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Oxytocin, Vasopressin, and Social Behavior: From Neural Circuits to Clinical

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DOI: 10.1210/endocr/bqac111

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Endocrinology, 2022, 163, 1–13
https://doi.org/10.1210/endocr/bqac111
Advance access publication 21 July 2022
Mini-Review

Oxytocin, Vasopressin, and Social Behavior: From Neural

Circuits to Clinical Opportunities

Downloaded from https://academic.oup.com/endo/article/163/9/bqac111/6648172 by Georgia State University user on 12 October 2022

Nicole Rigney,1 Geert J. de Vries,1,2 Aras Petrulis,1 and Larry J. Young3,4,5,
1
Neuroscience Institute and Center for Behavioral Neuroscience, Georgia State University, Atlanta, Georgia 30303, USA
2
Department of Biology, Georgia State University, Atlanta, Georgia 30303, USA
3
Center for Translational Social Neuroscience, Emory University, Atlanta, Georgia 30329, USA
4
Silvio O. Conte Center for Oxytocin and Social Cognition, Emory National Primate Research Center, Emory University, Atlanta, Georgia 30329,
USA; and
5
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Correspondence: Larry J. Young, PhD, Emory National Primate Center, Emory University, 954 Gatewood Rd, Atlanta, GA 30329, USA. Email: lyoun03@emory.edu.

Abstract
Oxytocin and vasopressin are peptide hormones secreted from the pituitary that are well known for their peripheral endocrine effects on child-
birth/nursing and blood pressure/urine concentration, respectively. However, both peptides are also released in the brain, where they modulate
several aspects of social behaviors. Oxytocin promotes maternal nurturing and bonding, enhances social reward, and increases the salience of
social stimuli. Vasopressin modulates social communication, social investigation, territorial behavior, and aggression, predominantly in males.
Both peptides facilitate social memory and pair bonding behaviors in monogamous species. Here we review the latest research delineating the
neural circuitry of the brain oxytocin and vasopressin systems and summarize recent investigations into the circuit-based mechanisms modu-
lating social behaviors. We highlight research using modern molecular genetic technologies to map, monitor activity of, or manipulate neuro-
peptide circuits. Species diversity in oxytocin and vasopressin effects on social behaviors are also discussed. We conclude with a discussion of
the translational implications of oxytocin and vasopressin for improving social functioning in disorders with social impairments, such as autism
spectrum disorder.
Key Words: autism, neuropeptides, social communication, social behavior, oxytocin, vasopressin
Abbreviations: AON, accessory olfactory nucleus; AMY, amygdala; AVP, arginine vasopressin; ASD, autism spectrum disorder; BNST, bed nucleus of the stria
terminalis; DR, dorsal raphe; HYP, hypothalamus; KO, knockout; LHb, lateral habenula; LS, lateral septum; LC, locus coeruleus; MeA, medial amygdala; MPOA,
medial preoptic area; NAcc, nucleus accumbens; OB, olfactory bulb; OXT, oxytocin; OXTR, oxytocin receptor; PAG, periaqueductal gray; PVN, paraventricular nu-
cleus of the hypothalamus; PMd, premammillary nucleus (dorsal); SON, supraoptic nucleus of the hypothalamus; VP, ventral pallidum; VTA, ventral tegmental area.

Social distancing and isolation during the COVID-19 pan-
demic have caused major disruptions to our social relation-
ships, likely affecting our well-being, as social interactions are
fundamental for physical and mental health (1). Dysfunction
in social communication and behavior is also a prominent
aspect of many psychopathologies including autism, schizo-
phrenia, and social anxiety (2). Considerable insights into the
biological framework regulating functional social behavior,
and therefore its dysfunction, have been gained through exam-
ination of oxytocin (OXT) and arginine vasopressin (AVP)
neuropeptide systems and their nonmammalian homologues.
OXT and AVP were first identified as regulators of periph-
eral physiology, being secreted into the bloodstream through
hypothalamic terminals in posterior pituitary and median
eminence to influence parturition and lactation (OXT) and
water retention, blood pressure, body temperature, and the
hypothalamic-pituitary-adrenal axis (AVP) (3-6). In the 1960s,
work by de Wied substantially advanced the field of endocrin-
ology by demonstrating that AVP can act in the brain to alter
behavior, thereby introducing the concept of “neuropeptide”
(7). Since then, OXT acting centrally has been shown to be es-
sential for maternal behavior, mother-infant bonding, sexual
behavior, and other affiliative behaviors such as pair bonding
Received: 1 April 2022. Editorial Decision: 11 July 2022. Corrected and Typeset: 27 July 2022
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail:
journals.permissions@oup.com
and empathy-like consoling (8-14), whereas central AVP has
been shown to regulate social communication, territorial ag-
gression, pair bonding, and mate guarding, especially in males
(9, 15, 16). Some of the behavioral effects of OXT and AVP
are functionally linked to their peripheral function, as OXT
promotes birth and nursing but also parental nurturing, while
AVP modulates urine production and also territorial behavior,
which often involves urine and scent marking (17, 18). Since
these peptides modulate social cognition and motivation, ma-
nipulations of the OXT and AVP systems offer promising fu-
ture therapeutics for individuals with social deficits, such as in
autism spectrum disorder (ASD) (19-21).
Although the neural mechanisms underlying social behavior
are highly complex, recent anatomical, genetic, and molecular
technologies have considerably advanced our understanding
of how OXT and AVP act within the brain to regulate so-
cial behavior. Most of this recent work has been conducted in
laboratory mice because of the availability of powerful gen-
etic tools in this species, such as recombinase-expressing and
conditional knockout (KO) strains that, when combined with
site-specific targeting with viral vectors, allow unprecedented
access to chemically and spatially defined neural systems.
These advancements have allowed researchers to manipulate
2 Endocrinology, 2022, Vol. 163, No. 9
neurons expressing OXT and AVP and their cognate recep-
tors within the “social behavior neural network” (SBNN), as
well as in other areas, such as the hippocampus, and thereby
determine how these discrete, interlinked systems alter social
behavior (6, 16, 22). Since laboratory mice have limited be-
havioral diversity, and species differences in the distribution
of OXT/AVP receptors are well documented (10), it is im-
portant to expand these intersectional tools to other species
(23). For example, oxytocin and vasotocin modulate social
interactions in many species including teleost fish, lizards,
and birds (24-26) and genome editing approaches are now
being used to examine OXT and AVP circuitry and social be-
havioral functions in prairie voles and medaka fish (27-30).
Importantly, the disproportionate focus on OXT compared to
AVP systems suggests there is a need to rebalance research so
that the role of different AVP circuits in social behavior can
be refined and expanded.
Consequently, this mini-review will highlight recent work
on the behaviorally relevant sources of OXT and AVP, the
inputs and outputs of these sources, and the receptor systems
they act on to generate complex social behaviors; see (6, 16,
31-38) for reviews of foundational work that guided recent
discoveries of OXT/AVP’s role in social behavior.
Neuronal Sources of Oxytocin and Vasopressin
Hypothalamus
The paraventricular (PVN) and supraoptic nuclei (SON) of
the hypothalamus release OXT and AVP, both centrally and
peripherally. Within these regions, each peptide is stored in
large, dense core vesicles, which can be released through
somatodendritic, en passant axonal release, as well as
through synaptic terminals (39-41). AVP is also produced
in other hypothalamic nuclei such as the suprachiasmatic
nucleus, well known for regulating circadian rhythms
(42), and the accessory nuclei/nucleus circularis region, a
likely source of AVP regulating aggression and competitive
communication (43). OXT is also produced in the medial
preoptic area (MPOA), where it regulates maternal and
sexual behavior (44).
Both the PVN and SON contain magnocellular OXT and
AVP neurosecretory cells that project to the posterior pi-
tuitary, releasing each peptide peripherally as a hormone
(45), and the PVN contains an additional population of
nonneurosecretory, parvocellular cells that modulate anterior
pituitary release of adrenocorticotropin (46), as well as pro-
ject to other brain and spinal cord areas (47, 48); for a com-
prehensive review see (6, 40, 49). Some reports have shown
that AVP messenger RNA (mRNA) density measurements in
the SON of rats are greater in males (50), while, in mice, OXT
production is greater in females (51); however, other studies
have shown a similar amount of OXT and AVP in both sexes
in the PVN/SON of various rodent species, nonhuman pri-
mates, and humans (49, 52).
To better understand how OXT and AVP modulate neural
circuits controlling social behavior, it is important to delin-
eate the central nervous system projections of these neurons
as well as their inputs. The development of mice with Cre
recombinase driven by OXT or AVP neurons as well as vir-
uses with transgenes driven by neuropeptide promoters have
considerably enhanced our understanding of OXT and AVP
circuit architecture.
Oxytocin
PVN OXT-expressing cells send fibers to the SON forming
the neurohypophyseal tract (44), and classical retro-
grade tracing and modern viral tracing strategies in rats
and mice have shown that the PVN OXT-expressing cells
also send projections to the thalamus, cortex, amygdala,
striatum, and hippocampus (Fig. 1A (53-55). The SON
OXT-expressing cells have more restricted projections,
mainly to the posterior pituitary, but also project to the
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medial and central amygdala (44). In rats and mice, sev-
eral regions provide input to PVN OXT-expressing cells,
including the brainstem, thalamic, hypothalamic, and cor-
tical cell populations (56-58) (see Fig. 1A). Recently, Son
et al (59) found no correlation between OXT neuronal
projections and OXTR expression, consistent with para-
crine signaling.
Vasopressin
PVN AVP-expressing cells send projections to the thalamus,
cortex, amygdala, striatum, and hippocampus (Fig. 1B).
Although the number of PVN AVP neurons do not appear
to differ by sex, central projections from these neurons are
generally denser in female than in male mice (60). PVN/SON
AVP cells receive monosynaptic inputs locally and from lat-
eral septum (LS), bed nucleus of the stria terminalis (BNST),
MPOA, ventromedial hypothalamus, and suprachiasmatic
nucleus (Fig. 1B). Some differences between inputs to PVN
and SON cells are apparent. For example, PVN AVP cells re-
ceive stronger input from the BNST than does the SON. Few
of the inputs to PVN AVP cells are AVP immunoreactive,
and may, in fact, be OXT-ergic (61, 62), suggesting func-
tional crosstalk between OXT and AVP PVN cells. Whether
release of hypothalamic OXT and AVP is synchronized
across all OXT/AVP sources under various social conditions
or has region-specific projections for distinct social behav-
iors is still unclear.
Extended Amygdala
Oxytocin
OXT neurons have been reported in the extended medial
amygdala (eg, the BNST and medial amygdala proper [MeA])
in rats (63), California mice (64), and marmosets (65). Very
little is known about the neuroanatomical connectivity
of these neurons. However, OXT neurons in the BNST of
California mice make local connections within the BNST,
project to the hypothalamus, and are involved in social vigi-
lance (66).
Vasopressin
The extended medial amygdala contains neurons that ex-
press AVP in a steroid-dependent and sexually dimorphic
manner (33). Indeed, the BNST and MeA contribute to the
most pronounced sex difference in AVP innervation in the
brain (33, 60). For example, male rodents have 2 to 3 times
as many AVP cells as females in the BNST/MeA and pro-
nounced sex-different projections to areas involved in so-
cial behavior such as the ventral pallidum, lateral septum
(LS), lateral habenula, dorsal raphe (DR), periaqueductal
gray, as well as other forebrain areas (33, 60) (Fig. 1C).
The sex difference in AVP expression is driven primarily
by organizational effects of steroid hormones, although
hormone-independent influences of sex chromosomes play
Endocrinology, 2022, Vol. 163, No. 9 3

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Figure 1. Neural circuits (inputs and outputs) of oxytocin (OXT) and arginine vasopressin (AVP). Blue arrows indicate OXT and AVP neuronal inputs,
while red arrows indicate OXT and AVP neuronal outputs. Combined blue and red arrows indicate regions that share both inputs and outputs. HYP
refers to hypothalamic regions outside the paraventricular nucleus (PVN) and supraoptic nuclei (SON) of the hypothalamus. A, PVN and SON OXT
neurons. B, PVN and SON AVP neurons. C, Sexually dimorphic AVP neurons within the bed nucleus of the stria terminalis (BNST) and medial amygdala
(MeA).

a role (67). It is currently unknown which regions and Collectively, OXT and AVP cells in PVN receive and
neuronal cell types send monosynaptic inputs to BNST or send projections to similar regions, including thalamus,
MeA AVP. hypothalamus, midbrain, and extended amygdala. More
4 Endocrinology, 2022, Vol. 163, No. 9
neuroanatomical experiments are needed to map the con-
nectivity of OXT/AVP cells in the extended amygdala.
Oxytocin and Vasopressin Receptors
OXT has one canonical receptor type (ie, OXTR), whereas
AVP has 3: V1aR, V1bR, and V2. The behavioral effects of
AVP are mediated primarily by V1aR (or Avpr1a) and V1bR
(16, 37, 38, 49, 68), while AVP acts on V2 to regulate fluid
homeostasis in the kidney (69). Most research investigating
OXT and AVP functions do so by manipulating the recep-
tors, or receptor-expressing neurons, without regard to the
source of the peptide. One of the most interesting features
of the OXT/AVP system is the diversity in receptor func-
tion in relation to behavior. While there is remarkable con-
sistency in the distribution of OXT and AVP neurons and
their projections across vertebrates (33), there are striking
species differences in the distributions in the distribution
of OXT and AVP receptors in the brain, even between
closely related species (10). Humans, chimpanzees, and
other nonhuman primate species all show unique distribu-
tions of OXTR and V1aR in the brain, which may relate
to species differences in primate social behaviors (70). The
behavioral significance of diversity in receptor distribution,
both within and between species, has been highlighted by
studies of the neural basis of monogamy in prairie voles
(discussed later). In addition, the distribution of OXTR
messenger RNA in prairie vole brain is surprisingly wide-
spread, suggesting that OXT may modulate essentially
brain-wide circuit activity (71). In California mice, OXTR
is expressed in different cell types depending on the brain
region (72).
Modulation of Social Behavior
Sensory Processing of Social Cues
Olfactory processing is critical for appropriate social be-
havior driven by chemosignals produced by a conspecific
(73). While there are no known OXT cells in the olfac-
tory bulb (OB), PVN OXT can act early in the olfactory
processing stream, via OXT receptors in the anterior ol-
factory nucleus. This system facilitates social recognition in
rats by indirectly inhibiting the primary projection cells in
the OB (74, 75), thereby reducing background “noise” and
increasing signal salience. A similar process may also occur
via AVP release, from inhibitory OB interneurons, in con-
junction with cholinergic mechanisms (76, 77). This modu-
lation of signal to noise may be a common neural circuit
mechanism to enhance the salience of multimodal social
stimuli (10, 78).
Social Motivation and Investigation
To respond adaptively to their social environment, ani-
mals must be motivated to respond to social signals.
After processing social information (eg, on familiarity,
sex, age, health), animals must decide how to interact:
communicate, fight/compete, flee, cooperate, reproduce,
and, in some species, form pair bonds and raise offspring
together. OXT and AVP sources in the hypothalamus and
extended amygdala play pivotal and distinct roles in so-
cial investigation, motivation, and social reward (dis-
cussed later). Further, OXT (and likely AVP) is important
for long-term neural plasticity after social interactions
(10).
Although constitutive KO of OXT does not alter social ap-
proach in mice (79), specific OXT systems do influence so-
cial reward, approach, and investigation. For example, Dölen
et al (80), using elegant circuit manipulations, demonstrated
that PVN OXT and DR serotonin projections to the nucleus
accumbens (NAcc) are required for social reward in mice.
Further, PVN OXT cells are responsible for the facilitatory
effects of 3,4-methylendioxymethamphetamine (MDMA) on
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mouse prosocial behavior and social reward memory (81).
PVN OXT can also facilitate social reward through its ac-
tions on brain dopamine systems (82), originating, for ex-
ample, in the ventral tegmental area (VTA), and through
endocannabinoid-dependent mechanisms (83). In male
and female Syrian hamsters, social interaction increases the
amount of c-Fos expression (a marker for neural activity) in
OXT-immunoreactive neurons in the PVN and SON, while
OXTRs in the VTA mediate the rewarding properties of these
social interactions (84).
Similarly, in mice, social touch during early life increases
both PVN OXT neuronal firing and social approach later
in adulthood through interaction with substance P systems
within the periaqueductal gray (58). PVN OXT cells in adults
are also active during interactions with juveniles (85), and
stimulation of PVN OXT terminals in the VTA increased
social investigation through actions on OXTR specifically.
Moreover, deletion of OXTR from dopaminergic neurons in
the VTA eliminated preferences for interacting with juveniles
(82). Monogamous mandarin voles raised without a father
socialize less and have fewer PVN OXT cells, a behavioral
difference that can be reversed by optogenetic stimulation of
PVN OXT terminals within the prelimbic cortex (86). Taken
together, OXT from the PVN influences social behavior via its
actions on defined DR serotonin– and dopamine system–ex-
pressing populations as well as others, perhaps serving as a
“gating” mechanism for the flow of information to reward
systems (83, 87).
Historically OXT is known for having prosocial effects on
behavior, whereas AVP is thought to play more of a role in
aggression, stress, and anxiety. However, in California mice,
knockdown of OXT or administration of OXTR antagonist
in the anterior BNST increased social approach and decreased
social vigilance, an anxiety-like behavior, which suggests that
OXT may also drive social anxiety-like behavior depending
on its source or context (66, 88).
AVP can have prosocial effects as well. With site-specific
targeting using viral vectors, we have begun to identify which
AVP sources are responsible for specific social behaviors in
mice. AVP cell groups appear to play opposite roles in so-
cial investigation in males and females depending on the
source. BNST AVP cell ablation and AVP knockdown both
reduced male-male social investigation. These are similar to
effects of BNST AVP knockdown in avian species (reviewed
in [89]). PVN AVP cell ablation increased female social in-
vestigation, but does not alter investigation in males (52, 90,
91). However, PVN AVP cell stimulation in male mice caused
self-grooming instead of social interactions with female mice
(92). Nevertheless, there may be differential involvement of
PVN and BNST AVP cells in the control of social/emotional
behavior in each sex (52). There is also a sex-specific role of
AVP in the regulation of social play behavior in juvenile rats,
Endocrinology, 2022, Vol. 163, No. 9
as blocking V1aR in the LS increases social play behavior in
males and decreases it in females (49). The extreme sexually
dimorphic nature of BNST AVP cells may explain stronger
effects in males than in females. The female bias in the effects
of similar manipulations of PVN AVP cells may be related
to females having denser PVN AVP projections compared to
males (60).
Social Recognition
Although social behavior is diverse across species, one
common feature is that the animal must differentiate
between conspecifics, which is critical for the establish-
ment of relationships between animals (ie, affiliative, ter-
ritorial). OXT and AVP systems have long been known
to play a major role in the formation of social memory
(93). For example, mice with impairments in either system
show deficits in distinguishing between familiar and novel
conspecifics (74, 94, 95). OXTRs in the MeA receive OXT
input from the PVN that help discriminate between sex-
and individual cues (53, 74, 96). Ablating OXTR expres-
sion in aromatase-positive neurons in the MeA abolishes
male mouse preferences for females (96). Social memory
processing also requires the hippocampus. OXT and AVP-
expressing cells in PVN and SON send projections to
the hippocampus, with the highest fiber density seen in
the CA2 region for AVP and CA2/CA3 regions for OXT
projections (97-100). OXTRs in the anterior DG-CA2/
CA3 circuit facilitate social, but not object discrimin-
ation (101), and AVP projections from PVN to hippo-
campus influence recognition of conspecifics as well as
spatial features in mice (102). For example, Smith et al
(99) demonstrated that optogenetic activation of the PVN
AVP cell inputs to hippocampal CA2 area enhances social
memory, via a V1bR mechanism, in mice. Further, when
the PVN to CA2 pathway is activated chemogenetically,
nonmonogamous C57Bl6 mice form partner preferences
in a species-atypical way (103). Projections from PVN to
other brain regions can also alter aspects of social rec-
ognition. For example, PVN OXT input to the central
amygdala mediates the ability of mice to discriminate be-
tween negative and positive emotional states of conspe-
cifics (104).
Taken together, these studies suggest that AVP and OXT
cells in the PVN help generate social preferences and influ-
ence social recognition by direct hippocampal, amygdala,
and cortical synaptic release. One explanation for OXT and
AVP effects on social recognition may be that these peptides
act as attentional modulators, increasing the salience of so-
cial information through different circuits (10). Indeed, acti-
vated PVN OXT neurons increased not only affiliative, but
also agonistic behaviors (105). For a comprehensive review
on OXT and AVP’s role in social memory via the hippo-
campus, see (106). However, it is unlikely that just PVN
projections contribute to AVP effects on social recognition
as ablation of AVP cells in PVN and SON did not affect
social recognition (52, 107). Extrahypothalamic AVP pro-
jections may therefore be an important regulator of social
recognition. For example, BNST AVP cell ablation impairs
social recognition in males, likely through its projection to
the LS (94, 108, 109), and restoration of BNST—LS AVP
signaling in Magel2-KO mice ameliorated social discrimin-
ation deficits (110).
5
Social Communication, Territoriality, and
Aggression
AVP was first shown to influence social communication by
its ability to induce flank marking in Syrian hamsters in the
anterior hypothalamus and MPOA (16, 111-113). AVP in
these areas is also critical for the establishment of domin-
ance relationships; for a comprehensive review on AVP effects
on aggression and communication, see (114). Mice deposit
urine marks to communicate social status and dominance
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(115). Removal of BNST AVP cells in mice increases male
urine marking toward females. However, AVP knockdown in
this region did not affect urine marking but did reduce other
aspects of male communication (eg, vocalizations and tail rat-
tles), suggesting that BNST AVP is involved in some aspects of
male offensive/territorial signaling (91). In contrast, blockade
of V1a receptors in the lateral habenula and DR (downstream
BNST structures) reduced, instead of increased, male urine
marking toward potential competitor males. More work is
clearly needed to dissect which AVP sources and output re-
gions are responsible for urine marking and other forms of
social communication in mice.
AVP also plays a role in aggression in prairie voles and
Syrian hamsters, sometimes in a sex-specific manner. For ex-
ample, pharmacological studies revealed that AVP in the an-
terior hypothalamus facilitates intermale aggression both in
prairie voles and hamsters (16, 43, 116), while the opposite
effect was found in female hamsters (117). In hamsters, social
isolation increases aggression both in male and females, but
V1aR density is higher in males than females (114). Recently,
constitutive KO of Avpr1a in Syrian hamsters paradoxic-
ally increased flank marking and aggression in both sexes,
highlighting the complex role of Avpr1a in territorial behav-
iors and potentially highlighting the role of compensatory
mechanisms and/or effects on Avpr1a KO in multiple brain
regions (118). Collectively, these data suggest more work is
needed using comparative and gene-editing approaches to
elucidate AVP’s role in social communication and aggression.
Sexual Behavior
OXT is strongly involved both in male and female sexual be-
havior through central and peripheral action (38). OXT con-
tributes to sexual arousal and sexual reward in males, while
OXT influences lordosis and orgasm in females (38). In rats,
PVN OXT neurons are active during sexual behavior in males
and females and blocking OXT action in ventromedial hypo-
thalamus and MPOA reduces female receptivity (38).
In mice, BNST and MeA AVP cells are active during male
sexual behavior (101, 119) and knockdown of AVP within
the BNST reduced the number of intromissions and ejacula-
tions in males, but did not alter sexual behavior in females
(91). Hormonal action on this cell population may help drive
aspects of steroid-sensitive sexual behavior since gonadal hor-
mones affect both male sexual behavior (120, 121) and AVP
expression within the extended amygdala (33).
Parental Behavior
OXT is well known for its influence on social bonding and
maternal behavior (9, 18), and its role in parental behavior
highlights the putative function of OXT as an attentional
modulator (122). For example, OXT from PVN increases the
salience of mouse pup vocalizations, while a dam’s experience
with pups adjusts the balance of excitatory and inhibitory
6 Endocrinology, 2022, Vol. 163, No. 9
tuning in the auditory cortex (54, 123, 124). Further, PVN
OXT neurons are activated when virgin mice observe pup
retrievals by another mother and optogenetic stimulation of
PVN OXT efferents to auditory cortex enhances pup retrieval
learning in virgin mice (124, 125). This increase in OXT re-
lease by the PVN may be driven by the posterior intralaminar
complex of the thalamus inputs to the PVN (56). Other loci
of PVN OXT action include the VTA and NAcc as PVN OXT
projections to these areas promote paternal behaviors in man-
darin voles (126). An animal’s transition to parenthood is
known to affect sensory perception of infant cues. How PVN
OXT modulates this change through various OXT circuits
remains to be further explored. Additionally, parental/sensory
deprivation or cesarean delivery can lead to disruptions of
hypothalamic OXT and maternal behavior (127-130), while,
in rats, enriched environments increase hypothalamic OXT in
dams and their male offspring (131). Therefore, OXT, social
experience, and environment heavily influence functional par-
ental behavior.
There are far fewer studies examining the role of central
AVP on parental behavior. This is not surprising given that
AVP is traditionally associated with territorial behavior and
anxiety. However, the seminal paper demonstrating the effect
of OXT on maternal behavior also showed that AVP stimu-
lates maternal behavior, but with a longer latency of action
(132). Recent work has demonstrated that chemogenetic
inhibition of PVN AVP cell activity increases nest building
in male mice (while excitation decreases nest building in fe-
males), without altering other aspects of parental behavior
(133). Knockdown of V1aR in the MPOA impairs maternal
behavior in rats (134). Although the precise sources of AVP
regulating parental behavior is undefined, AVP projections
from the extended amygdala may also influence maternal be-
havior, as AVP in the LS facilitates paternal behavior in prairie
voles (135, 136). While hypothalamic OXT plays a substan-
tial role in rodent maternal behavior compared to AVP, the
sources of AVP responsible for V1aR-mediated changes in
parental behavior require further examination.
Pair Bonding and Mate Choice
Studies in monogamous prairie voles have revealed the critical
roles of OXT and AVP and their receptors in pair bonding,
biparental care, and mate guarding. For a detailed review of
this topic, see (9). Bonding with a partner is the culmination
of many of the interdependent processes discussed earlier. To
pair bond, mates need to sense their partner’s social cues, be
motivated to interact with them, and remember their partner’s
identity. Mate guarding is a form of territoriality, while the
pair bond has similarities to the maternal bond. Thus, it is not
surprising that OXT and AVP are integrally involved in pair
bonding in monogamous species, and mate choices more gen-
erally. Here we provide a brief overview of OXT’s and AVP’s
role in pair bonding and mate choice, highlighting recent ad-
vances in the context of more classic studies.
Oxytocin and monogamy
Mating and cohabitation stimulates a partner preference in
both male and female prairie voles. Blocking brain OXT recep-
tors in either sex prevents pair bonding, potentially disrupting
coordinated activity across a social salience network (137).
Pharmacological studies revealed that OXT signaling in the
prefrontal cortex and NAcc facilitate mating-induced pair
bonding. Viral-mediated small interfering RNA knockdown
of OXTR in NAcc of prairie voles inhibits partner preference
(138), while overexpressing NAcc OXTR enhances partner
preference formation (139). The OXT fibers in the NAcc ori-
ginate from the PVN (140), and OXT is released in females
during mating (141).
Robust individual differences in NAcc relate to individual
variation in alloparental nurturing behavior, and resilience
to early-life adversity with respect to later-life pair bonding
(142, 143). This variation in OXTR density in the NAcc is de-
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termined by genetic variation in the Oxtr gene (144), which in
turn predicts how early-life nurturing experience affects later-
life bonding ability (143).
Recent ex vivo electrophysiological studies provide clues
about how one’s social experience can alter OXTR signaling
effect on NAcc activity to influence pair-bond formation and
expression. In virgin female prairie voles, OXTR signaling,
mimicking the first mating, decreases spontaneous activity of
NAcc neurons, effectively reducing the noise in the circuit,
perhaps to facilitate synaptic plasticity to make partner cues
rewarding. After pair bonding, OXTR signaling increases
evoked NAcc cell activity from neural inputs, perhaps amp-
lifying the signal of the neural representation of the partner,
making the partner reinforcing and motivating affiliation
(140). This experience-dependent change in OXTR signaling
on physiology is mediated by OXTR-endocannabinoid inter-
actions, and blocking CB1 receptor elicits defensive rejection
by the female of the partner. Interestingly, OXT stimulates the
activation of NAcc activity in men in monogamous relation-
ships when viewing images of their partner (145).
Once the pair bond is formed, withdrawal of PVN OXT
signaling in NAcc mediates “grieving”-like passive coping
behavior following the loss of the partner, which is mim-
icked in the presence of the partner by small interfering RNA
knockdown of NAc OXTR (140, 146). The negative affect
stimulated by the loss of OXT signaling when separated by
the partner may serve to motivate partners to stay together in
enduring relationships.
Prairie voles also display empathy-based consoling behavior
toward their distress partner, sibling, or familiar cage mate,
which is mediated by OXTR in the anterior cingulate cortex,
a region involved in empathetic responses in humans (8). Oxtr
KO prairie voles display altered social preferences and reduced
helping behavior toward a familiar cagemate (27, 147).
Vasopressin and monogamy
AVP stimulates partner preferences as well as selective ag-
gression, or mate guarding, in male prairie voles (15, 148).
V1aR signaling in the ventral pallidum and LS promote
partner preferences (149), while pair bond-induced aggres-
sion is mediated by V1aR in the lateral hypothalamus (43,
150). Viral-mediated Avpr1a receptor overexpression studies
show that species differences in Avpr1a expression mediate
species differences in social behavior, and variation in Avpr1a
expression in the brain is related to microsatellite diversity in
the gene’s 5′ flanking region (151-154). Voles display remark-
able individual variation in V1aR density in the retrosplenial
cortex (155), a region involved in spatial memory, and this
receptor density is related to Avpr1a polymorphisms, space
use in relation to nesting, and sexual fidelity in males (156).
The sources of AVP regulating any of these behaviors have
not been explored.
Endocrinology, 2022, Vol. 163, No. 9 7

Mate choice compromised. OXT has been more intensively investigated in

Medaka fish are promiscuous breeders of which females
prefer to mate with familiar males that manage to maintain
proximity to the female despite efforts of competing males,
while males mate indiscriminately. Females with targeted Oxt
or Oxtr mutations lose preference for familiar males and
mate indiscriminately, while Oxt or Oxtr mutant males pref-
erentially mate with familiar females. Thus, OXTR signaling
promotes the adaptive mate preference of particular species,
this regard, and its therapeutic potential is related to its modu-
lation of social motivation and the salience of social stimuli
(19-21). Single-cell transcriptomics studies show that PVN
OXT neurons projecting within the brain that mediate social
reward behaviors are disrupted in a mouse model of ASD,
and those neurons are enriched for ASD-risk genes (159).
Further transcriptomic work exploring the function of sub-
types of OXT and AVP-expressing cells (160) would be useful
in delineating relevant subcircuits driving social reward. In

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which in promiscuous species may be sexually dimorphic
(28). In zebrafish, OXT and OXTR drive social behavior in a
context-dependent manner, suggesting a broad role of OXT/
OXTR in social grouping (157, 158). Like voles, both AVP
and V1aR homologues in medaka fish mediate mate guarding
behavior, which is related to territorial behaviors. Thus, both
OXT and AVP mediate adaptive sociosexual behaviors across
vertebrate taxa, although the behavior that is adaptive may
differ across species.
Translational Opportunities
Because of the effects of OXT and AVP on social behaviors,
both peptide systems are potential therapeutic targets for
treating disorders such as ASD, in which social functioning is
another ASD mouse model, OXTR signaling in VTA dopa-
mine neurons, which mediate social reward, is disrupted, and
a kinase inhibitor that restores OXTR signaling also restores
disrupted ASD-relevant social behaviors (161). Prairie vole
studies suggest that pharmacologically evoking OXT using
melanocortin agonists may be another strategy for enhancing
social functioning (162). Clinically, the efficacy of intranasally
delivered OXT has been mixed, and there is a critical need for
clinical trials to be designed based on our understanding of
OXT’s function in the brain, such as enhancing the salience of
social stimuli (20).
Both AVP and V1aR antagonists have been explored as
potential ASD, schizophrenia, and drug-abuse therapies

Figure 2. Oxytocin (OXT) and arginine vasopressin (AVP) circuits that regulate social behavior. The paraventricular nucleus (PVN) and bed nucleus of the
stria terminalis (BNST) contain OXT and AVP cell bodies that directly influence specific social behaviors: social recognition, social approach and reward,
social communication, sexual behavior, parental behavior, and pair bonding and mate choice. A, PVN and BNST OXT circuits. B, PVN and BNST AVP
circuits. Some contributions of AVP sources and sites of action are unknown, indicated by a short black arrow and “?”. All systems are not depicted for
clarity.
8 Endocrinology, 2022, Vol. 163, No. 9
(163). Based on a subset of preclinical studies demonstrating
anxiogenic and agonistic effects of AVP, the V1aR antagonist
balovaptan has been tested in clinical trials in ASD indi-
viduals with mixed effects on social end points (164, 165).
Similarly, male rhesus macaques in large groups that have
naturally impaired social functioning have decreased AVP in
cerebrospinal fluid (166). This led to investigations in pedi-
atric ASD and control samples that also found decreased
cerebrospinal fluid AVP (167, 168). Finally, intranasal AVP
treatment considerably improved social abilities in children
with ASD (169).
Translational opportunities for OXT and AVP may extend
beyond mental health as polymorphisms in V1aR and OXTR
have been linked to variations in normal as well as disordered
human behavior (170). Social relationships are important for
physical well-being as well (171). A recent lung cancer study
found that a factor in serum samples of bonded monogamous
California mice decreased oncogenic potential of tumor cells
when compared to serum samples from bond-disrupted ani-
mals (172). Identifying the molecular mechanisms by which
positive social relationships are transduced to improved
health and reduce social stress could lead to novel approaches
for improving well-being, and as OXT and AVP are inextric-
ably involved in social relationships, they may have unfore-
seen translational opportunities based on their function in the
brain (173).
Concluding Remarks
Modern molecular approaches are greatly enhancing our
understanding of how and where OXT and AVP act to regu-
late social processes. Despite this progress, considerably more
attention has been directed toward the OXT system than the
AVP system in the past decade because of its perceived trans-
lational applications. However, more recent translational re-
search suggests that both peptides have important clinical
potential. Consequently, it will be important to rebalance
OXT/AVP research in behavioral neuroscience. Specifically,
more attention needs to be devoted to understanding the con-
tribution of different peptide sources and their specific targets,
particularly with respect to AVP (Fig. 2). Finally, the incorp-
oration of modern molecular genetic approaches into studies
of alternative model organisms with diverse social systems is
essential for gaining a complete understanding of OXT and
AVP function in the brain, and thereby maximizing transla-
tional opportunities (19, 174).
Acknowledgments
We thank Dr Elliott Albers for helpful comments on the
manuscript. Figures were created with BioRender.com.
Financial Support
This work was supported by the National Institutes of
Health (grant Nos. R01MH115831, P50MH100023,
and R01MH112788 to L.J.Y.; R01 MH121603 and R03
MH120549 to A.P. and G.J.D.; and F31 MH125659 to N.R.).
Disclosures
The authors have nothing to disclose.
Data Availability
Data sharing is not applicable to this article because no data
sets were generated or analyzed during the present study.
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