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Oxytocin Receptor Dynamics in the Brain across
Development and Species
Radhika Vaidyanathan,
1,2
Elizabeth A.D. Hammock
1,2
1
Department of Psychology, Florida State University, Tallahassee, FL
2
Program in Neuroscience, Florida State University, Tallahassee, FL
Received 28 March 2016; revised 19 May 2016; accepted 27 May 2016
ABSTRACT: Oxytocin (OXT) signaling through
the OXT receptor plays a significant role in a variety of
physiological processes throughout the lifespan. OXT’s
effects depend on the tissue distribution of the receptor.
This tissue specificity is dynamic and changes across
development, and also varies with sex, experience, and
species. The purpose of this review is to highlight these
themes with examples from several life stages and several
species. Important knowledge gaps will also be empha-
sized. Understanding the effective sites of action for OXT
via its receptor will help refine hypotheses about the roles
of this important neuropeptide in the experience-
dependent development and expression of species-typical
social behavior. V
C2016 Wiley Periodicals, Inc. Develop Neurobiol
00: 000–000, 2016
Keywords: ontogeny; ornithine vasotocin; oxytocin; OT;
OXT; oxytocin receptor; OTR; OXTR; OT-R; OXT-R
INTRODUCTION
Oxytocin (OXT), a nine amino acid neuropeptide and
hormone, has a range of central and peripheral
effects, demonstrated by numerous studies in humans
and other animals. First appreciated for its well-
known role in uterine contractions and milk ejection,
OXT was hypothesized (Klopfer, 1971) and then
demonstrated (Pedersen and Prange, 1979; Pedersen
et al., 1982) to play a role in the transformation of the
na€
ıve to maternal brain, priming the brain to attend to
and care for infants. In addition to maternal care,
OXT modulates sexual behavior, social recognition,
and affiliative behaviors (Caldwell et al., 1986; Insel
and Winslow, 1991; Williams et al., 1992; Ferguson
et al., 2001; Neumann and Landgraf, 2012). Within
the context of adult social behavior, OXT appears to
have an effect through modulation of the salience of
and/or reinforcement by social stimuli (Ferguson
et al., 2001; Young et al., 2001; Dolen et al., 2013;
Marlin et al,. 2015). In the past several decades, it
has become clear that the OXT system (the peptide
and its receptor, OXTR) plays a significant role in the
modulation of species-typical social behavior, which
is diverse: some species provide abundant parental
care, some are monogamous, some are highly aggres-
sive to conspecifics, and so on. How could this single
peptide system regulate such diverse behaviors across
species? The answer to this question is complicated,
but at its core, seems to be driven by species differen-
ces in OXTR location throughout the brain (Young,
1999). This perspective is heavily informed by social
behavior differences in adulthood either associated
with neuropeptide receptor distribution or caused by
direct manipulation of OXTR function (e.g., Bale
et al., 2001; Ferguson et al., 2001) or OXTR levels
(e.g. Lee et al., 2008a, 2008b; Ross et al., 2009).
OXTR is a seven trans-membrane domain G
protein-coupled receptor (GPCR) and its expression
undergoes dramatic upregulation and downregulation
Correspond ence to: E.A.D. Hammock (ehammock@fsu.edu)
Contract grant sponsor: The Florida State University.
Ó2016 Wiley Periodicals, Inc.
Published online 00 Month 2016 in Wiley Online Library
(wileyonlinelibrary.com).
DOI 10.1002/dneu.22403
1
in specific tissues. It is important to remember that
the functions of OXT/OXTR are pleiotropic and that
the Oxtr gene is not only expressed in the brain but
only in several other tissues such as uterus, kidney,
ovary, testis, thymus, heart, vascular endothelium,
osteoclasts, and myoblasts (Gimpl and Fahrenholz,
2001; Zingg and Laporte, 2003). For example, OXTR
is downregulated in uterine tissue after parturition as
demonstrated by a rapid decrease in the levels of
ligand-binding while it is upregulated in the mam-
mary glands during the entire period of lactation
(Soloff et al., 1979). As described above, there is a
great degree of diversity in the anatomical distribu-
tion of this receptor across species, which is espe-
cially well demonstrated within the brain (Insel et al.,
1991; Dubois-Dauphin et al., 1992; Insel and
Shapiro, 1992; Insel et al., 1993; Young et al., 1996;
Wang and Young, 1997; Rabhi et al., 1999; Olazabal
and Young, 2006; Beery et al., 2008; Campbell et al.,
2009; Freeman et al., 2014a, 2014b). Even among
closely related species there is dramatic variation in
the distribution of OXTR density which influences
species-typical social organization (Insel and Sha-
piro, 1992; Young et al., 1996; Young, 1999; Olaza-
bal and Young, 2006; Beery et al., 2008; Campbell
et al., 2009). For example, in voles, the binding
profile of the monogamous prairie (Microtus
ochrogaster) and pine (Microtus pinetorum) voles
show significant levels of OXTR in the nucleus
accumbens, but the closely related polygamous mon-
tane (Microtus montanus) and meadow (Microtus
pennsylvanicus) voles have much lower receptor den-
sity in this area (Insel and Shapiro, 1992; Ross et al.,
2009). Individual differences in OXTR density in the
nucleus accumbens within the prairie vole species are
associated with the probability of partner preference
behavior (a laboratory measure of monogamous mat-
ing systems) (King et al., in press) as well as monog-
amous behavior in prairie voles in the wild (Ophir
et al., 2012). Directly manipulating the numbers of
OXTR in the nucleus accumbens by viral vector gene
transfer enhances partner preference behavior in prai-
rie voles (Ross et al., 2009), although increasing the
levels of OXTR in this area is not sufficient to confer
partner preference behavior in the non-monogamous
meadow vole (Ross et al., 2009). These differences in
the neuroanatomical distribution of OXTR across spe-
cies, and even within related species, indicate a
strong association with social organization. Are these
differences present during development? Are the
adult differences a result of different developmental
trajectories? We can answer “yes” and “it depends”
to both of these questions. Species differences are
present during development, some differences are
transient, and species and experience-dependent dif-
ferences depend on the brain area in question. Identi-
fying the species-typical roles of OXT and OXTR in
development will be particularly valuable to further
our understanding of the neural basis of social
behavior.
Importantly, it is well appreciated that brains pre-
pare for adulthood through experience-dependent
developmental processes. Not only do species vary in
their developmental social experiences which then
shape adult species-typical behaviors and preferences
(Denenberg et al., 1964) but they also vary in devel-
opmental patterns of OXTR, to be reviewed below. If
we are to convince ourselves that developmental pat-
terns of OXTR are important for the emergence of
social behavior, then there must be a role for OXT-
OXTR signaling during development. Indeed, OXT is
a developmentally significant neuropeptide as several
studies have revealed the developmental effects of
OXT exposure on subsequent social behavior. The
developing brain is sensitive to early life experiences,
and the OXT system may be both a target and a medi-
ator of developmental experience (Bales and Perkey-
bile, 2012; Veenema, 2012; Hammock, 2015). In
other words, developmental experience shapes the
adult OXT system, and the infant OXT system medi-
ates some of the effects of the social environment.
There is ample evidence that the early environment
programs adult levels of OXT and OXTR contributing
to diversity in OXT function in adulthood. Addition-
ally, there is emerging evidence of sex, individual,
and species differences in the OXT system during
development, which likely contributes to altered
developmental trajectories, suggesting that OXT is a
mediator of the early environment. The early post-
natal environment exposes the infant to intense social
interactions, such as parent-infant and sibling interac-
tions. In humans as well as other mammalian species,
these early interactions expand to include a broad
range of extra-familial, cross-species, and other ani-
mate interactions. Species-typical developmentally
transient OXTR patterns might define social sensitive
periods for particular brain areas or stimuli.
ADULT OXTR ARE A TARGET OF
DEVELOPMENTAL EXPERIENCE
In the following paragraphs, we will discuss develop-
mental factors, including gonadal hormones and
maternal care, known to alter OXTR expression and
distribution into adulthood, supporting the hypothesis
that the OXT system is a target of developmental
2Vaidyanathan and Hammock
Developmental Neurobiology
experience [reviewed in (Bales and Perkeybile, 2012;
Veenema, 2012; Alves et al., 2015)].
Adult males and females show different levels of
OXTR in some brain regions. These differences could
be due to differences in exposure to gonadal hormones
during development (organizational effects) or changes
in hormone levels during adulthood (activational
effects). Estrogens regulate gene transcription of the
Oxtr gene in some brain areas. In adult rats, the transi-
tion to motherhood via pregnancy and parturition
enhances the expression of OXTR in several brain areas
post-partum which could be mimicked with estradiol
benzoate treatment after ovariectomy (Insel, 1986,
1990; Young et al., 1997; Young et al., 1998). Further-
more, there are sex differences in the expression of
OXTR that depend on gonadal hormones, in a brain-
region specific manner (de Kloet et al., 1986; Tribollet
et al., 1990; Bale and Dorsa, 1995a, 1995b; Bale et al.,
1995a, 1995b). These sex differences are maintained in
adulthood by gonadal steroids, but are also influenced
by neonatal exposure to gonadal steroids in a brain
region specific manner (Uhl-Bronner et al., 2005). As
an added layer of complexity, the direction of the effect
of sex steroid dependence of OXTR levels depends on
the species studied. For example, adult male rats have
higher levels of OXTR in the ventromedial hypothala-
mus than females, while in male mice, gonadal hor-
mones seem to suppress OXTR expression in this same
brain region (Insel et al., 1993). In meadow voles,
gonadal hormones and day length predict OXTR bind-
ing density, which is associated with seasonal social
affiliative behaviors (Beery and Zucker, 2010).
Maternal behavior and early-life experiences are
species-typical and are highly variable even within
individuals of the same species. Natural variation in
maternal care can confer enduring changes in OXTR
levels which are sex-specific (Francis et al., 2000;
Champagne et al., 2001; Francis et al., 2002). For
example, virgin female offspring born to high licking
and grooming mothers are quicker to exhibit maternal
behavior and also show significant differences in
OXTR distribution compared to the virgin female off-
spring of low licking and grooming mothers, and
these effects appear to depend on estrogens (Cham-
pagne et al., 2001). The offspring of high licking and
grooming and low licking and grooming dams also
show differences in Oxtr mRNA as well as estrogen
receptor alpha (ERa) during development, with a sig-
nificant effect of region and developmental age (Pena
et al., 2013). Manipulating the OXT system and
maternal care from infancy confers enduring changes
in the adult OXTR expression profile (Lukas et al.,
2010), but the mechanisms are unknown. Similarly,
in the biparental monogamous mandarin vole, pater-
nal deprivation during post-natal development
reduces adult OXTR expression in the nucleus accum-
bens and medial amygdala and disrupts social behav-
ior in a social recognition task in adulthood (Cao
et al., 2014).
Epigenetic mechanisms like methylation can
potentially contribute to the species and tissue diver-
sity of OXTR (Kusui et al., 2001; Kumsta et al.,
2013). In a recent study that aimed to test this
hypothesis in mice, methylation status of Oxtr was
associated with tissue specificity of expression in the
mammary glands and uterus (Mamrut et al., 2013) as
well as the brain (Harony-Nicolas et al., 2014) of
adult mice. While these studies were performed in
adult mice, it is possible that developmental experi-
ence leads to changes in methylation status of human
OXTR, to set up lifetime function of OXTR expres-
sion. This has been suggested in two recent studies in
humans which try to make a preliminary link
between child abuse (Smearman et al., 2016) or rat-
ings of parental care (Unternaehrer et al., 2015) and
OXTR methylation.
OXT/OXTR MAY BE A MEDIATOR
OF THE EARLY SOCIAL
AND SENSORY ENVIRONMENT
In the following paragraphs, we will provide evi-
dence that the OXT system is a potential mediator of
the early environment, as OXT activity during devel-
opment affects both short term and long term out-
comes. We describe some potent acute and long term
effects of OXT/OXTR manipulation in newborns.
Miller and Caldwell provide a very thorough tabu-
lated summary of research to date on neonatal manip-
ulations and the consequences of these manipulations
(Miller and Caldwell, 2015). Significantly, the pre-
cise neural circuit-based mechanisms of most of the
acute and long-term effects are not yet known.
Developmental OXT Has Acute Effects
There is growing evidence that OXT-OXTR has acute
effects on physiology or behavior during develop-
ment (Tyzio et al., 2006; Alberts, 2007; Pournajafi-
Nazarloo et al., 2007; Schaller et al., 2010; Mazzuca
et al., 2011; Meziane et al., 2015; Zheng et al., 2014)
[reviewed in (Kenkel et al., 2014; Hammock, 2015)].
During early postnatal development, rodents exhibit
huddling behavior, which primarily derives cues
from tactile and thermal peripheral sensations. At
postnatal day (P), 15 rat pups develop a filial hud-
dling behavior, guided by olfactory cues (Alberts,
OXT Receptor Dynamics in the Brain 3
Developmental Neurobiology
2007). Prior to this, rat pups are unable to differenti-
ate between a familiar conspecific and members of
other species (Alberts, 2007), which suggests that the
developmental learning of what it means to be a con-
specific occurs in the developmental period leading
up to P15. Maternal skin-to-skin contact is important
for acquiring these filial preferences and central
application of OXT increases contact between mother
and pups (Kojima and Alberts, 2011). In rats, daily
20-min maternal (and littermate) separation has been
shown to transiently reduce the amount of OXTR
ligand binding in dissected hippocampal membrane
homogenates during development on postnatal day 8,
yet transiently decrease at P4 and increase at P8 the
amount of ligand binding in the cingulate cortex
(Noonan et al., 1994). These same brain areas did not
show long term changes in OXTR ligand binding after
daily separation when measured at 1 year of age,
although it is unclear if the transient changes due to
altered maternal care lead to consequences for other
markers of developmental plasticity. Rat neonates
have peak expression in some brain areas in the first
week of life. The developmental curve was shifted in
a brain region dependent manner by maternal separa-
tion, suggesting that environmental inputs may shift
brain area sensitivity to OXT.
In the two populations of hypothalamic neurons
where OXT is produced, the supraoptic nucleus
(SON) and paraventricular nucleus (PVN), there is a
steady increase in OXT immunoreactive cell number
from postnatal day 1 to 21 (measured at P1, P8 and
P21), in male and female prairie voles (Yamamoto
et al., 2004). OXT immunoreactivity measured at
postnatal day 8, after a single neonatal OXT injec-
tion, shows no difference in males or females
between treatment group and control animals. How-
ever, at postnatal day 21, females that were given
neonatal OXT injections showed significantly
increased immunoreactivity in the PVN and not in
the SON compared to untreated females. Surpris-
ingly, females given an OXTR antagonist also showed
an increase in OXT immunoreactive cell number
(Yamamoto et al., 2004). Neonatal treatment with
OXT increases c-Fos immunoreactivity in the SON
in male pups, and treatment with OXT antagonist
increases c-Fos immunoreactivity in the SON of
female pups (Cushing et al., 2003). The important
distinction between OXT injections and OXT antago-
nist injections, is that the former is supplementary to
the endogenous OXT system (i.e., exogenous), and
the latter blocks the endogenous OXT system during
the neonatal period. Keeping in mind this distinction,
it can be hypothesized that male prairie vole pups are
more responsive to exogenous OXT, while female
prairie vole pups may have a more robust endogenous
OXT system, which makes them resilient to OXT
manipulations.
During development, there are several temporal
windows when different sensory systems and their
neural circuits become receptive to environmental
stimuli. Due to this, the acute effects of OXT may
depend on the specific OXTR-containing neural cir-
cuits that are undergoing maturation and develop-
ment at a given time. In immature neurons, GABA is
an excitatory neurotransmitter, and shortly before
parturition (E21) in rat neonates, there is a transient
switch from being excitatory to inhibitory (Tyzio
et al., 2006). This transient switch from depolarizing
to hyperpolarizing GABA
A
receptor signaling is trig-
gered by an OXT-mediated decrease in intracellular
[Cl
2
] (Tyzio et al., 2006). This transient switch has
been shown to exert neuroprotective and analgesic
effects on newborns (Tyzio et al., 2006; Khazipov
et al., 2008; Mazzuca et al., 2011; Tyzio et al., 2014).
Blocking OXT signaling in na€
ıve mothers produces
offspring that display behavioral and electrophysio-
logical autism-like traits (Tyzio et al., 2014).
Prader–Willi syndrome (PWS) is a neurodevelop-
mental disorder with a complex phenotype that
includes feeding and suckling problems from birth
(Holm et al., 1993). OXT injections 3–5 h after birth
rescues the feeding and suckling deficits in mice
lacking the Magel-2 gene, which is altered in PWS
(Schaller et al., 2010). In particular, the onset of
suckling behavior, which involves coordination of
sensory and motor processes to orient to olfactory
and tactile cues, is disturbed in these mice (Schaller
et al., 2010) and OXT may likely be important in
modulating these multisensory processes [reviewed
in (Hammock, 2015)], with long term consequences
for social behavior (Meziane et al., 2015). OXT mod-
ulation of oromotor behavior may be present in rats
as well. A very early study demonstrated that acute
administration of OXT into rat pup cisterna increases
autogrooming and oromotor behaviors (Pedersen
et al., 1988), including paw-sucking in rats (Nelson
and Alberts, 1997). These oromotor behaviors may
be functionally related to the OXT-facilitated suck-
ling processes as in the mouse.
Kramer et al. (2003) tested the effects of giving a
single dose of OXT or OXT-antagonist (OXTA) ver-
sus daily doses, on stress-related behavior in socially
isolated infant prairie voles. A single dose of OXTA
within the first 24 h after birth, decreased separation-
induced vocalizations in females but not males a
week later, suggesting a sex-specific effect of OXT.
In contrast, repeated daily treatment with the OXTA
had the opposite effect on separation-induced
4Vaidyanathan and Hammock
Developmental Neurobiology
vocalizations in females (Kramer et al., 2003). The
mechanisms of the sex-dependent effects are
unknown.
Developmental OXT Has Long
Term Effects
There is a significant amount of evidence that OXT-
OXTR during development has long-term effects on
adult physiology and/or behavior (Boer and Kruis-
brink, 1984; Boer, 1993; Boer et al., 1994; Bales and
Carter, 2003a, 2003b; Kramer et al., 2003; Bales
et al., 2004a, 2004b, 2007a, 2007b, 2013; Yamamoto
et al., 2004, 2006; Kramer et al., 2006; Jia et al.,
2008a, 2008b; Perry et al., 2009; Bales and Perkey-
bile, 2012; Eaton et al., 2012; Hashemi et al., 2013;
Meziane et al., 2015; Mogi et al., 2014; Tyzio et al.,
2014) reviewed in (Carter, 2003, 2007; Carter et al.,
2009; Young, 2013; Grinevich et al., 2014). Many of
these studies explore single doses of OXT given to
vole neonates and later determining the effects on
social behavior outcomes.
Neonatal OXT can have organizational effects on
the neural substrates underlying these changes in
adult physiology and behavior. Early postnatal OXT
injections have differential and sexually dimorphic
effects on adult animals (Kramer et al., 2003; Yama-
moto et al., 2004, 2006; Kramer et al., 2006; Mogi
et al., 2014). For example, a single neonatal dose of
OXT results in an increased partner preference in
male prairie voles in adulthood and decreased
anxiety-like behaviors (Carter et al., 2009). Female
prarie voles require a higher dose of postnatal OXT
injections, for an increased partner preference in
adulthood (Carter et al., 2009). A single dose of OXT
in newborn rats decreases the levels of dopamine and
serotonin metabolites in regions such as the striatum
and hypothalamus, in adult rats (Hashemi et al.,
2013), suggesting the potential indirect effect that
OXT can have on other neurotransmitter systems.
Several behaviors exhibited by the model systems
used in research are sexually dimorphic. Reproduc-
tive behavior and aggressive behavior are two exam-
ples that have been tested in the laboratory setting.
What is the neurological basis for this difference
and when do these divergent trajectories emerge?
Gonadal hormone exposure during early life has an
organizational effect on the brain and can induce per-
manent changes in the central nervous system. OXT
injections in male prairie voles during the neonatal
period increases pair-bonding in adulthood, and
males respond to a lower dose of OXT compared to
females, suggesting that male voles are particularly
sensitive to neonatal manipulations of OXT system.
OXT antagonists produce the opposite effect of
reduced pair-bonding in males (Bales and Carter,
2003a, 2003b). Intra-sexual aggression in adult prai-
rie voles is displayed by a significantly greater num-
ber of males than females. Adult female prairie voles
exhibit increased aggressive behavior toward strang-
ers after prolonged exposure to a male partner. OXT
injections during development increase adult intra-
sexual aggressive behavior in female prairie voles
following a few hours of exposure to a male partner
(Bales and Carter, 2003a, 2003b). The mechanisms
underlying the role of OXT in intra-sexual aggressive
behavior in females is unknown.
In adult females, many of the reproductive effects
of OXT are estrogen dependent, where estradiol ben-
zoate injections increase the female responses to
OXT (Caldwell et al., 1986). Neonatal manipulations
of OXT have been shown to alter ERaimmunoreac-
tivity, ERamRNA expression, as well as estrogen-
dependent responses during adulthood in female
prairie voles (Yamamoto et al., 2006; Pournajafi-
Nazarloo et al., 2007). In male prairie voles, develop-
mental manipulations of OXT seem to influence the
expression of sexual behavior and sperm transport in
adulthood (Bales et al., 2004a,b). There are sex-
differences in the brain after neonatal manipulations;
endogenous OXT during development has a sexually
dimorphic neural activation in males and females,
and exogenous OXT has been shown to affect neural
activity (measured by c-Fos immunoreactivity), spe-
cifically in males (Cushing et al., 2003; Yamamoto
et al., 2004).
Adult male mice deficient in Magel-2 gene, a can-
didate gene for PWS, show deficits in learning and
social behavior. These deficits are rescued by a single
dose of OXT in the adults. The deficits were also
shown to be rescued in adulthood by multiple doses
of OXT injections on six consecutive days from the
day of birth (Meziane et al., 2015). To better under-
stand the acute and long-term effects of OXT/OXTR
in development on social behavior outcomes, it is
important to know where the receptors are located
during development.
WHERE ARE THE EFFECTOR SITES
OF OXT DURING DEVELOPMENT?
The examples above provide strong evidence for an
organizational role for OXT/OXTR signaling during
development. Understanding the developmental, spe-
cies, and sex-specific circuit expression of OXTR at
the cellular level will be crucial to identifying the
mechanistic role of the OXT system during
OXT Receptor Dynamics in the Brain 5
Developmental Neurobiology
experience-dependent development. Where are these
effector sites? Anatomically, in both the adult and in
development, there is not substantial overlap between
all of the regions that express OXTR and the cells that
express OXT. The working model based on the avail-
able evidence indicate that OXT can act as a local
signal (i.e., synaptic transmission) and as a neurohor-
mone to modulate circuits at a distance from the
source of OXT (i.e., volume transmission) (Landgraf
and Neumann, 2004). This latter neuroendocrine
action of OXT can negate the need for OXT innerva-
tion into OXTR-expressing circuits, and thus
increases the dynamic developmental flexibility of
the system. The ontogeny of OXTR in the brain has
been explored prenatally and postnatally in rats,
mice, voles, and humans. Studies have approached
this question by predominantly two methods; expres-
sion profile of the mRNA transcript for OXTR, and
ligand binding studies to determine receptor distribu-
tion in the brain. Reporter mice have also been used,
especially to identify adult expression patterns. Until
recently, a truly convincing antibody (Mitre et al.,
2016) has not been available for use in mouse tissue.
The available data across developmental (prenatal
and postnatal) time points are presented in Figure 1.
At both the mRNA and protein level, the expres-
sion and distribution of OXTRs are significantly dif-
ferent during development compared to adulthood.
Using ligand binding receptor autoradiography, three
types of OXTR binding profiles have been identified:
(1) continuous binding from the time of first detection
through adulthood, (2) binding that has a pubertal
onset, and (3) transient binding in some brain areas
that only occurs during certain periods of
Figure 1 Coded summary of developmental maps of OXTR in various rodent species. Only studies
that include preweaning developmental time points are included here. M 5male; F 5female;
E5embryonic; P 5postnatal; ND 5no data; Signal intensity estimates5111 (peak) >
11 >1>1/2>2(none). Schematized patterns represent three types of brain-region specific
developmental profiles evident from developmental mapping studies across species. Some brain
regions follow the infant pattern, with a peak expression during pre-weaning development. Other
brain regions follow the pubertal pattern, evident at puberty. Finally, some brain regions show the
adult pattern, with a gradual onset throughout development which persists in adulthood. The spe-
cific brain regions which follow these patterns vary across species.
6Vaidyanathan and Hammock
Developmental Neurobiology
development. Transient OXTR expression in different
brain regions during development suggests that dif-
ferent regions are made sensitive to OXT during dif-
ferent stages of development. The functional role of
this transient expression is still largely unknown.
Hormonal imprinting (Csaba, 1986; Hashemi et al.,
2013) and experience-dependent sensitive period
plasticity (Hammock and Levitt, 2013; Hammock,
2015) are two non-mutually exclusive hypotheses
about the role of these transient patterns. Here, we
highlight developmental differences in OXTR, and
the similarities and differences in rodent species dur-
ing the early postnatal period will help to dissect the
roles of OXT in the development of species-typical
behaviors.
In rats (Chen et al., 2000) and mice (Tamborski
et al., 2016), detection of Oxtr mRNA expression is
possible as early as E12 by qPCR, and at E13 by in
situ hybridization in rats (Yoshimura et al., 1996). In
the developmental in situ hybridization study con-
ducted by Yoshimura et al. (1996) in rats, Oxtr
mRNA was detected by E13 in the dorsal motor
nucleus of the vagus nerve, with a progressive
increase in expression in other regions over time. The
authors of this study noted two distinct expression
patterns: transient and constant type (Yoshimura
et al., 1996). Both kinds of patterns were evident in
the brainstem, mesencephalon, diencephalon, and tel-
encephalon. Transient Oxtr mRNA during the early
postnatal period was detected in the caudate, puta-
men, cingulate cortex, anterior thalamic nuclei, ven-
tral tegmental area, and the hypoglossal nucleus,
while constant expression, once detected, persisted
into adulthood in the anterior olfactory nucleus, tenia
tecta, some amygdaloid nuclei, piriform cortex, the
ventromedial hypothalamic nucleus, subiculum, and
the dorsal motor nucleus of the vagus (Yoshimura
et al., 1996).
As alluded to above, OXTR detection by receptor
autoradiography has been used with great success
because it is easy to use and quantitative. Two types
of ligands have been used to map OXTR: tritiated-
OXT (
3
H-OXT) and iodinated- ornithine vasotocin
(
125
I-OVTA), a specific OXTR ligand. Because of the
sequence similarity between OXT and its paralog,
arginine-vasopressin (AVP), their cognate receptors
must be discriminated using labeled ligands that are
very specific or by competing off ligand binding with
highly selective agonists/antagonists. One of the ear-
liest developmental mapping studies to detect OXTR
by receptor autoradiography used
3
H-OXT in rats
(Snijdewint et al., 1989). In that report, numerous
binding sites for OXT were identified, including
developmentally transient expression in the dorsal
hippocampus and parietal cortex measured at post-
natal day 5, with adult levels of expression observed
on post-natal day 15. Because
3
H-OXT can bind to
other members of the OXT/AVP family of GPCRs,
some of the early results were not actually OXTR, but
included other receptor types. This is important to
keep in mind, because OXT and OXTR KO mice do
not have identical phenotypes, which indicates that
the OXT peptide can act at other receptors and the
OXTR may also signal effectively after AVP binding.
To get around the problem of specificity, several
groups have developed selective ligands for the
OXT/AVP family of GPCRs. The highly selective
ornithine vasotocin ligand (Elands et al., 1988) is the
most commonly used agent, which is commercially
available from NEN/Perkin Elmer (ornithine vasoto-
cin analog (vasotocin, d(CH2)5[Tyr(Me)
2
,Thr
4
,Or-
n
8
,[
125
I]Tyr
9
NH2]; ([
125
I]-OVTA, NEX254, Perkin-
Elmer, Boston, MA), and used in numerous studies
(Shapiro and Insel, 1989; Snijdewint et al., 1989; Tri-
bollet et al., 1989; Wang and Young, 1997; Chen
et al., 2000; Hammock and Levitt, 2013). The first
report of a developmental map of OXTR using this
ligand was in 1989. Tribollet et al. (Tribollet et al.,
1989) mapped OXTR ligand binding in rats and
clearly demonstrated that there were two phases of
expression: an “infant” pattern and an “adult” pattern.
Whereas Snijdewint et al. (1989) measured
3
H-OXT
ligand binding at E20, P1, P5, and P15, Tribollet
et al. sampled tissue at E12, E14, E16, E18, E20, and
P1, P3, P5, P10, P13, P16, P19, P22, P25, P30, P35,
P40, P45, P60, and P90. While the Snijdewint study
concluded that P5 expression was higher than P15,
with higher temporal resolution sampling, Tribollet
found a peak of expression in the cingulate cortex
closer to P10 in the rat. The onset of enhanced OXTR
in some brain areas in puberty is likely also due to
gonadal hormones at puberty (Tribollet et al., 1992).
The brain region specificity of OXTR expression
not only varies across development but also between
species. The earliest detectable OXTR ligand binding
signal is at E14 in rats (Tribollet et al., 1989) and
E16.5 in mice (Tamborski et al., 2016). While the
gestational periods of rats and mice are similar, there
is approximately a two-day difference in neural
development between rats and mice (Clancy et al.,
2001). Even closely related species vary in their
OXTR distribution during infant development. For
example, Wang and Young (1997) showed that dur-
ing postnatal development there is an accelerated
increase in OXTR ligand binding in the lateral septum
of the polygamous montane vole compared to
monogamous prairie vole, similar to the adults of
these species that showed a differential binding in the
OXT Receptor Dynamics in the Brain 7
Developmental Neurobiology
lateral septum (Insel and Shapiro, 1992). These find-
ings contribute to the hypothesis that species differen-
ces in adult social behavior have early developmental
origins.
The brain regions that show a transient develop-
mental OXTR expression are variable between spe-
cies. In rats (Sprague-Dawley), a transient binding
peak has been described at postnatal day 10 [with
adjacent sampling at P5 or P13 (Tribollet et al.,
1989) or P5 and P14 (Shapiro and Insel, 1989)], in
several regions such as the cingulate cortex, dorsal
subiculum, anterior and paraventricular thalamic
nuclei, nucleus accumbens, caudate putamen, mam-
millary complex, substantia gelatinosa of the spinal
trigeminal nucleus, and the reticular nucleus, lateral
septum, fornix, globus pallidus, and anterior CA1
region of the hippocampus (Shapiro and Insel, 1989;
Tribollet et al., 1989). Transient OXTR immunoreac-
tivity was observed in several sensory nuclei of the
brainstem of the rat neonate (Murata et al., 2011),
which at the electron microscope level, appeared to
be enriched in the Golgi apparatus. These regions in
rats can be contrasted with the transient expression in
C57BL/J6 mice when sampled at P0, P7, P14, P21,
P35, and P60: a transient developmental peak has
been identified throughout the neocortex at P14,
quantified in S1 neocortex (Hammock and Levitt,
2013). This transient post-natal expression by recep-
tor autoradiography in mice is also evident at the
level of mRNA (Fertuzinhos et al., 2014; Mitre et al.,
2016), as well as by immunohistochemistry with a
specific antibody to OXTR (Mitre et al., 2016).
Although the receptor autoradiography technique
is rapid and quantifiable, it offers less cell-specific
resolution. Reporter mice can also be used to deter-
mine the developmental origins of OXTR and these
mice have been made to assist in mapping the cell-
type specific expression of the mouse OXTR,asan
additional approach to complement in situ hybridiza-
tion studies, and out of necessity due to the historic
lack of suitable antibodies for OXTR in mouse. As an
example, the Oxtr-yfp mouse (Yoshida et al., 2009),
has a Venus yellow fluorescent protein coding region
in place of the OXTR coding region. Mice that have
two copies of the Venus-YFP are also knock-outs for
OXTR. These mice have not yet been used for a
developmental expression study.
The Oxtr-lacZ mouse contains the Oxtr promoter
driving the expression of beta galactosidase from the
lacZ gene (Gould and Zingg, 2003). While the coding
region for OXTR was still present in these mice, they
did show a knock-down of Oxtr expression in the
uterus (75% of expression in hemizygous mice and
50% expression in homozygous lacZ mice). These
mice have not been used in developmental studies,
but seem like a valuable tool to explore the effects of
partial loss of OXTR levels in OXTR circuitry.
The GENSAT consortium has made an Oxtr-EGFP
mouse (Gong et al., 2003). Similar to the two lines of
mice just described, this mouse has an Oxtr promoter
driving EGFP expression. An important difference,
however, is that this mouse is a BAC transgenic, and
thus the construct containing the Oxtr-EGFP ran-
domly inserted into the founder mouse genome. The
native OXTR locus in the mouse is presumably unaf-
fected. These mice have been used in developmental
characterization of expression of the transgene,
including embryonic and early post-natal ages. As
with ligand binding, mRNA, and protein studies, the
EGFP expression is striking in earlier ages, especially
for the neocortex.
A new tool has recently been made to be able to
selectively manipulate detectable OXTR circuits
(Hidema et al., 2016). This transgene has an HA
epitope-tagged OXTR that also includes an IRES Cre
construct. With these mice, OXTR cells can be identi-
fied easily with immunohistochemistry for the HA
tag and those same cells also express Cre recombi-
nase. These mice could be bred with a ROSA reporter
strain to detect expression, or combined with viral
vector technologies to perform tract tracing or opto-
genetics experiments, or in combination with other
mice with floxed transgenes to achieve selective dele-
tion of genes in OXTR circuits. This should be a valu-
able tool in the developmental dissection of the OXT-
dependent developmental emergence of social behav-
ior in mice.
We have tightly focused this review on the develop-
mental dynamics of brain OXTR, but it is important to
point out that the OXT/OXTR system has functions
beyond the brain and social behavior. For example,
emerging data indicate a role for OXT/OXTR in the
development of the gastrointestinal system and its reg-
ulation in adulthood (Welch et al., 2009; Welch et al.,
2014), metabolism (Chaves et al., 2013), osteogenesis
(Colaianni et al., 2015), and thermoregulation (Kasa-
hara et al., 2015). These pleiotropic OXT activities
may have downstream consequences that interact with
the brain and, as in the brain, may vary across devel-
opment, species, sex, and individual.
WHAT IS THE DEVELOPMENTAL OXTR
DISTRIBUTION PROFILE IN HUMANS?
OXT affects human social behavior [reviewed in
(Meyer-Lindenberg, 2008; Heinrichs et al., 2009;
Guastella and MacLeod, 2012; Zink and Meyer-
8Vaidyanathan and Hammock
Developmental Neurobiology
Lindenberg, 2012; Feldman, 2015)], although our
toolset to look at human-specific OXTR expression
and in vivo function is understandably limited. The
historic lack of a comprehensive set of tools to iden-
tify OXTRs makes it a challenge to map these recep-
tors in the human brain. Loup et al. (1989, 1991)
used
3
H-OXT and
125
I-OVTA to map OXT binding
sites in adult brain tissue. While,
125
I-OTA has high
specificity to OXTR in rats (Shapiro and Insel, 1989),
and subsequently in other rodents (Wang and Young,
1997; Takayanagi et al., 2005; Ross et al., 2009;
Hammock and Levitt, 2013), it appears not to be
selective for OXTR in the primate brain (Toloczko
et al., 1997; Freeman and Young, 2016). A com-
monly held interpretation of these results is that the
ligand specificity is lost between rodents and prima-
tes and thus the absence of specific binding in pri-
mate tissue with this ligand does not demonstrate that
there are not OXTR in the primate brain. More recent
studies demonstrate both OXTR mRNA and protein
in the human brain (Kang et al., 2011; Boccia et al.,
2013; Freeman et al., 2016).
The available information about OXTR expression
or binding in the developing human brain is sparse.
While ligand binding and immunohistochemical
studies have yet to be performed in human develop-
ment, data from the Human Brain Atlas indicate a
heightened transient profile of OXTR mRNA in the
human neocortex during the first postnatal years
(Kang et al., 2011). New ligands with better specific-
ity for the human OXTR are being developed (Man-
ning et al., 2008; Smith et al., 2012, 2013a, 2013b;
Freeman et al., 2016), and an antibody to primate
OXTR looks promising (Boccia et al., 2013), so it
may be possible to observe the developmental loca-
tions of OXTR in the human brain in the near future.
Based on recent studies in OXTR in mouse neocortex
(Marlin et al., 2015; Mitre et al., 2016), special atten-
tion to lateralization of OXTR expression is war-
ranted. A clear picture of the developmental
distribution in humans is important to evaluate the
clinical application of OXT in human disorders like
autism and schizophrenia [argued in (Insel, 2016)].
IMPLICATIONS OF DEVELOPMENTALLY
TRANSIENT OXTR
What is the potential significance of a neocortical
OXTR signal (e.g., in humans in the early postnatal
years, in the cingulate cortex in rats, and widespread
throughout upper layers II/III in the neocortex of
mice) in the context of development? During the first
two postnatal weeks in altricial rodents, early experi-
ences are mediated by chemosensory and thermotac-
tile processes (Brunjes and Alberts, 1979; Kojima
and Alberts, 2011), and unless a pup is separated
from the litter, the entire neonatal period is contin-
gent with social chemosensory and thermotactile
inputs. By the end of the second postnatal week, as
the eyes and ears open, input-dependent signals for
visual and auditory information emerge in the neo-
cortex, joining the activity-dependent input in soma-
tosensory cortex (Colonnese et al., 2010), and this
period coincides with peak levels of white matter
stimulation-induced LTP in layers II/III (Rozas et al.,
2001). We have hypothesized that OXT, via develop-
mentally transient OXTR, may be important in shap-
ing the experience-dependent plasticity of the
neocortex during the developmental onset of multi-
sensory processes, because of their location in layers
II/III (Hammock and Levitt, 2013; Hammock, 2015),
known for its heavy cortico-cortical projections.
Direct experimental evidence supports this conjecture
(Zheng et al., 2014). In an effort to understand mech-
anisms of developmental multisensory plasticity in
layers II/III of the neocortex, at postnatal day 14,
Zheng et al. compared typically developing mice to
mice that had one of two modes of sensory depriva-
tion since birth—either whisker trimming or constant
dark rearing. In the neocortex, animals that had been
whisker trimmed not only showed reduced frequency
of miniature excitatory post-synaptic currents
(mEPSCs) in layer II/III pyramidal neurons of S1
neocortex in the area representing the whiskers but
also in primary visual cortex and primary auditory
cortex. This suggests that the reduction of input from
a single modality (the whiskers) affected the develop-
ment of the neocortical processing of the other
modalities. The same phenomenon was observed
after constant dark-rearing: in addition to reduced
mEPSC frequency in the primary visual cortex, there
was also a reduction evident in primary somatosen-
sory cortex and primary auditory cortex. To identify
potential mechanisms that might mediate the effects
of sensory deprivation on this cross-modal neocorti-
cal plasticity, Zheng et al. performed separate tran-
scriptomic analyses of both the neocortex and the
thalamus/hypothalamus. The most robust transcript
to emerge from this analysis after either form of
deprivation was Oxt mRNA in the hypothalamus.
Either form of sensory deprivation led to reduced Oxt
mRNA and protein at P14. Zheng et al. went on to
characterize the effects of direct manipulation of
OXT and observed that increasing OXT levels
increased mEPSC frequency in all three primary sen-
sory areas and that decreasing OXT decreased
mEPSC frequency in all three primary sensory areas.
OXT Receptor Dynamics in the Brain 9
Developmental Neurobiology
Thus, manipulating OXT levels was sufficient to
recapitulate the effects of 2 weeks of sensory depriva-
tion on multi-modal neocortical activity. Transient
OXTR binding patterns may reflect a developmental
sensitive period for functional activation by OXT in
those regions through volume transmission. Addi-
tionally, transient binding profiles may also reflect
developmental changes such as neurite growth, den-
dritic branching, synaptic pruning, and synaptogene-
sis. OXT, perhaps increased by social contexts, may
make contingent multisensory inputs more likely to
induce neural activity during activity-dependent mul-
tisensory neocortical development, right at a time
when these inputs are first available to the neocortex.
This might permit socially contingent sensory inputs
to increase and/or refine the neocortical real estate
devoted to detecting and processing social inputs
(Hammock, 2015).
CONCLUSIONS AND FUTURE
DIRECTIONS
In this review, we highlighted data on diverse pat-
terns of brain expression of OXTR due to experience,
gonadal sex, and species. These differences are brain
region specific. For each of these dimensions, there is
evidence that receptor quantity influences some
aspect of social behavior. We also highlighted emerg-
ing research on species differences in developmental
patterns of expression. This leads to the hypothesis
that developmental differences between (and individ-
ual differences within) species can contribute to
species-typical developmental trajectories (or indi-
vidual and sex differences in trajectories). Transient
peaks of OXTR expression may define sensitive peri-
ods for OXT to shape the brain development of those
areas, and perhaps in a social-environment dependent
manner. In other words, OXTR may be a developmen-
tal plasticity gene that serves as a transducer of the
social environment to fine-tune the experience-
dependent plasticity of the social brain (Hammock
and Levitt, 2006; Hammock and Levitt, 2013;
Hammock, 2015).
This is a fairly broad hypothesis which needs to be
broken down into smaller testable questions.
a. How does the social or sensory environment
begin to elicit OXT activity in socially na€
ıve
neonates?
b. How does OXT modulate sensory activity in
neonates?
a. Which sensory modalities? Is it species
dependent?
b. At what level(s)? Sensation? Perception?
Motivation? Cognition?
c. What cells and circuits are especially affected
by OXT during development? How are circuit
dynamics affected?
d. Is there a true sensitive period for OXT effects?
Does this have implications for human clinical
efforts attempting to use OXT to improve social
behavior?
e. How does region specific OXT/OXTR activity
in development affect emergence of species
typical behavior?
f. How do species and individual level differences
in OXT system genetics lead to differences in
function- both during development and in
adulthood?
g. How do sex differences in the OXT system lead
to differences in function during development
and in adulthood?
h. What is the experience-dependent developmen-
tal trajectory of this system in humans?
A focus on OXT-dependent neural circuit activity
during development and the mechanisms of sensitive
period plasticity will greatly enhance our understanding
of the role of OXT in social behavior development.
The authors declare no conflict of interest in preparing this
work.
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