] K.L. Bales, L.A. Pfeifer, C.S. Carter, Sex differences and developmental effects of
manipulations of oxytocin on alloparenting and anxiety in prairie voles, Dev Psychobiol, 44
(2004) 123-131.
[4] K.L. Bales, J.A. van Westerhuyzen, A.D. Lewis-Reese, N.D. Grotte, J.A. Lanter, C.S. Carter,
Oxytocin has dose-dependent developmental effects on pair-bonding and alloparental care in
female prairie voles, Horm Behav, 52 (2007) 274-279.
[5] A.K. Beery, E.A. Lacey, D.D. Francis, Oxytocin and vasopressin receptor distributions in a
solitary and a social species of tuco-tuco (Ctenomys haigi and Ctenomys sociabilis), J Comp
Neurol, 507 (2008) 1847-1859.
[6] A. Benelli, A. Bertolini, R. Poggioli, B. Menozzi, R. Basaglia, R. Arletti, Polymodal dose-
response curve for oxytocin in the social recognition test, Neuropeptides, 28 (1995) 251-255.
[7] O.J. Bosch, S.A. Kromer, P.J. Brunton, I.D. Neumann, Release of oxytocin in the hypothalamic
paraventricular nucleus, but not central amygdala or lateral septum in lactating residents and
virgin intruders during maternal defence, Neuroscience, 124 (2004) 439-448.
[8] O.J. Bosch, L.J. Young, Oxytocin and Social Relationships: From Attachment to Bond
Disruption, Current topics in behavioral neurosciences, (2017).
[9] R. Bredewold, C.J. Smith, K.M. Dumais, A.H. Veenema, Sex-specific modulation of juvenile
social play behavior by vasopressin and oxytocin depends on social context, Front Behav
Neurosci, 8 (2014) 216.
[10] A.R. Caffe, P.C. Van Ryen, T.P. Van der Woude, F.W. Van Leeuwen, Vasopressin and
oxytocin systems in the brain and upper spinal cord of Macaca fascicularis, J Comp Neurol, 287
(1989) 302-325.
[11] H.K. Caldwell, Oxytocin and Vasopressin: Powerful Regulators of Social Behavior,
Neuroscientist, (2017) 1073858417708284.
[12] H.K. Caldwell, H.E. Albers, Oxytocin, Vasopressin, and the Motivational Forces that Drive
Social Behaviors, Current topics in behavioral neurosciences, 27 (2016) 51-103.
[13] P. Campbell, A.G. Ophir, S.M. Phelps, Central vasopressin and oxytocin receptor
distributions in two species of singing mice, J Comp Neurol, 516 (2009) 321-333.
[14] X. Chen, P.D. Hackett, A.C. DeMarco, C. Feng, S. Stair, E. Haroon, B. Ditzen, G. Pagnoni, J.K.
Rilling, Effects of oxytocin and vasopressin on the neural response to unreciprocated
cooperation within brain regions involved in stress and anxiety in men and women, Brain
imaging and behavior, (2015).

Page 8 of 17
[15] M.M. Cho, A.C. DeVries, J.R. Williams, C.S. Carter, The effects of oxytocin and vasopressin
on partner preferences in male and female prairie voles ( Microtus ochrogaster ), Behavioral
Neuroscience, 113 (1999) 1079.
[16] E. Choleris, J.A. Gustafsson, K.S. Korach, L.J. Muglia, D.W. Pfaff, S. Ogawa, An estrogen-
dependent four-gene micronet regulating social recognition: a study with oxytocin and
estrogen receptor-alpha and -beta knockout mice, Proc Natl Acad Sci U S A, 100 (2003) 6192-
6197.
[17] G.J. de Vries, P. Sodersten, Sex differences in the brain: the relation between structure and
function, Horm Behav, 55 (2009) 589-596.
[18•] B.T. DiBenedictis, E.R. Nussbaum, H.K. Cheung, A.H. Veenema, Quantitative mapping
reveals age and sex differences in vasopressin, but not oxytocin, immunoreactivity in the rat
social behavior neural network, J Comp Neurol, 525 (2017) 2549-2570.

This study is the first to map oxytocin immunoreactivity, both fibers and cell bodies, in
numerous parts of the social behavior neural network in both sexes of juveniles and adults
rats.

[19] B. Ditzen, M. Schaer, B. Gabriel, G. Bodenmann, U. Ehlert, M. Heinrichs, Intranasal oxytocin

increases positive communication and reduces cortisol levels during couple conflict, Biol
Psychiatry, 65 (2009) 728-731.
[20] D.E. Dluzen, S. Muraoka, M. Engelmann, R. Landgraf, The effects of infusion of arginine
vasopressin, oxytocin, or their antagonists into the olfactory bulb upon social recognition
responses in male rats, Peptides, 19 (1998) 999-1005.
[21] G. Domes, M. Heinrichs, J. Glascher, C. Buchel, D.F. Braus, S.C. Herpertz, Oxytocin
attenuates amygdala responses to emotional faces regardless of valence, Biol Psychiatry, 62
(2007) 1187-1190.
[22] K.M. Dumais, A.G. Alonso, R. Bredewold, A.H. Veenema, Role of the oxytocin system in
amygdala subregions in the regulation of social interest in male and female rats, Neuroscience,
330 (2016) 138-149.
[23• •] K.M. Dumais, A.G. Alonso, M.A. Immormino, R. Bredewold, A.H. Veenema, Involvement
of the oxytocin system in the bed nucleus of the stria terminalis in the sex-specific regulation of
social recognition, Psychoneuroendocrinology, 64 (2016) 79-88.

This study is one of very few that has linked a sex difference in structure of the oxytocin system
with a sex difference in behavior.

[24] K.M. Dumais, R. Bredewold, T.E. Mayer, A.H. Veenema, Sex differences in oxytocin
receptor binding in forebrain regions: correlations with social interest in brain region- and sex-
specific ways, Horm Behav, 64 (2013) 693-701.
[25] K.M. Dumais, P.P. Kulkarni, C.F. Ferris, A.H. Veenema, Sex differences in neural activation
following different routes of oxytocin administration in awake adult rats,
Psychoneuroendocrinology, 81 (2017) 52-62.

Page 9 of 17
[26•] K.M. Dumais, A.H. Veenema, Vasopressin and oxytocin receptor systems in the brain: Sex
differences and sex-specific regulation of social behavior, Front Neuroendocrinol, 40 (2016) 1-
23.

An in depth review of the oxytocin and vasopressin systems and the links, or lack thereof,
between the neuroantomical structure of these systems and their sex-specific modulation of
social behaviors.

[27] K. Ebner, C.T. Wotjak, R. Landgraf, M. Engelmann, A single social defeat experience
selectively stimulates the release of oxytocin, but not vasopressin, within the septal brain area
of male rats, Brain Res, 872 (2000) 87-92.
[28] M. Engelmann, K. Ebner, R. Landgraf, F. Holsboer, C.T. Wotjak, Emotional stress triggers
intrahypothalamic but not peripheral release of oxytocin in male rats, J Neuroendocrinol, 11
(1999) 867-872.
[29] M. Engelmann, K. Ebner, C.T. Wotjak, R. Landgraf, Endogenous oxytocin is involved in
short-term olfactory memory in female rats, Behav Brain Res, 90 (1998) 89-94.
[30] C. Feng, P.D. Hackett, A.C. DeMarco, X. Chen, S. Stair, E. Haroon, B. Ditzen, G. Pagnoni, J.K.
Rilling, Oxytocin and vasopressin effects on the neural response to social cooperation are
modulated by sex in humans, Brain imaging and behavior, (2014).
[31] C. Feng, A. Lori, I.D. Waldman, E.B. Binder, E. Haroon, J.K. Rilling, A common oxytocin
receptor gene (OXTR) polymorphism modulates intranasal oxytocin effects on the neural
response to social cooperation in humans, Genes Brain Behav, 14 (2015) 516-525.
[32] J.N. Ferguson, J.M. Aldag, T.R. Insel, L.J. Young, Oxytocin in the medial amygdala is essential
for social recognition in the mouse, J Neurosci, 21 (2001) 8278-8285.
[33] J.N. Ferguson, L.J. Young, E.F. Hearn, M.M. Matzuk, T.R. Insel, J.T. Winslow, Social amnesia
in mice lacking the oxytocin gene, Nat Genet 25 (2000) 284-288.
[34] M. Fischer-Shofty, Y. Levkovitz, S.G. Shamay-Tsoory, Oxytocin facilitates accurate
perception of competition in men and kinship in women, Social cognitive and affective
neuroscience, 8 (2013) 313-317.
[35] E. Fliers, D.F. Swaab, C.W. Pool, R.W. Verwer, The vasopressin and oxytocin neurons in the
human supraoptic and paraventricular nucleus; changes with aging and in senile dementia,
Brain Res, 342 (1985) 45-53.
[36] S. Gao, B. Becker, L. Luo, Y. Geng, W. Zhao, Y. Yin, J. Hu, Z. Gao, Q. Gong, R. Hurlemann, D.
Yao, K.M. Kendrick, Oxytocin, the peptide that bonds the sexes also divides them, Proc Natl
Acad Sci U S A, 113 (2016) 7650-7654.
[37] J.L. Goodson, D. Kabelik, Dynamic limbic networks and social diversity in vertebrates: from
neural context to neuromodulatory patterning, Front Neuroendocrinol, 30 (2009) 429-441.
[38] J.L. Goodson, D. Kabelik, S.E. Schrock, Dynamic neuromodulation of aggression by
vasotocin: influence of social context and social phenotype in territorial songbirds, Biology
letters, 5 (2009) 554-556.
[39] E.A. Hammock, P. Levitt, Oxytocin receptor ligand binding in embryonic tissue and
postnatal brain development of the C57BL/6J mouse, Front Behav Neurosci, 7 (2013) 195.

Page 10 of 17
[40] A.C. Harmon, T.O. Moore, K.L. Huhman, H.E. Albers, Social experience and social context
alter the behavioral response to centrally administered oxytocin in female Syrian hamsters,
Neuroscience, 109 (2002) 767-772.
[41] H.U. Haussler, G.F. Jirikowski, J.D. Caldwell, Sex differences among oxytocin-
immunoreactive neuronal systems in the mouse hypothalamus, J Chem Neuroanat, 3 (1990)
271-276.
[42] G. Herzmann, C.W. Bird, M. Freeman, T. Curran, Effects of oxytocin on behavioral and ERP
measures of recognition memory for own-race and other-race faces in women and men,
Psychoneuroendocrinology, 38 (2013) 2140-2151.
[43] T.R. Insel, R. Gelhard, L.E. Shapiro, The comparative distribution of forebrain receptors for
neurohypophyseal peptides in monogamous and polygamous mice, Neuroscience, 43 (1991)
623-630.
[44] T.R. Insel, T.A. Hulihan, A gender-specific mechanism for pair bonding: oxytocin and
partner preference formation in monogamous voles, Behavioral Neuroscience, 109 (1995) 782-
789.
[45] T.A. Ishunina, D.F. Swaab, Vasopressin and oxytocin neurons of the human supraoptic and
paraventricular nucleus: size changes in relation to age and sex, The Journal of clinical
endocrinology and metabolism, 84 (1999) 4637-4644.
[46] R. Jia, F. Tai, S. An, H. Broders, R. Sun, Neonatal manipulation of oxytocin influences the
partner preference in mandarin voles (< i> Microtus mandarinus</i>), Neuropeptides, 42 (2008)
525-533.
[47] R. Jia, F.D. Tai, S.C. An, H. Broders, X.L. Ding, Q. Kong, L. Zhao, H. Zhang, Effects of neonatal
oxytocin treatment on aggression and neural activities in mandarin voles, Physiol Behav, 95
(2008) 56-62.
[48] Z.V. Johnson, H. Walum, Y. Xiao, P.C. Riefkohl, L.J. Young, Oxytocin receptors modulate a
social salience neural network in male prairie voles, Horm Behav, 87 (2017) 16-24.
[49•] Z.V. Johnson, L.J. Young, Oxytocin and vasopressin neural networks: Implications for social
behavioral diversity and translational neuroscience, Neurosci Biobehav Rev, 76 (2017) 87-98.

A thoughtful review of the role the oxytocin system may play the diversity of social behaviors
that are found in different species, with an emphasis on the neural networks that modulate
these behaviors.

[50] A.C. Keebaugh, C.E. Barrett, J.L. Laprairie, J.J. Jenkins, L.J. Young, RNAi knockdown of
oxytocin receptor in the nucleus accumbens inhibits social attachment and parental care in
monogamous female prairie voles, Soc Neurosci, (2015) 1-10.
[51] L.B. King, H. Walum, K. Inoue, N.W. Eyrich, L.J. Young, Variation in the Oxytocin Receptor
Gene Predicts Brain Region-Specific Expression and Social Attachment, Biol Psychiatry, 80
(2016) 160-169.
[52] H.J. Lee, H.K. Caldwell, A.H. Macbeth, S.G. Tolu, W.S. Young, 3rd, A conditional knockout
mouse line of the oxytocin receptor, Endocrinology, 149 (2008) 3256-3263.
[53•] Y. Li, A. Mathis, B.F. Grewe, J.A. Osterhout, B. Ahanonu, M.J. Schnitzer, V.N. Murthy, C.
Dulac, Neuronal Representation of Social Information in the Medial Amygdala of Awake
Behaving Mice, Cell, 171 (2017) 1176-1190 e1117.

Page 11 of 17
This study performed in vivo calcium imaging of the medial amygdala in awake behaving mice
and found that previous experience moderates the sex-specific effects of oxytocin in this brain
region.

[54] Y. Liu, Z.X. Wang, Nucleus accumbens oxytocin and dopamine interact to regulate pair
bond formation in female prairie voles, Neuroscience, 121 (2003) 537-544.
[55] M.A. Lockard, M.S. Ebert, C.I. Bargmann, Oxytocin mediated behavior in invertebrates: An
evolutionary perspective, Dev Neurobiol, 77 (2017) 128-142.
[56] T.M. Love, Oxytocin, motivation and the role of dopamine, Pharmacol Biochem Behav, 119
(2014) 49-60.
[57] M. Lukas, I. Toth, A.H. Veenema, I.D. Neumann, Oxytocin mediates rodent social memory
within the lateral septum and the medial amygdala depending on the relevance of the social
stimulus: male juvenile versus female adult conspecifics, Psychoneuroendocrinology, 38 (2013)
916-926.
[58] S. Luo, Y. Zhu, Y. Xu, Q. Kong, The oxytocinergic system modulates sadistic context-
dependent empathy in humans, Scientific reports, 7 (2017) 12463.
[59] S.K. Lynn, E.A. Hoge, L.E. Fischer, L.F. Barrett, N.M. Simon, Gender differences in oxytocin-
associated disruption of decision bias during emotion perception, Psychiatry Res, 219 (2014)
198-203.
[60] A.H. Macbeth, H.J. Lee, J. Edds, W.S. Young, 3rd, Oxytocin and the oxytocin receptor
underlie intrastrain, but not interstrain, social recognition, Genes Brain Behav, 8 (2009) 558-
567.
[61] B.J. Marlin, R.C. Froemke, Oxytocin modulation of neural circuits for social behavior, Dev
Neurobiol, 77 (2017) 169-189.
[62• •] M.M. McCarthy, Multifaceted origins of sex differences in the brain, Philos Trans R Soc
Lond B Biol Sci, 371 (2016) 20150106.

A thought-provoking review of why and how we study sex differences in the brain.

[63] A.R. McIntosh, Contexts and catalysts: a resolution of the localization and integration of
function in the brain, Neuroinformatics, 2 (2004) 175-182.
[64] L.C. Merrill, C.W. Jones, S.S. Drury, K.P. Theall, The differential impact of oxytocin receptor
gene in violence-exposed boys and girls, Int J Dev Neurosci, 59 (2017) 60-67.
[65] T.V. Miller, H.K. Caldwell, Oxytocin during Development: Possible Organizational Effects on
Behavior, Frontiers in endocrinology, 6 (2015) 76.
[66] M.E. Modi, K. Inoue, C.E. Barrett, K.A. Kittelberger, D.G. Smith, R. Landgraf, L.J. Young,
Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation
in the Prairie Vole, Neuropsychopharmacology, 40 (2015) 1856-1865.
[67] K. Mogi, R. Ooyama, M. Nagasawa, T. Kikusui, Effects of neonatal oxytocin manipulation on
development of social behaviors in mice, Physiology & behavior, 133 (2014) 68-75.
[68] M. Nakajima, A. Gorlich, N. Heintz, Oxytocin modulates female sociosexual behavior
through a specific class of prefrontal cortical interneurons, Cell, 159 (2014) 295-305.

Page 12 of 17
[69] I. Neumann, M. Ludwig, M. Engelmann, Q.J. Pittman, R. Landgraf, Simultaneous
microdialysis in blood and brain: oxytocin and vasopressin release in response to central and
peripheral osmotic stimulation and suckling in the rat, Neuroendocrinology, 58 (1993) 637-645.
[70] S.W. Newman, The medial extended amygdala in male reproductive behavior. A node in
the mammalian social behavior network, Ann N Y Acad Sci, 877 (1999) 242-257.
[71] K.D. Nyuyki, M. Waldherr, S. Baeuml, I.D. Neumann, Yes, I am ready now: differential
effects of paced versus unpaced mating on anxiety and central oxytocin release in female rats,
PLoS One, 6 (2011) e23599.
[72] P. Popik, J.M. Van Ree, Oxytocin but not vasopressin facilitates social recognition following
injection into the medial preoptic area of the rat brain, Eur.Neuropsychopharmacol., 1 (1991)
555-560.
[73] X. Qiao, Y. Yan, R. Wu, F. Tai, P. Hao, Y. Cao, J. Wang, Sociality and oxytocin and vasopressin
in the brain of male and female dominant and subordinate mandarin voles, J Comp Physiol A
Neuroethol Sens Neural Behav Physiol, 200 (2014) 149-159.
[74•] M.A. Rice, L.E. Hobbs, K.J. Wallace, A.G. Ophir, Cryptic sexual dimorphism in spatial
memory and hippocampal oxytocin receptors in prairie voles (Microtus ochrogaster), Horm
Behav, 95 (2017) 94-102.

This study expanded our understanding of oxytocin's role in the modulation of social behavior
evaluating sex differences in hipppocampual dependent spatial memory in prairie voles.

[75] J.K. Rilling, A.C. Demarco, P.D. Hackett, X. Chen, P. Gautam, S. Stair, E. Haroon, R.
Thompson, B. Ditzen, R. Patel, G. Pagnoni, Sex differences in the neural and behavioral
response to intranasal oxytocin and vasopressin during human social interaction,
Psychoneuroendocrinology, 39 (2014) 237-248.
[76] J.K. Rilling, A.C. DeMarco, P.D. Hackett, R. Thompson, B. Ditzen, R. Patel, G. Pagnoni, Effects
of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in
men, Psychoneuroendocrinology, 37 (2012) 447-461.
[77] Y. Takayanagi, M. Yoshida, I.F. Bielsky, H.E. Ross, M. Kawamata, T. Onaka, T. Yanagisawa, T.
Kimura, M.M. Matzuk, L.J. Young, K. Nishimori, Pervasive social deficits, but normal parturition,
in oxytocin receptor-deficient mice, Proc Natl Acad Sci U S A, 102 (2005) 16096-16101.
[78•] S. Tamborski, E.M. Mintz, H.K. Caldwell, Sex Differences in the Embryonic Development of
the Central Oxytocin System in Mice, J Neuroendocrinol, 28 (2016).

This is the first study to demonstrate that there are significant sex differences in the
development of the central oxytocin system in mice.

[79] J.H. Taylor, J. Cavanaugh, J.A. French, Neonatal oxytocin and vasopressin manipulation
alter social behavior during the juvenile period in Mongolian gerbils, Dev Psychobiol, 59 (2017)
653-657.
[80] M.C. Teles, O. Almeida, J.S. Lopes, R.F. Oliveira, Social interactions elicit rapid shifts in
functional connectivity in the social decision-making network of zebrafish, Proc Biol Sci, 282
(2015) 20151099.

Page 13 of 17
[81] A. Theodoridou, A.C. Rowe, C. Mohr, Men perform comparably to women in a perspective
taking task after administration of intranasal oxytocin but not after placebo, Frontiers in human
neuroscience, 7 (2013) 197.
[82] S. Uhl-Bronner, E. Waltisperger, G. Martinez-Lorenzana, M. Condes Lara, M.J. Freund-
Mercier, Sexually dimorphic expression of oxytocin binding sites in forebrain and spinal cord of
the rat, Neuroscience, 135 (2005) 147-154.
[83] M. Waldherr, I.D. Neumann, Centrally released oxytocin mediates mating-induced
anxiolysis in male rats, Proc Natl Acad Sci U S A, 104 (2007) 16681-16684.
[84] R. Waller, N.S. Corral-Frias, B. Vannucci, R. Bogdan, A.R. Knodt, A.R. Hariri, L.W. Hyde, An
oxytocin receptor polymorphism predicts amygdala reactivity and antisocial behavior in men,
Social cognitive and affective neuroscience, 11 (2016) 1218-1226.
[85] Y. Wang, L. Xu, Y. Pan, Z. Wang, Z. Zhang, Species differences in the immunoreactive
expression of oxytocin, vasopressin, tyrosine hydroxylase and estrogen receptor alpha in the
brain of Mongolian gerbils (Meriones unguiculatus) and Chinese striped hamsters (Cricetulus
barabensis), PLoS One, 8 (2013) e65807.
[86] Z. Wang, K. Moody, J.D. Newman, T.R. Insel, Vasopressin and oxytocin immunoreactive
neurons and fibers in the forebrain of male and female common marmosets (Callithrix jacchus),
Synapse, 27 (1997) 14-25.
[87] S.R. Wersinger, J.L. Temple, H.K. Caldwell, W.S. Young, 3rd, Inactivation of the oxytocin and
the vasopressin (Avp) 1b receptor genes, but not the Avp 1a receptor gene, differentially
impairs the Bruce effect in laboratory mice (Mus musculus), Endocrinology, 149 (2008) 116-121.
[88] M. Wierda, E. Goudsmit, P.F. Van der Woude, J.S. Purba, M.A. Hofman, H. Bogte, D.F.
Swaab, Oxytocin cell number in the human paraventricular nucleus remains constant with aging
and in Alzheimer's disease, Neurobiol Aging, 12 (1991) 511-516.
[89] J.R. Williams, K.C. Catania, C.S. Carter, Development of partner preferences in female
prairie voles (Microtus ochrogaster): the role of social and sexual experience, Horm Behav, 26
(1992) 339-349.
[90] J.R. Williams, T.R. Insel, C.R. Harbaugh, C.S. Carter, Oxytocin administered centrally
facilitates formation of a partner preference in prairie voles ( Microtus ochrogaster ), J
Neuroendocrinol., 6 (1994) 247-250.
[91] J.T. Winslow, N. Hastings, C.S. Carter, C.R. Harbaugh, T.R. Insel, A role for central
vasopressin in pair bonding in monogamous prairie voles, Nature, 365 (1993) 545-548.
[92] L. Xu, Y. Pan, K.A. Young, Z. Wang, Z. Zhang, Oxytocin and vasopressin immunoreactive
staining in the brains of Brandt's voles (Lasiopodomys brandtii) and greater long-tailed
hamsters (Tscherskia triton), Neuroscience, 169 (2010) 1235-1247.
[93] S. Yao, J. Bergan, A. Lanjuin, C. Dulac, Oxytocin signaling in the medial amygdala is required
for sex discrimination of social cues, Elife, 6 (2017).
[94] L.J. Young, M.M. Lim, B. Gingrich, T.R. Insel, Cellular mechanisms of social attachment,
Horm Behav, 40 (2001) 133-138.

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Figure Legends

Figure 1. Graphs of the relative expression levels of oxytocin (Oxt) and oxytocin receptor (Oxtr)
mRNA in the heads/brains of male and female mice on embryonic day (E) 12.5 (♀=6; ♂= 5),
E14.5 (♀=5; ♂=5), E16.5 (♀=5; ♂=5), E18.5 (♀=5; ♂=5), and postnatal day 2 (PND2) (♀=5;
♂=5). A: In females, Oxt mRNA was detected by E16.5 and in males at PND2; females at PND2
also had more Oxt mRNA than males. B: Oxtr mRNA as detected at all time points, though
females had a greater expression of Oxt at E14.5, E16.5, E18.5, and PND2 compared to males.
A indicates a statistically significant difference (p < 0.05) in detection levels between males
and females at that particular time point. An * indicates a statistically significant difference (p <
0.05) in expression levels between males and females at that particular time point. Originally
published in [78•] and reprinted with permission from John Wiley & Sons, Inc.

Figure 2. Sex differences in the function of the posterior bed nucleus of the stria terminalis
(pBNST)- oxytocin system in social recognition memory in rats. (A) Oxytocin injected into the
pBNST improved social recognition in males, but not in females. Bars indicate mean + SEM; #:
significantly different from chance level (p < 0.05, one sample T-test); *p < 0.05, **p < 0.01,
two-way ANOVA followed by T-test. (B) The percentage of oxytocin (OT) release in the pBNST of
rats that showed social recognition is significantly higher during T1 versus dialysate 1 and 3 and
during dialysate 5 versus dialysate 1 in males only ( = female; = male). The percentage of
oxytocin release in the pBNST of rats that showed social recognition is also significantly higher
in males than in females during T1 and T2. Data are expressed as mean + SEM. *p < 0.05 versus
dialysate 1, #p < 0.05 versus dialysate 3, $p < 0.05 versus other sex; T1, 4-min exposure to first
juvenile; T2, 4-min exposure to previously-exposed juvenile along with a novel juvenile.
Reprinted from Psychoneuroendocrinology, 64 (2016): 79-88 [23• •] with permission from
Elsevier.

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