The neurobiology of pair bonding: Insights from a socially monogamous rodent
Kimberly A. Young, Kyle L. Gobrogge, Yan Liu, Zuoxin Wang*
Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, FL 32306, USA
a r t i c l e i n f o
Available online 3 August 2010
a b s t r a c t
The formation of enduring relationships between adult mates (i.e., pair bonds) is an integral aspect of
human social behavior and has been implicated in both physical and psychological health. However,
due to the inherent complexity of these bonds and the relative rarity with which they are formed in other
mammalian species, we know surprisingly little about their underlying neurobiology. Over the past few
decades, the prairie vole (Microtus ochrogaster) has emerged as an animal model of pair bonding. Research
in this socially monogamous rodent has provided valuable insight into the neurobiological mechanisms
that regulate pair bonding behaviors. Here, we review these studies and discuss the neural regulation of
three behaviors inherent to pair bonding: the formation of partner preferences, the subsequent develop-
ment of selective aggression toward unfamiliar conspecifics, and the bi-parental care of young. We focus
on the role of vasopressin, oxytocin, and dopamine in the regulation of these behaviors, but also discuss
the involvement of other neuropeptides, neurotransmitters, and hormones. These studies may not only
contribute to the understanding of pair bonding in our own species, but may also offer insight into the
underlying causes of social deficits noted in several mental health disorders.
? 2010 Elsevier Inc. All rights reserved.
Intense attraction between mates, often referred to as romantic
or passionate love, is one of the most powerful forces driving hu-
man social behavior, and often precedes the formation of enduring,
selective attachments between sexual partners (i.e., pair bonds).
Although such sociosexual attachments are most prevalent in
industrialized cultures with a monogamous social organization,
they occur in nearly all human societies, regardless of subsistence
mode (e.g., pastoralist, agriculturalist, etc.) or mating strategy (e.g.,
polygamy and monogamy), and are therefore an intrinsic part of
human social behavior. While the definition of a pair bond varies
throughout the literature, it is typically described, across species,
as an enduring preferential association formed between two sexu-
ally mature adults, and is characterized by selective contact, affili-
ation, and copulation with the partner over a stranger (partner
preference) . In addition to a preference for a partner, a vari-
ety of other behaviors are intrinsically involved in this complex so-
cial bond. For example, pair bonds in humans, as well as in other
mammalian species, are regularly associated with mate-guarding
(e.g., highly aggressive behavior towards sexual competitors) and
the bi-parental care of young [32,86,136]. The co-occurrence of
these behaviors in pair-bonded individuals makes sense when
viewed through the lens of evolutionary theory, which suggests,
in part, that pair bonding became adaptive under conditions in
which additional parental investment was required to ensure the
successful rearing of young [45,85,89,105,208]. Indeed, the same
selection pressures that necessitated the presence of both parents
for offspring survival would likely facilitate the formation of a part-
nership between mates  and mechanisms through which to
maintain this partnership (e.g., mate-guarding).
The functional significance of pair bonding in humans has been
documented cross-culturally. Paired individuals, particularly those
in stable marital relationships, live longer than their unpaired
[116,144]. Additionally, high levels of intimacy between pairs has
been inversely correlated with negative psychological states, such
as depressed mood, and positively correlated with immune func-
tion and cardiovascular health [131,212]. Another widely acknowl-
edged benefit of pair bonding in humans, as in other species, is the
physical and psychological well-being of children, an effect likely
due to the co-occurrence of pair bonding with the bi-parental care
of young. Indeed, paternal involvement in childcare has become
increasingly recognized as equally important as maternal influ-
ences on successful childhood development. In preindustrial socie-
ties and developing countries, for example, where food and
healthcare are not readily available, children of monogamously
married women have lower mortality rates than children of wo-
men who are not married or who are in a polygynous union
. In industrialized societies, the presence of caring fathers im-
proves the emotional and cognitive health and development of
children, as indicated by higher levels of child success on various
0091-3022/$ - see front matter ? 2010 Elsevier Inc. All rights reserved.
* Corresponding author. Address: Department of Psychology, Florida State
University, Tallahassee, FL 32306-1270, United States. Fax: +1 850 644 7739.
E-mail address: email@example.com (Z. Wang).
Frontiers in Neuroendocrinology 32 (2011) 53–69
Contents lists available at ScienceDirect
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indices, including academic achievement [41,71,83,88,181,191]
and the prevention and treatment of anxiety problems , atten-
tion-deficit/hyperactivity disorder (ADHD) , substance use, and
criminal behavior .
Although enduring bonds between adult mates are important
for the physical and mental health of individuals and their chil-
dren, and may also influence societal stability, we know surpris-
ingly little about the neurobiology of pair bonding. This is partly
due to the fact that traditional laboratory rodents used in the study
of behavioral neuroendocrinology generally do not display behav-
ioral characteristics of a pair bond, and thus cannot be used as
model systems for the study of pair bonding. While a variety of
nontraditional animal models have emerged to study this rare
behavior, including marmoset and titi monkeys [15,197] and Cali-
fornia mice [24–26,59,189], we will focus on one that has become
increasingly popular; the prairie vole (Microtus ochrogaster). We
will begin by describing field and laboratory studies that document
prairie vole pair bonding behavior. Then we will discuss early work
in the laboratory that described the neural correlates of pair
bonding behavior in prairie voles. Next, we will discuss the neuro-
biological mechanisms involved in three separate behaviors associ-
ated with pair bonding; the formation of partner preferences, the
development of selective aggression toward unfamiliar conspecif-
ics, and the bi-parental care of young—concentrating primarily
on paternal care as maternal care is common to all mammalian
species and has been extensively reviewed elsewhere [31,170,
171,199]. We will focus on the involvement of the neuropeptides
arginine vasopressin (AVP) and oxytocin (OT) and the neurotrans-
mitter dopamine (DA) in these behaviors, but will also review
other neurochemicals that have been implicated in pair bonding.
Finally, we will explore how these neurochemicals may work to-
gether to regulate the formation and maintenance of pair bonds.
2. The prairie vole model
2.1. Field studies of behavior
The prairie vole is a socially monogamous rodent species that
lives primarily in the grasslands of the central United States
. It has been suggested that adaptation to this harsh environ-
ment, with limited food sources and scarce water supplies
[27,92,159], may have contributed to the evolution of a socially
monogamous life strategy in this species [38,218].1Early field stud-
ies using multiple-capture traps offered evidence that prairie voles
form long-term bonds and travel together in the wild, as male and
female pairs were repeatedly captured together . Further, the
use of radiotelemetry combined with repeat-trapping allowed for
the observation that male and female pairs co- occupy nests and
share home ranges during both breeding and nonbreeding seasons
[69,94,95]. Additional studies demonstrated that such breeding pairs
typically remain together until one member dies, and in many cases,
the surviving partner does not pair with a new mate [38,96,97]. Fur-
ther, male prairie voles contribute to nest guarding, by excluding
unfamiliar males and females from the vicinity of the nest and home
range, and also contribute to nest building [97,205]. Although male
parental behaviors were difficult to observe in natural conditions,
due to the findings described above and the high degree of paternal
investment found in other monogamous species, it was predicted
that male prairie voles were highly paternal [205,230], and this pre-
diction was confirmed in subsequent behavioral studies under labo-
2.2. Laboratory studies of behavior
Prairie vole pair bonding behaviors have been extensively char-
acterized in the laboratory. Sexually naïve prairie voles are highly
social and display nonselective affiliative behavior toward conspe-
cifics . Following extended cohabitation and/or mating, prai-
rie voles develop social and sexual preferences for their familiar
partner [68,69,102,229]. This selective affiliation (Fig. 1A) is
accompanied by selective aggression toward unfamiliar conspecif-
ics [8,99,100,124,223,224,231]. Additionally, the mated pair shares
a nest, remains together during gestation, and displays bi-parental
care throughout lactation [158,174]. Below, we describe in detail
these behaviors and the behavioral paradigms used to measure
Partner preference formation is a reliable index of pair bonding,
and is characterized by selective contact, affiliation, and copulation
with the partner over a stranger . In a controlled environ-
ment, this behavior is studied using a three-chamber partner pref-
erence test first developed in the laboratory of Dr. Sue Carter 
and subsequently adopted by many other laboratories. The testing
apparatus consists of a central cage that is connected by hollow
tubes to two identical cages, one containing a familiar animal
(partner) and the other an unfamiliar animal (stranger) (Fig. 1B).
These two stimulus animals are loosely tethered into their respec-
tive cages and are not allowed to interact with one another. During
a 3 h partner preference test, the subject is placed into the central
chamber and allowed to move freely throughout the testing appa-
ratus. In some laboratories, a customized computer program—in
conjunction with photobeam light sensors placed across the hol-
low tubes that connect the cages—is used to monitor the amount
of time that the subject spends in each cage and the frequency of
cage entries. Social behaviors, including mating and side-by-side
contact, are videotaped during this test and subsequently quanti-
fied. Partner preference formation is inferred when the subject
spends significantly more time in side-by-side contact with the
partner than with the stranger. In both male and female prairie
voles, 24 h of cohabitation with mating reliably induces partner
preference formation, whereas 6 h of social cohabitation in the ab-
sence of mating does not induce this behavior [124,125,229]
(Fig. 1C). This behavioral paradigm has been successfully used in
neuroanatomical, neurochemical, and pharmacological studies to
examine the neurobiology of
Another behavior that emerges after mating in prairie voles is
aggression toward conspecific strangers. This aggression is direc-
ted toward unfamiliar males and females, but not the familiar part-
ner, and has therefore been termed ‘selective aggression’. Selective
aggression in prairie voles is assessed in the laboratory using a res-
ident-intruder paradigm similar to that used in mice [162,231]. In
this paradigm, an unfamiliar conspecific animal (intruder) is placed
into the home cage of the subject (resident). Behavioral interac-
tions between the resident and intruder are videotaped during a
6–10 min test, and the frequency and duration of a variety of
aggressive behaviors are subsequently quantified. Studies using
this paradigm have demonstrated that sexually naïve male prairie
voles display very low levels of aggression toward intruders
[124,224,231]. However, after 24 h of cohabitation with mating,
aggressive behaviors toward intruders are dramatically increased
[124,224,231]. While this aggression is directed at both males
and females, intense offensive attack behaviors are only noted to-
ward stranger males at this time point . Selective aggression
1While prairie voles that originate from Illinois display behaviors indicative of a
monogamous life strategy in the field, and reliably display mating-induced pair
bonding behaviors under laboratory conditions, it is important to note that prairie
voles from Kansas [55,186] and Tennessee [175,235] show subtle differences in some
aspects of their behavior . These differences support the theory that variations in
ecological conditions may influence animal behavior and mating strategies between
populations within the same species . As a result of this variation, prairie voles
from Illinois are most commonly used in laboratory studies of the neurobiology of
pair bonding. Data from those studies are the focus of the current review.
K.A. Young et al./Frontiers in Neuroendocrinology 32 (2011) 53–69
is also enduring; it lasts for at least two weeks after partner pref-
erence formation [8,99,100]. Further, males paired for this ex-
tended period of time (i.e. pair-bonded males), in contrast to
those paired for only 24 h, show intense attack behaviors toward
stranger females, even those that are sexually receptive, thereby
rejecting potential new mates (Fig. 1D) [8,99,100]. It has therefore
been suggested that selective aggression not only plays an impor-
tant role to guard mate and territory [37,38], but may also function
to maintain the existing pair bond [8,10] and to limit extra-pair
copulations. Although selective aggression has only been system-
atically tested in male prairie voles, evidence exists to suggest that
females may also display this behavioral pattern . The reliable
expression of both partner preference and selective aggression by
prairie voles in carefully controlled laboratory conditions high-
lights the utility of this animal model in behavioral neuroendocrine
Prairie voles, similar to most species that form pair bonds be-
tween adult mates , display bi-parental care of young (i.e., both
the mother and father help to rear offspring) (Fig. 1E). As maternal
care is ubiquitous across mammalian species, we will focus our
discussion of bi-parental care on the role of the father (i.e., paternal
care). Paternal behavior in prairie voles has been observed in the
laboratory using semi-naturalistic enclosures [104,158,174]. After
litter birth, fathers display all patterns of parental behaviors exhib-
ited by females, except nursing [174,205]. These include direct
parental behaviors, such as huddling over (i.e., crouching), groom-
ing, contacting, and retrieving pups as well as indirect behaviors,
such as nest building and food hoarding [104,174,205,230]. Fathers
even continue to display paternal care toward their juvenile off-
spring after the birth of subsequent litters [218,220]. However, in
the presence of juveniles, prairie vole fathers spend less time in
the natal nest displaying paternal behavior and more time foraging
[93,218]. The presence of juveniles may reduce the need for direct
paternalcare bythe father,as juvenilesthatremain inthe natal nest
beyond weaning often contribute to the care of subsequent litters—
a behavior called ‘alloparenting’ [104,198,218,220,222]. Alloparen-
tal behavior in juvenile and sexually naïve adult male prairie voles
qualitatively resembles paternal care in fathers [198,218,220], and
these paternal behaviors are enhanced by social/sexual experience
with a nonrelated female . Importantly, the presence of the
father and the display of paternal behavior have been shown to
facilitate the physical and behavioral development of offspring
[4,218,220], a finding similar to the aforementioned beneficial ef-
fects of paternal care on our own children. Thus, understanding
the mechanisms regulating paternal behaviors could provide
important information about optimal parental care in mammalian
species that form pair bonds, including our own.
3. Neural correlates of prairie vole pair bonding
Early studies investigating the neural correlates of pair bonding
compared neuropeptide and neurotransmitter systems between
vole species that displayed disparate life strategies. The four species
used were prairie, pine (Microtus pinetorum), meadow (Microtus
pennsylvanicus) and montane (Microtus montanus) voles. Monoga-
mous prairie and pine voles form pair bonds between adult mates
and show bi-parental care of offspring while promiscuous meadow
care [37,82,91,95,104,124,126,127,154,155,158,174,230]. The close
taxonomic relationship shared by these species, coupled with their
differences inlifestrategymaketheserodents idealforcomparative
studies investigating social behavior (for review, see ).
As AVP and OT were known to regulate species-specific social
behaviors, including sexual behavior (for review, see ), aggres-
sion , and maternal care [129,176,177], it was predicted that
Fig. 1. Laboratory characterization of behaviors associated with pair bonding. (A) Photo illustrates a male and female prairie vole displaying side-by-side contact. (B) Three-
chamber apparatus used to test for partner preferences. Three identical cages are connected by hollow tubes with light sensors allowing for automated analysis of the
subject’s movements throughout the apparatus. Social behaviors between the subject (white) and the partner (black) and stranger (gray) during the three hour test are
recorded and subsequently scored. Duration of side-by-side contact is the primary behavior of interest. (C) In both male and female prairie voles, 6 h of cohabitation without
mating does not result in partner preference formation, as the subject spends equal amounts of time in contact with the partner as with the stranger. In contrast, 24 h of
cohabitation with mating leads to the formation of partner preferences, as indicated by the subject spending significantly more time in side-by-side contact with the partner
than the stranger during the 3 h partner preference test. (D) Photo depicts a pair-bonded male prairie vole (left) displaying attack behavior toward an unfamiliar female.
Sexually naïve (Naïve) males do not exhibit aggressive behavior toward a stranger, however males paired with a female for two weeks (Paired) demonstrate robust aggression
toward stranger male and female conspecifics but not toward familiar female partners. (E) Photo shows a male and female prairie vole sharing a natal nest and contacting
offspring. Male and female prairie vole parents spend equal amounts of time in the natal nest. Bars indicate means ± standard error of the mean. Bars with different Greek
letters differ significantly from each other.?: p < 0.05. Adapted from [10,99,222,231].
K.A. Young et al./Frontiers in Neuroendocrinology 32 (2011) 53–69
these neuropeptide systems would differ between monogamous
and promiscuous species [17,122]. To test this hypothesis, the dis-
tribution patterns of AVP and OT cells, fibers, and receptors were
mapped in the vole brain. In all vole species examined, regardless
of life strategy, AVP-immunoreactive (AVP-ir) neurons were found
in several brain regions, including the paraventricular (PVN) and
supraoptic (SON) nuclei of the hypothalamus, the bed nucleus of
the stria terminalis (BNST), medial amygdala (MeA), anterior hypo-
thalamus (AH), and preoptic area (POA) [17,221,223]. AVP-ir fibers
were found in the lateral septum (LS), lateral habenular nucleus
(LHN), diagonal band (DB), BNST, medial preoptic area (MPOA),
and MeA [17,223]. OT-immunoreactive (OT-ir) cells and fibers
were located in several brain areas in each species, including the
PVN, SON, MPOA, and BNST , and OT-ir fibers were also found
in the nucleus accumbens (NAcc) . Although subtle species
differences were found, in general, the distribution patterns of
AVP-ir and OT-ir neurons and fibers are highly conserved between
monogamous and promiscuous vole species [187,221,223].
Remarkable species differences were noted, however, in the dis-
tribution patterns and regional densities of AVP and OT receptors
(OTRs). Prairie voles, for example, had higher densities of AVP-
V1a receptors (V1aRs) in the BNST, ventral pallidum (VP), central
(CeA) and basolateral (BLA) nuclei of the amygdala, and accessory
olfactory bulb (AOB), among other regions, than montane voles,
whereas higher densities of V1aRs are noted in the LS and medial
prefrontal cortex (mPFC) of montane voles than prairie voles
[123,145,196,225,241] (Fig. 2A). Interestingly, when multiple vole
species were compared, monogamous prairie and pine voles
showed a similar pattern of V1aR binding, and this pattern differed
from that of promiscuous meadow and montane voles [123,145],
indicating the potential involvement of region-specific V1aRs in
cognitive and behavioral functions associated with different life
strategies in voles [123,145,196,241]. Similarly, the distribution
patterns and regional densities of OTRs also differed between
monogamous and promiscuous vole species. Monogamous prairie
and pine voles, for example, had higher OTR densities in the BNST,
mPFC, and NAcc than promiscuous meadow and montane voles
(Fig. 2D), whereas the opposite pattern was found in the levels of
OTR binding in the ventromedial hypothalamus (VMH), LS, and
anterior cortical amygdala (AcA) [122,196,239]. Species differences
in V1aR and OTR distribution were stable across the lifespan
[215,225] and were receptor-specific, as no such differences
existed in benzodiazepine or opiate receptor systems . There-
fore, given the role of AVP and OT in social behaviors, species dif-
ferences in V1aRs and OTRs are thought to be specifically related
to species differences in social behaviors associated with different
life strategies in voles .
The drastic species differences in neuropeptide receptor distri-
bution described above may be due to the subtle species differ-
ences noted in the promoter regions of the V1aR and OTR
[239,240,242,243]. Although the genetic structure of the V1aR
and OTR coding regions are strikingly similar across vole species
[239,240,242,243], prairie and pine voles carry several repetitive
microsatellite DNA sequences in the promoter region of the V1aR
gene that are not found in meadow or montane voles, and these se-
quence changes may underlie species differences in receptor
expression [107,108,242,243]. In support of this idea, mice carry-
ing a transgene coding for the prairie vole V1aR, exhibited central
Fig. 2. Vasopressin (AVP) and oxytocin (OT) regulation of partner preference formation. (A) Species differences in vasopressin receptor (V1aR) binding in the ventral pallidum
(VP) of prairie and montane voles. Higher densities of receptors are indicated by more red coloration. (B) Site-specific manipulation of AVP neurotransmission in the lateral
septum (LS) of male prairie voles. Data demonstrate that after 6 h of non-sexual cohabitation with a female (Cohab), control males given LS injections of vehicle
(cerebrospinalfluid; CSF) do not display partner preferences. However, AVP infusion into the LS induces partner preferences. Following 24 h of cohabitation with mating
(Mated), CSF treated control males display partner preferences. However, blockade of V1aRs, via infusion of a V1aR antagonist (V1aR Ant) into the LS inhibits the formation of
mating-induced partner preferences. (C) Male prairie voles overexpressing the V1aR gene (AAV-V1aR) in the ventral pallidum display partner preferences after 17 h of non-
sexual cohabitation with females, whereas control males do not. (D) Species differences in oxytocin receptor (OTR) binding in the medial prefrontal cortex (mPFC) and
nucleus accumbens (NAcc) of prairie and montane voles. (E) Site-specific manipulation of OT neurotransmission in the NAcc of female prairie voles. After 6 h of non-sexual
cohabitation with a male (Cohab), female prairie voles infused with OT in the NAcc display partner preferences, whereas control females infused with CSF do not. After 24 h of
cohabitation with mating (Mated), control females infused with CSF form partner preferences. However, intra-NAcc blockade of OTRs, via infusion of an OTR antagonist (OT
Ant), inhibits the formation of mating-induced partner preferences. (F) Female prairie voles overexpressing the OTR (AAV-OTR) in the NAcc form partner preferences after less
than 24 h of mating and cohabitation with a male whereas control females do not. Bars indicate means ± standard error of the mean. ?: p < 0.05. Adapted from
K.A. Young et al./Frontiers in Neuroendocrinology 32 (2011) 53–69
V1aR patterns similar to prairie voles . Interestingly, when in-
jected with AVP, these transgenic mice displayed enhanced social
affiliation, indicating that receptor distribution patterns may influ-
ence brain responsiveness to endogenous neuropeptides and, in
this way, may modulate social behaviors .
More recently, comparative studies have investigated central
DA systems in vole species, because DA, like AVP and OT, plays a
well-known role in processes and behaviors associated with pair
bonding, including learning and memory [1,23,141,234], olfaction
, sexual behavior [22,117], and parental behavior [170,171].
These studies have noted differences in both DA cell and receptor
distribution patterns, as well as differences in their regional densi-
ties, between monogamous and promiscuous voles that may be re-
lated to social behavior.
Consistent with findings in other rodent species [44,114,167,
210], DA cells—those that label for tyrosine hydroxylase (TH; the
rate limiting enzyme in catecholamine synthesis) in the absence
of DA beta hydroxylase (the enzyme that converts DA to norepi-
nephrine)—have been found in multiple regions in the monoga-
mous prairie vole brain, including the principal nucleus of the
BNST (pBNST), posterodorsal MeA (MeApd), and ventral tegmental
area (VTA) [99,168]. Additionally, a high density of DA terminal
innervation is present in the NAcc and caudate putamen (CP) ,
and recent tract tracing experiments in males have demonstrated
that these terminals arise from projection neurons in the VTA
, as has been demonstrated in other species [34,128,193].
However, promiscuous meadow voles contain very few, if any,
DAergic cells in the pBNST and MeApd , further demonstrat-
ing neuroanatomical differences between monogamous and pro-
miscuous vole species.
Dopamine receptor (DAR) distributions in the vole brain have
also been characterized. DARs can be classified into two main fam-
ilies, D1-like (D1R) and D2-like (D2R) receptors, that are differen-
tiated by their molecular structures, pharmacological affinities,
and effects on intracellular signaling pathways [163,166]. In prairie
voles, D1Rs are found in the NAcc, CP, and mPFC, as well as other
brain regions [8,196] (B.J. Aragona, Y. Liu, and Z.X. Wang, unpub-
lished data). D2Rs, while present in these same regions, can also
be found in the VTA and substantia nigra (SN) [8,196] (B.J. Aragona,
Y. Liu, and Z.X. Wang, unpublished data). Although these receptor
distributions are similar to those found in other rodent species,
their relative densities are species-specific and may correlate with
species differences in social behavior [8,196]. For example, monog-
amous prairie voles have higher densities of D2Rs and lower levels
of D1Rs in the mPFC than promiscuous meadow voles . Fur-
ther, meadow voles have a significantly higher density of D1Rs in
the NAcc than prairie voles, a finding thought to be related to the
relatively low degree of social affiliation noted in meadow voles
. Indeed, pharmacological blockade of D1Rs in the NAcc in-
creased affiliative behaviors in meadow voles .
Taken together, these studies have demonstrated differences in
AVP, OT, and DA systems between vole species with distinct life
strategies. As a result, researchers have focused on these systems
in the prairie vole brain to systematically examine the neurobiol-
ogy of behaviors intrinsically associated with pair bonding, includ-
ing partner preference formation, selective aggression, and
paternal behavior. We will discuss the neurobiological regulation
of each of these behaviors, in turn, in the following sections.
4. Neurobiology of partner preference formation
4.1. Brain activation associated with partner preference formation
One commonly used approach in the study of interactions be-
tween the brain and behavior is to map immediate early gene
expression in the brain following a behavioral test. For example,
Fos is the protein product of the immediate early gene, fos, that
is rapidly expressed in neurons following activation and can be
easily visualized by immunocytochemistry. Therefore, Fos-immu-
noreactive (Fos-ir) staining has been used in behavioral neuroen-
docrine experiments to identify regional neuronal activation in
the brain associated with the display of specific behaviors.
In prairie voles, heterosexual pairing, cohabitation, and/or mat-
ing induced Fos-ir staining in several brain areas including the
MeA, BNST, and MPOA in both males and females [56,169]. Mating,
in particular, was related to increased Fos-ir levels in the MeA,
BNST, MPOA, and gracile nucleus of the medulla oblongata, impli-
cating these brain areas as functional components of a mating cir-
cuitry that may contribute to partner preference formation
[50,51,169]. A role for the MeA in prairie vole partner preference
has been further implied by lesion studies, as axon-sparing lesions
of the MeA in male prairie voles decreased their affiliative behavior
toward a familiar female but had no effect on exploratory behavior,
locomotion, or olfactory investigation .
4.2. Neuropeptide regulation of partner preference formation
The first evidence indicating that AVP and OT may play an
important role in partner preference formation came from studies
investigating the effects of social and sexual experience—prerequi-
sites for naturally induced partner preference formation—on these
neuropeptide systems in the prairie vole brain. In male prairie
voles, cohabitation with mating increased the number of AVP
mRNA-labeled cells in the BNST  and decreased the density
of AVP-ir fibers in the LS . As BNST-AVP neurons project to
the LS , these data suggest that mating facilitates AVP synthesis
in the BNST and AVP release in the LS of male prairie voles .
Since mating is essential for partner preference formation in males
, these data offer correlative evidence of the involvement of
AVP in partner preference formation. In females, instead, exposure
to male chemosensory cues altered OTR density in the AOB, indi-
cating that OT may play a role in partner preference formation in
female prairie voles .
Direct evidence of a role for AVP and OT in partner preference
formation was provided by pharmacological manipulation of these
systems. Intracerebroventricular (icv) administration of a V1aR
antagonist blocked partner preference formation in male prairie
voles, while central AVP administration induced partner prefer-
ences in the absence of mating [43,231]. Similarly, icv administra-
tion of AVP induced partner preferences in female prairie voles
after just 1 h of cohabitation with a male, and this effect was
blocked by concurrent administration of a V1aR antagonist, indi-
cating that AVP regulates partner preference formation in both
sexes . OT treatment also influenced partner preference forma-
tion in both sexes. Specifically, icv OT administration induced part-
ner preferences in both males and females and these effects were
blocked by concurrent administration of an OTR antagonist .
While these data indicate that both AVP and OT regulate partner
preference formation in both sexes, it is important to note that
the effective doses of neuropeptides differ between males and fe-
Site-specific manipulations have since demonstrated several
brain regions important for the AVP and OT regulation of partner
preference formation. In males, administration of a V1aR antago-
nist directly into the LS or VP, but not several other brain regions,
inhibited the formation of mating-induced partner preferences,
whereas administration of AVP directly into the LS induced partner
preferences in the absence of mating (Fig. 2B) [146,149]. Further,
administration of an OTR antagonist into the LS of male prairie
voles also prevented mating-induced partner preference formation
. In females, instead, the prelimbic cortex (PLC; a part of the
K.A. Young et al./Frontiers in Neuroendocrinology 32 (2011) 53–69
mPFC) and the NAcc have been implicated in the neuropeptidergic
regulation of partner preference formation [150,244]. OT levels in-
creased in the NAcc during sociosexual experience with a male
. Additionally, OT injection directly into the NAcc induced
partner preferences in the absence of mating, while blockade of
OTRs in this region or the PLC prevented the formation of mat-
ing-induced partner preferences (Fig. 2E) [150,244].
Several studies utilizing viral vector-mediated gene transfer to
deliver and regulate the expression of genes of interest to specific
brain regions have supported the findings that AVP neurotransmis-
sion in the VP and OT neurotransmission in the NAcc regulate part-
ner preferences in male and female prairie voles, respectively. In
males, for example, an adeno-associated viral vector was used to
deliver the V1aR gene into the VP . As expected, this manip-
ulation resulted in an increased density of V1aRs in this region.
Interestingly, these males formed partner preferences in the ab-
sence of mating, supporting the findings that enhanced AVP neuro-
transmission in the VP can facilitate partner preference formation
in male prairie voles  (Fig. 2C). Further, V1aR overexpression
in the VP of male meadow voles, induced partner preference for-
mation in this socially promiscuous species . Similarly, OTR
overexpression in the NAcc of sexually naïve female prairie voles
accelerated partner preference formation as compared to controls
(Fig. 2F), but this treatment did not alter partner preference forma-
tion in female meadow voles . Taken together, these studies
highlight the importance and site-specific effects of AVP and OT
on partner preference formation in male and female prairie voles.
4.3. DA regulation of partner preference formation
Recent work has demonstrated that partner preference forma-
tion in prairie voles is also regulated by central DA, particularly
the mesolimbic DA system—a group of DA producing cells that
originate in the VTA and project to the NAcc, mPFC, and other fore-
brain regions. This neural circuit is thought to be integrally in-
volved in the assignment of motivational value to environmental
stimuli, resulting in the generation of adaptive goal-directed
behaviors [120,232]. For example, mesolimbic DA has long been
implicated in assigning salience to incentives such as food and
receptive mates, thereby mediating behaviors such as feeding
and reproduction that are essential for survival [120,232]. Simi-
larly, mesolimbic DA has been proposed to facilitate mate choice,
enabling mating effort to be focused on preferred conspecifics
, a hypothesis supported by the data described below. The
involvement of this system in partner preference formation makes
sense in an evolutionary context, as selection pressures that neces-
sitate the formation of a partnership between mates would likely
lead to an increased motivational value assigned to one’s partner,
and the selective affiliation that is characteristic of a pair bond.
partner preference formation came from peripheral pharmacologi-
cal manipulations. Recall that 24 h of cohabitationwith mating reli-
ably induces partner preferences in male and female prairie voles.
tion prior to pairing, treatment with the nonselective DAR antago-
nist, haloperidol, blocked mating-induced partner preferences in
both sexes [7,217]. Further, treatment with low doses of apomor-
phine, a nonselective DAR agonist, facilitated the formation of part-
ner preferences after only 6 h of cohabitation in the absence of
vation is essential for partner preference formation in prairie voles.
The first functional evidence to implicate mesolimbic DA in
partner preference formation was the finding that mating increases
DA activity in the NAcc of both male and female prairie voles
[7,98]. In females, for example, extracellular DA levels increased
nearly 51% above baseline during mating . Similarly, mated
males had 33% more DA turnover in this region compared to
non-mated males . Direct evidence for the role of NAcc DA in
partner preference formation came from site-specific pharmaco-
logical manipulations of DA neurotransmission. Microinjection of
haloperidol into the NAcc prevented the formation of mating-in-
duced partner preferences, while microinjection of apomorphine
into this region facilitated partner preference formation in the ab-
sence of mating . These effects were site-specific, as DAR manip-
ulation in the CP, a region adjacent to the NAcc that also receives
DAergic innervation from midbrain regions, did not alter partner
preference formation .
Additional experiments used receptor-specific agonists/antago-
nists to demonstrate that D1Rs and D2Rs in the NAcc differentially
regulate partner preference formation (Fig. 3A and B). Specifically,
NAcc D2R activation facilitated, and D2R blockade prevented, part-
ner preference formation in both male and female prairie voles,
indicating that NAcc D2R activation is both necessary and suffi-
cient for partner preference formation [8,98]. In contrast, NAcc
D1R activation prevented mating- and D2R agonist-induced part-
ner preference formation in male prairie voles, indicating an inhib-
itory role of NAcc D1Rs on this behavior . Importantly, these
manipulations were only effective when delivered into the NAcc
shell, but not the core, indicating a subregional regulation of part-
ner preferences within the NAcc .
The DAR-specific regulation of partner preference formation in
the NAcc has recently been examined on an intracellular level.
D2Rs and D1Rs are both 7-transmembrane receptors whose intra-
cellular effects are mediated by heterotrimeric GTP-binding pro-
teins (G-proteins) (for reviews, see [163,166]). While D2Rs and
D1Rs have similar effects on some signaling pathways, they differ-
entially regulate the intracellular cyclic adenosine 30,50-monophos-
phate (cAMP) signaling cascade through the alpha subunit of the
G-proteins with which they interact [163,166](Fig. 3C). D2Rs bind
to inhibitory G-proteins (Gaiand Gao). When D2Rs are activated,
the alpha subunit of Gai/oinhibits adenylate cyclase (AC) activity,
leading to the inhibition of cAMP production and a decrease in
the activity of protein kinase A (PKA) [163,166]. D1Rs, instead, bind
to stimulatory G-proteins (Gasand Gaolf). D1R activation leads to
an increase in AC activity, cAMP production and PKA activation
[163,166]. As D1R and D2R activation differentially affect cAMP
signaling, it has been suggested that this signaling pathway may
underlie the DAR-specific regulation of partner preference forma-
tion . In support of this hypothesis, reduction of PKA activity
within the NAcc shell, but not core, facilitated partner preference
formation in male prairie voles, a result consistent with the effects
of D2R activation [8,9] (Fig. 3D). Further, in two separate experi-
ments, activation of stimulatory G-proteins and activation of PKA
in the NAcc shell each prevented the formation of mating-induced
partner preferences, consistent with the effects of D1R activation
[8,9] (Fig. 3D). Importantly, these manipulations did not alter mat-
ing or the duration of contact during the 24 h of pairing, suggesting
that increased cAMP signaling directly interferes with partner pref-
erence formation. Taken together, these experiments demonstrate
that cAMP intracellular signaling in the NAcc shell regulates part-
ner preference formation, and may underlie the DAR-specific ef-
fects on this behavior.
5. Neurobiology of selective aggression
As previously mentioned, after 24 h of mating and the forma-
tion of partner preferences, male prairie voles display high levels
of aggression toward conspecific strangers, particularly male
strangers, but not toward their partners [124,224,231]. Addition-
ally, after one to two weeks of extended cohabitation and mating
with their partner, pair-bonded male prairie voles display intense
K.A. Young et al./Frontiers in Neuroendocrinology 32 (2011) 53–69
aggression toward both male and female intruders, including sex-
ually receptive females, thereby rejecting potential new mates
[8,99,100,231]. This selective aggression is thought to be essential
for mate-guarding, nest defense, and the maintenance of the exist-
ing bond between the male and his partner [8,37,38,99,100,231].
As described below, studies have indicated multiple brain regions,
and the involvement of both AVP and DA in this behavior.
5.1. Brain activation associated with selective aggression
A variety of brain regions have been implicated in selective
aggression. For example, display of this behavior has been associ-
ated with elevated Fos-ir in the MeA, BNST, MPOA, LS, and AH
(Fig. 4A) [99,224]. In one of these regions, the AH, differential acti-
vation was noted between exposure to the familiar partner and an
unfamiliar stranger . Specifically, male prairie voles that were
paired with a female for two weeks (i.e., pair bonded) and were
then exposed to a conspecific male or female stranger had a signif-
icantly higher density of Fos-ir cells in the AH than pair-bonded
males re-exposed to their partner. Interestingly, males exposed
to either male or female intruders also had a significantly higher
density of cells double labeled for AVP-ir and Fos-ir in this brain re-
gion than males re-exposed to their partners, suggesting that AH
AVP may regulate selective aggression  (Fig. 4B).
5.2. Neuropeptide regulation of selective aggression
Due to the known role of AVP in territorial displays , and the
differences in AVP receptor distribution in forebrain regions be-
tween monogamous and polygamous voles [123,225], AVP was
hypothesized to be involved in the regulation of selective aggres-
sion. In the first experiment to test this hypothesis, Winslow
et al.  found that injection of a V1aR antagonist, but not cere-
brospinal fluid (CSF), into the lateral ventricle during 24 h of mat-
ing prevented the subsequent display of mating-induced selective
aggression in male prairie voles. Additionally, infusion of AVP into
the lateral ventricles induced aggression toward an intruder in sex-
ually naïve, non-female exposed males. Similar manipulations of
the OT system did not alter aggressive behaviors, indicating that
central AVP, but not OT, neurotransmission regulates selective
aggression in male prairie voles .
Site-specific manipulations in the AH have further supported
this hypothesis . Sexually naïve males that received AVP infu-
sion directly into the AH showed significantly higher levels of
aggression toward a novel female than males treated with vehicle
or with both AVP and a V1aR antagonist, indicating that AVP neu-
rotransmission in the AH can induce aggression in prairie voles
(Fig. 4E). Further, in pair-bonded male prairie voles, AVP release
in the AH was significantly higher in subjects exposed to a stranger
animal than those exposed to their partners (Fig. 4C). Interestingly,
the magnitude of AVP release in these animals was correlated pos-
itively with their frequency of aggression and negatively with the
duration of affiliation. Additionally, blockade of V1aRs in the AH,
but not other brain regions, prevented the display of selective
aggression in pair-bonded males, directly implicating AH AVP in
this behavior (Fig. 4E). In the same study, it was found that pair-
bonded males had significantly higher densities of V1aRs, but not
OTRs, in the AH than sexually naïve males (Fig. 4D), suggesting that
Fig. 3. Dopamine (DA) in the nucleus accumbens (NAcc) regulates partner preference formation in prairie voles. (A) Cartoon illustrates the mesolimbic DA circuit. DAergic
cells in the ventral tegmental area (VTA) project to the NAcc and prefrontal cortex (PFC), as well as other forebrain regions. Released DA binds to one of two DA receptor
subtypes, D1-like receptors (D1R) and D2-like receptors (D2R), which are both present in the NAcc of prairie voles, as shown in the photoimage. (B) Activation of D2Rs via
injection of a D2R agonist (D2 Ago) into the NAcc of males induces partner preferences after 6 h of non-sexual cohabitation (Cohab). Twenty-four hours of mating (Mated)
induces partner preferences in control males that receive intra-NAcc injection of CSF. However, mating-induced partner preference formation was inhibited by intra-NAcc
blockade of D2Rs (via injection of a D2R antagonist (D2 Ant)) or activation of NAcc D1Rs (via injection of a D1R agonist (D1 Ago). (C) Cartoon illustrating the effects of D1R and
D2R activation on cAMP intracellular signaling. D1Rs are coupled to stimulatory G-proteins (Gas/olf) and D2Rs are coupled to inhibitory G-proteins (Gai/o). D1R activation
increases adenylate cyclase (AC) activity, leading to an increase in the production of cAMP and the activation of PKA. D2R activation leads to the inhibition of AC, through the
effects of the alpha subunit of Gai/o, decreasing cAMP production and PKA activity. (D) Pharmacologically decreasing PKA activity (; PKA) in the NAcc induces partner
preference formation in male prairie voles after 6 h of non-sexual cohabitation (Cohab). Pharmacologically increasing NAcc PKA activity (" PKA) during 24 h of mating (Mated)
blocks mating-induced partner preferences. Bars indicate means ± standard error of the mean.?: p < 0.05. Adapted from [7–9,238].
K.A. Young et al./Frontiers in Neuroendocrinology 32 (2011) 53–69
pair bonding experience may cause neuroplastic changes in the AH
AVP system that underlie the emergence of selective aggression
. This hypothesis was supported by the finding that artificial
overexpression of the V1aR by viral vector-mediated gene transfer,
in sexually naïve prairie voles enhanced aggression toward novel
females (Fig. 4F). Taken together, these data indicate that
AVP in the AH plays an integral role in the regulation of selective
aggression in male prairie voles.
5.3. DA regulation of selective aggression
Mesolimbic DA has also been implicated in selective aggression,
particularly, the aggression displayed by pair-bonded males to-
ward stranger females . In two separate experiments, DAR den-
sities in the brains of male prairie voles that were sexually naïve
were compared to that of males either paired with a female for
24 h or two weeks (i.e. pair bonded) . Although no differences
in DAR densities were noted between sexually naïve males and
those that had mated with a female for 24 h, pair-bonded males
had significantly higher levels of D1Rs, but not D2Rs, in the NAcc,
but not CP, than their sexually naïve counterparts (Fig. 4G and H).
As two weeks, but not 24 h, of cohabitation and mating increased
NAcc D1Rs, these results indicate that this neuroplastic change is
not necessary for the initial formation of partner preferences—a re-
sult that is consistent with the D2R, but not D1R, regulation of
partner preference formation aforementioned—but is instead
indicative of extended sociosexual experience with the partner
(i.e. the full establishment of a pair bond) . Interestingly, this in-
crease in D1R levels in pair-bonded males coincides with the
behavioral emergence of offensive aggression toward a stranger fe-
male (males that are paired with a female for two weeks display
robust offensive aggression toward stranger females [8,99,100],
whereas males that are sexually naïve or allowed to mate with a
female for 24 h do not ). Therefore, it was hypothesized that
Fig. 4. Vasopressin (AVP) and dopamine (DA) involvement in selective aggression in male prairie voles. (A) Photomicrograph shows AVP-immunoreactive (AVP-ir) cell bodies
and fibers (brown cytoplasmic staining), Fos-immunoreactive (Fos-ir) staining (dark nuclear staining), or both (insert) in the anterior hypothalamus (AH). (B) Males pair-
bonded with a female for two weeks displaying aggression toward either male or female strangers, have a significantly higher density of AVP-ir/Fos-ir double labeled cells in
the AH compared to males re-exposed to their partner or not exposed to any conspecific (control). (C) AH-AVP release is higher in pair-bonded males that are exposed to a
stranger female than those that are re-exposed to their partner. (D) Males paired with a female for two weeks (Paired) have higher densities of vasopressin receptors (V1aRs)
in the AH than males that are sexually naïve (Naïve). (E) Sexually naïve males (Naïve) given intra-AH injections of AVP display significantly more aggression than males
treated with CSF, and this AVP-induced aggression is blocked by concurrent administration of AVP with a V1aR antagonist (V1aR Ant). Pair-bonded males (Paired) display
robust aggression toward novel females and this behavior is significantly decreased by intra-AH injection of a V1aR antagonist. (F) Sexually naïve males injected in the AH
with an adeno-associated virus expressing the V1aR gene (AAV-V1aR) display significantly more aggression toward stranger females than control males. (G) Pair-bonded
males (Paired) have higher densities of D1Rs in the NAcc than sexually naïve males (Naïve). (H) These differences in D1R density between paired and naïve males are
significant, however no group differences are found in NAcc D2R density. (I) Pair-bonded males display aggression toward a stranger female, but not their partner, and these
effects are blocked by the infusion of a D1R antagonist (D1R Ant), but not D2R antagonist (D2R Ant), into the NAcc. Bars indicate means ± standard error of the mean. Bars
with different Greek letters differ significantly from each other.?: p < 0.05. Adapted from [8,99,100].
K.A. Young et al./Frontiers in Neuroendocrinology 32 (2011) 53–69
increased D1R levels in the NAcc of pair-bonded males may regu-
late selective aggression toward stranger females. Site-specific
pharmacological blockade of NAcc D1Rs was used to test this
hypothesis. While pair-bonded males treated with CSF displayed
robust offensive aggression toward a female intruder, intra-NAcc
injection of a D1R antagonist abolished this aggression (Fig. 4I). Ta-
ken together, these data suggest that NAcc D1R upregulation may
underlie the important behavioral transition that occurs in male
prairie voles as they progress from the state of being sexually naïve
to being fully pair bonded, leading to offensive aggression toward
stranger females and the maintenance of the established pair bond
. In an interesting parallel to this finding, repeated exposure to a
common drug of abuse, amphetamine, increased aggression to-
ward conspecifics and prevented the formation of partner prefer-
ences [100,151]. Importantly, these behavioral changes coincided
with an upregulation of D1Rs in the NAcc and V1aRs in the AH,
indicating that drugs of abuse can hijack natural forms of neuro-
plasticity that evolved to maintain pair bonds [100,151].
6. Neurobiology of paternal behavior
Paternal behavior has been reported in several nonhuman
monogamous mammalian species including tamarins , mar-
mosets , titis [160,161], hamsters , gerbils , mice
 and voles [174,205]. Studies in nonhuman primates have fo-
cused on the characterization of paternal behaviors and the effects
that manipulations of the social environment have on the display
of these behaviors, and have provided important translational
information for human health. Studies in rodents, instead, have fo-
cused on the central regulation of paternal behaviors and have pro-
vided valuable information concerning the neural mechanisms
underlying paternal behavior. Although the California mouse has
proven a useful rodent model for this purpose [24–26,59], the vole
model has perhaps been used most extensively in studies of the
neurobiology of paternal behavior, and data from these studies
are summarized below.
6.1. Brain activation associated with paternal behavior
As in the study of partner preference formation and selective
aggression, early studies examining vole paternal behavior used
Fos-ir to map brain areas that are activated by pup exposure and
the display of paternal behavior. After exposure to a conspecific
pup, male prairie voles displayed increased Fos-ir staining in some
forebrain areas including the AOB, MeA, BNST, MPOA, and LS,
implicating the involvement of these regions in processing pup-
associated cues and/or in the regulation of paternal behavior
[134,222]. The role of the olfactory system and MeA in paternal
behavior was further confirmed by lesion studies in prairie voles.
Males that received bilateral bulbectomy showed a significant de-
crease in paternal behavior along with other social behaviors, com-
pared to males that received a sham-operation . Further,
axon-sparing lesions of the MeA decreased paternal behavior in
male prairie voles without affecting other behaviors such as explo-
ration, locomotion, and olfactory investigation . Finally, un-
like prairie voles, pup exposure did not significantly elevate Fos-
ir labeling in the MeA, BNST, MPOA, or LS of male meadow voles,
further suggesting the importance of these brain regions in the reg-
ulation of male parental care .
6.2. Neuropeptide regulation of paternal behavior
In addition to those behaviors previously mentioned, central
AVP and OT have also been implicated in parental behaviors, par-
ticularly in females. Injections of AVP into the lateral ventricle of
female rats induces persistent parental behavior . Further,
Long-Evans rats display superior parental behavior compared to
their closely related AVP-deficient mutant variants, Brattleboro
rats . OT, both in the periphery and brain, also plays an
important role in behaviors associated with maternal care, includ-
ing uterine contraction at parturition, milk ejection during lacta-
tion [87,211] and the regulation of maternal behavior in females
[142,177]. As OT and AVP have therefore been implicated in
parental behavior in females, and other social behaviors in both
females and males, researchers began evaluating the role that
these neuropeptides played in the regulation of male parental
The first evidence to suggest a role for these neuropeptides in
paternal behavior was provided by studies investigating the rela-
tionship between paternal experience and AVP-ir fiber density or
AVP/OT mRNA expression in the brain. Prairie voles that had been
paired with a female for two weeks or were first-time fathers dem-
onstrated significantly more paternal behaviors and had lower
densities of AVP-ir fibers in the LS, but not the MPOA, than their
sexually naïve counterparts [17,18]. Interestingly, this alteration
in LS AVP-ir fiber density was not found in meadow vole
fathers—that naturally show little to no paternal behaviors toward
pups—suggesting that changes in LS AVP may indeed play a role in
prairie vole paternal behavior . AVP in the PVN has also been
implicated in prairie vole paternal behaviors, as AVP mRNA label-
ing in this region was increased in male prairie voles that had re-
cently become fathers, but did not change in naturally non-
paternal male montane vole fathers . Although little is known
about the role of OT in paternal behavior in prairie voles, there ex-
ists some evidence that this neuropeptide may be involved. For
example, prairie vole pups reared by mothers-only received less
licking/grooming and matured more slowly, compared to pups
reared by both parents. In adulthood, the former showed less
pup-directed parental behavior and increased OT mRNA expres-
sion in the hypothalamus than the latter, but such effects were
mainly noted in females . Taken together, these data indicate
that AVP and OT in various brain regions may regulate paternal
Few studies have directly assessed the functional significance of
central AVP and OT in paternal behavior. In one of these studies,
subtle changes were noted in the paternal behaviors of sexually
naïve males after icv administration of AVP or OT, whereas com-
bined icv treatment of an OTR and V1aR antagonist affected pater-
nal behaviors in a dose-dependent manner . At low doses (1 ng
each), OTR/V1aR antagonists tended to increase the latency for pup
approach and huddling, while at high doses (10 ng each) paternal
behavior was significantly reduced and the occurrence of pup at-
tacks was significantly increased . While this study demon-
strates that central AVP and OT indeed have functional effects on
paternal behavior, further experimentation is required to further
understand the role of each neuropeptide on specific paternal
behaviors and their sites of action within the brain. In the only
study to do so to date, Wang et al.  examined the effects of
AVP manipulation in the LS on four of the most common paternal
behaviors, including licking/grooming, crouching/huddling over,
contacting and retrieving pups. Sexually naïve male prairie voles
injected with AVP directly into the LS spent significantly more time
displaying paternal activities, specifically contacting and crouching
over pups, than voles injected with saline. These effects were
blocked by pre-injection of a V1aR antagonist in the LS, suggesting
that LS AVP is both necessary and sufficient in the regulation of
paternal behavior .
Although site-specific effects of OT on paternal behavior have
never been tested, there is evidence to suggest that NAcc OT may
be involved. This evidence stems from comparative studies demon-
strating species differences in NAcc OTR densities that correlate
K.A. Young et al./Frontiers in Neuroendocrinology 32 (2011) 53–69
with species differences in paternal behavior , the importance
of OTR activation in other behaviors associated with pair bonding
in males (e.g., partner preference formation) [150,244], and various
studies documenting a role of NAcc OTRs in female parental behav-
ior. For example, NAcc OTR densities have been related to sponta-
neous maternal behavior in sexually naïve adult female prairie
voles. Specifically, females that displayed maternal behavior had
higher densities of OTRs in the NAcc than females that did not dis-
play maternal behaviors or attacked pups . A similar positive
correlation was noted between NAcc OTR density and alloparental
care in juvenile female prairie voles . Further, OTR density in
the NAcc has been positively associated with other affiliative
behaviors, including partner preference formation . Although
never directly tested in males, these data indicate the potential for
NAcc OT to be involved in paternal behavior.
6.3. DA regulation of paternal behavior
While a great deal of research has documented the importance
of central DA in maternal behaviors (see  for review), fewer
studies have investigated a role for central DA in paternal behavior.
Although limited in number, these studies have provided compel-
ling preliminary evidence that DA is also involved in male parental
In the only pharmacological experiment to examine the DAer-
gic regulation of paternal behavior in prairie voles, Lonstein 
illustrated that DAR blockade has differential effects on distinct
aspects of paternal behavior (e.g. contacting, licking, and hud-
dling over pups). Specifically, blockade of DARs with the nonse-
lective DAR antagonist, haloperidol, impaired some paternal
behaviors—including contacting and licking pups—yet enhanced
others, such as huddling over pups. Although haloperidol disrupts
general motor activity at some doses , the effects of halo-
peridol on some paternal behaviors, specifically pup licking, were
noted at doses that did not alter total activity scores, indicating
that DAR activation has primary effects on paternal behavior.
Therefore, these data not only demonstrate a role for DA in pater-
nal behavior but also illustrate that the DAergic regulation of
paternal behavior is behavior-specific . No site-specific
manipulations have yet been used to reveal brain regions in-
volved in the DAergic regulation of paternal behavior. However,
an experiment mapping neuronal activation in response to pups
has offered some insight into this matter. Recall that the prairie
vole brain contains a group of DAergic cells in the pBNST and
MeApd that is sexually dimorphic—males have more DAergic
cells in these areas than females —and these cells are poten-
tially sensitive to androgens and estrogens . Interestingly,
these cell populations are activated (indicated by Fos/TH dou-
ble-labeling) in the male prairie vole brain after interactions with
conspecific pups , and may therefore be involved in paternal
Although no studies have yet been conducted to this end, it is
suggested that NAcc DA may also play a role in paternal behavior.
As described previously, the vole NAcc contains dense DA termi-
nals and receptors and NAcc DA plays an important role in the reg-
ulation of other social behaviors associated with pair bonding,
including partner preference formation and selective aggression
in male prairie voles [7,8]. Additionally, NAcc DA plays a well-
known role in maternal behavior in other rodent species. In rats,
for example, DA is released in the NAcc in response to pup stimuli
 and alterations in NAcc DA activity across postpartum peri-
ods are correlated with changes in a variety of parental behaviors
ranging from pup retrieval, nursing, licking/grooming, and mater-
nal memory . It may therefore be worthwhile for future investi-
gations of male parental behavior to examine the possibility that
NAcc DA plays an important role.
7. Other neurochemicals/hormones implicated in pair bonding
In addition to AVP, OT and DA, several other neurotransmitters
and hormones have been implicated in social behaviors associated
with pair bonding in prairie voles. One interesting example in-
volves neurochemicals associated with the hypothalamic–pitui-
responses. Briefly, during a stressor, corticotrophin-releasing factor
(CRF) released from the hypothalamus binds to CRF receptors in
the anterior pituitary leading to the synthesis of adrenocorticotro-
phic hormone (ACTH) . ACTH is then released into the blood-
stream and acts on the adrenal cortex to produce glucocorticoids,
such as corticosterone (CORT), which can then act on glucocorti-
coid receptors (GR) in the brain to mediate responses to stress
. Prairie voles are considered to be glucocorticoid resistant ro-
dents as they have about 5- to 10-fold greater basal plasma CORT
and 3-fold greater basal levels of ACTH, along with 10-fold lower
affinity GRs, especially the type-I GR, that are expressed in lower
densities in the brain, compared to rats and promiscuous voles
Data from behavioral experiments indicate that the effect of
CORT on pair bonding is sexually dimorphic. In female prairie
voles, cohabitation with a male, which led to partner preference
formation, significantly decreased serum CORT levels . Further,
reduction in GR activity, either by decreasing circulating CORT
through adrenalectomy  or by treating animals with a GR
antagonist , facilitated partner preference formation. In con-
trast, CORT injections or a stressful swim test, which increased cir-
culating CORT , prevented the development of partner
preference formation . Together, these data suggest that a de-
crease in HPA axis activity facilitates partner preference formation
in female prairie voles. In males, on the other hand, adrenalectomy
inhibited partner preference formation and this effect was reversed
by CORT replacement , indicating that CORT is necessary for
partner preference formation in males. Additionally, in a more re-
cent study, loss of a bonded partner significantly increased circu-
lating CORT levels and adrenal gland weight in male prairie
voles, suggesting that HPA axis activity may mediate the aversive
effects of partner separation and thus, play a role in the preserva-
tion and maintenance of existing pair bonds . The HPA axis has
also been implicated in paternal behavior. Males exposed to a
swimming stress spent significantly more time huddling over pups
and a trend toward more time licking and grooming pups than un-
stressed controls . These behavioral effects were not found in
female prairie voles, indicating that the effects of stress on parental
behavior—like partner preference formation—may be sexually
CRF has also been implicated in pair bonding behaviors. Male
prairie voles that received CRF injections displayed partner prefer-
ences in the absence of mating, and this induced behavior was
blocked by co-administration of a CRF receptor antagonist .
Brain areas involved in the CRF mediation of partner preferences
have also been identified. Local CRF injections into the NAcc facil-
itated, whereas CRF receptor antagonists inhibited, partner prefer-
ence formation in male prairie voles . Further, pairing with a
female elicited an increase in CRF mRNA in the BNST of male prai-
rie voles . Finally, icv administration of urocortin-II, a member
of the CRF peptide family, increased passive parental behavior in
both male and female prairie voles, but this treatment had no ef-
fects on anxiety or locomotor behaviors .
Several other neurochemicals are also involved in social bond-
ing in prairie voles. For example, in male prairie voles, intra-VTA
administration of NBQX, an AMPA receptor antagonist, or bicucul-
line, a GABA receptor antagonist, induced partner preference
formation, implicating these amino acids in selective affiliation
. Administration of the selective serotonin reuptake inhibitor,
K.A. Young et al./Frontiers in Neuroendocrinology 32 (2011) 53–69
fluoxetine, increased the latency to engage in parental behavior in
both male and female prairie voles, decreased aggression in males,
and had no effects on nonsocial behaviors , indicating that
serotonin may also mediate social behaviors associated with pair
bonding. Gonadal steroids can also be added to this list. Manipula-
tion of testosterone or estrogen during the first or second week of
life significantly altered subsequent affiliative and/or alloparental
behaviors in juvenile prairie voles [138,184]. Estrogen receptor al-
pha (ERa) may mediate some of the effects of gonadal steroids on
pair bonding behaviors in prairie voles. Studies have demonstrated
that females have more ERa-ir cells in several brain areas including
staining in the BNST, MPOA, and VMH of females was associated
with induction of sexual receptivity . In males, enhanced ERa
expression in the MeA, by transfection of an adeno-associated viral
vector, disrupted the display of alloparental behavior and impaired
partner preference formation . Similarly, males with enhanced
ERa expression in the BNST displayed decreased social affiliation
. These data indicate an inverse relationship between regional
ERa expression and social behavior in prairie voles. Taken together,
the studies described above highlight the involvement of multiple
neurochemicals and hormones in the regulation of pair bonding
behaviors in both male and female prairie voles.
8. Neurochemical/hormone interactions
As reviewed above, a variety of neurochemical, neurotransmit-
ter, and hormone systems have been implicated in pair bonding.
However, it is unlikely that these systems act independently to
regulate this complex social behavior. In the following section,
we will review studies documenting known interactions between
some of these systems, including CRF, OT, AVP, DA, glutamate
(GLU), gamma-aminobutyric acid (GABA), and gonadal steroid hor-
mones, in the regulation of pair bonding behaviors, primarily part-
ner preference formation.
Two of the first neurochemicals suggested to interact with one
another in the regulation of partner preference formation in prairie
voles were CORT and OT. Recall that in sexually-naïve females,
exposure to an unfamiliar male significantly increased central OT
release  and decreased serum CORT levels , effects
thought to facilitate partner preference formation. Interestingly,
icv injections of OT produced a comparable decrease in serum
CORT levels, suggesting that OT may interact with the HPA axis
to regulate partner preference formation  — an idea that may
warrant future investigation given the suggested interaction be-
tween OT and CORT in other social behaviors [6,39,42,132].
OT has also been shown to interact with AVP in the regulation of
partner preferences, a finding that is not surprising given that
these two neuropeptides are closely related to one another and
not only share similar chemical structures—differing by only two
amino acids—but can also interact with each other’s receptors
. As previously described, icv injection of AVP or OT can induce
partner preferences in both male and female prairie voles after as
little as 1 h of cohabitation with an opposite sex conspecific ani-
mal. Interestingly, the effects of AVP on partner preference forma-
tion are abolished in the presence of an OTR antagonist, and the
effects of OT are abolished in the presence on an V1aR antagonist,
indicating that AVP and OT can interact to mediate partner prefer-
ences . Further, these results indicate that the facilitation of
partner preference formation may require simultaneous activation
of both V1aR and OTRs . Site-specific manipulation in the LS of
male prairie voles has since supported this hypothesis. Partner
preference formation induced by AVP microinjection into the LS
was blocked by simultaneous administration of an OT receptor
antagonist . Taken together, these studies suggest that central
OT and AVP systems may work in concert with one another to
mediate partner preference formation.
OT and AVP have also been shown to interact with other neuro-
transmitter systems, such as DA, to mediate partner preferences. In
female prairie voles, for example, partner preferences induced by
NAcc D2R activation were prevented by concurrent administration
of an OTR antagonist . Conversely, partner preferences in-
duced by central OT administration were blocked by concurrent
administration of a D2R antagonist in the NAcc . These results
suggest that simultaneous activation of both D2Rs and OTRs in the
NAcc are required for the facilitation of partner preferences in fe-
male prairie voles. AVP-DA interactions have also been implicated
in partner preference formation. In a recent study, naturally pro-
miscuous male meadow voles—that would not otherwise form
partner preferences with a mate—received viral vector-mediated
transfer of the prairie vole V1aR gene into the VP, resulting in
upregulation of the V1aR in this region and the formation of part-
ner preferences after 24 h of mating . In a second experiment,
these viral vector-induced preferences were blocked by adminis-
tration of a D2R antagonist prior to mating, suggesting that AVP
and DA may interact to mediate pair bond formation . This
hypothesis is supported by the well-known neuroanatomical con-
nection between these two regions, as D2R expressing medium
spiny neurons in the NAcc project directly to the VP .
GLU, GABA, and CRF have also been suggested to interact with
DA in the regulation of partner preferences [52,53]. Blockade of
AMPA GLU or GABA receptors, via injection of NBQX or bicuculline,
respectively, into the VTA induced partner preferences in the ab-
sence of mating. As the VTA provides the major source of DAergic
afferents to mesolimbic brain regions, including the NAcc, it has
been suggested that the effects of these antagonists on partner
preference formation may have been mediated by their effects on
NAcc DAergic neurotransmission . In a separate study, periph-
eral administration of RU-486, a GR antagonist, induced partner
preferences in female prairie voles in the absence of mating .
These effects were blocked by co-administration of either a D1R
or D2R antagonist into the lateral ventricle, suggesting that the ef-
fects of GR antagonism on partner preference formation may be
mediated through an interaction with central DA systems .
Further experimentation is needed to detail the nature of interac-
tions between GLU, GABA, CRF, and DA in partner preference
Finally, gonadal steroids play an important role in pair bonding
and are thought to interact with a variety of neuropeptide and neu-
rochemical systems implicated in this behavior. For example, ex-
tended exposure to a male (or male chemosensory signals)
increases circulating estradiol levels and subsequently, behavioral
estrus, or sexual receptivity in female prairie voles [35,36,47,203].
Sexual receptivity can also be induced in ovariectomized females
through estrogen administration alone . Interestingly, in-
creased serum estrogen levels, induced by exposure to male
chemosensory signals or by exogenous estrogen administration,
significantly increased OTR binding in the prairie vole brain
, indicating that estrogen and OT may interact to regulate
mating—which facilitates partner preference formation in females
. In males, testosterone has been found to influence the ef-
fects of AVP on partner preference formation. Recall, that icv
administration of AVP facilitates the formation of partner prefer-
ences in male prairie voles following only 1 h of cohabitation
. Interestingly, AVP administration does not induce partner
preferences in adult male prairie voles that were castrated on the
day of their birth, suggesting that the organizational effects of tes-
tosterone are required for the effects of AVP on partner preference
formation . Testosterone and AVP may interact in the regula-
tion of paternal behavior as well, as male prairie voles that were
castrated in adulthood had a reduced density of AVP-ir fibers in
K.A. Young et al./Frontiers in Neuroendocrinology 32 (2011) 53–69
the LS and displayed less paternal behavior than controls with in-
tact gonads  (cf. [152,153]).
9. Summary and additional considerations
Pair bonding in prairie voles is a complex social behavior that
involves the coordination of several distinct behaviors, including
selective affiliation, selective aggression, and parental care. The
appropriate expression of these behaviors requires a variety of cog-
nitive functions, including sensory processing, memory formation,
and individual recognition, as well as motor output. Multiple brain
regions, such as the MeA, BNST, LS, NAcc, PFC, and AH, known to
mediate these processes, have been implicated in pair bonding
behaviors in prairie voles, as described above. Further, many of
the neurochemicals that have been implicated in pair bonding
behaviors, including AVP, OT, DA, CRF, and GLU are known to act
in these brain regions to mediate processes essential for pair bond-
ing. For example, AVP in the LS  and OT in the MeA  medi-
ate social recognition in other species, a process inherent to the
formation and display of partner preferences in prairie voles. As
another example, DA in the NAcc plays an important role in condi-
tioned reward learning [23,119], a process that likely contributes
to partner preference formation by mediating a learned association
between the reinforcing properties of mating and the specific
olfactory signature of the mate [8,10,245].
Although careful experimentation has revealed the importance
of each of these separate brain regions and neurochemicals for pair
bonding behaviors, each behavior tested is undoubtedly regulated
by a larger circuitry involving multiple brain regions and neuro-
chemicals. While not yet fully examined in voles, data from other
rodent species have demonstrated clear anatomical connections
between the brain regions noted above, and these connections
. For example, connections between the vomeronasal organ
(VNO), AOB, and MeA play an important role in processing chemo-
sensory cues [30,72,121,130,192], and not surprisingly, activation
discrete conspecific olfactory cues are present) are essential for the
MeA and AH regulate aggression [33,202], and activation of this
pathway likely regulates selective aggression in prairie voles
[99,224]. Additionally, the well-characterized mesolimbic DA sys-
tem, which consists of DAergic cells in the VTA that project to the
NAcc and mPFC, is regulated by reciprocal GLUergic projections
from the mPFC to the NAcc and VTA [34,193]. This neural circuit as-
signs motivational salience to environmentally relevant stimuli
[120,232], facilitating adaptive goal-directed behaviors, such as
copulation with a receptive mate [22,74,179,180] and the retrieval
of pups [2,112,171].It is important to note thatjust as the samesys-
tem can mediate more than one behavior, as evidencedby the latter
example, the same neurochemical can regulate more than one
behavior. For instance, AVP neurotransmission, in the LS, VP, and/
or AH plays an important role in partner preference formation,
selective aggression, and paternal behavior. Further, one behavioral
sociosexual experience – a prerequisite for partner preference for-
mation – induces both DA and OT release in the NAcc [98,187],
gested to release OT in the PFC . Thus, multiple neural circuits
and neurochemicals work in concert with one another to regulate
behaviors associated with pair bonding.
Finally, in the discussion of pair bonding in the prairie vole, sex
differences should not be overlooked. As discussed above, the neu-
ral regulation of pair bonding behaviors is in some cases sexually
dimorphic (e.g., CORT regulation of partner preference formation
[63,64]). Further, some neuropeptides, such as AVP and OT, may
have gender specific roles in certain behaviors related to pair bond-
ing: AVP regulates selective aggression [99,100,201] and paternal
behavior [149,213] in males, while OT regulates maternal care in
females [16,76,165,173,178]. Additionally, males and females seem
to differ in their sensitivities to AVP and OT. Although both neuro-
peptides have been implicated in partner preference formation in
both sexes , lower doses of AVP were sufficient to induce part-
ner preferences in males than females and peripheral OT adminis-
tration was effective to induce partner preference formation only
in female, but not male, prairie voles . Sexual dimorphisms in
physiology and neural substrates may underlie these differences
in behavior. For example, as found in other rodent species
[48,61,207], male voles have more AVP mRNA-labeled cells in the
BNST and MeA and a higher density of AVP-ir fibers in the LS (most
likely projections from AVP producing cells in the BNST and MeA)
than female voles [17,221]. Interestingly, 3 days of cohabitation
with an opposite sex conspecific induces an increase in the number
of AVP mRNA-labeled cells in BNST and a decrease in the density of
AVP-ir staining in the LS in male, but not female, prairie voles, indi-
cating a sexually-dimorphic effect of sociosexual experience on
AVP activity, which, in turn, may play a role in the regulation of
pair bonding behavior in male prairie voles. Sex differences have
also been found in a population of TH synthesizing cells in the
anteroventral periventricular preoptic area  and the extended
amygdala  in the prairie vole brain, however the functional
role of these cells in pair bonding still needs to be examined. It is
well recognized that sexual dimorphisms in physiology and neural
substrates may underlie sex differences in behavior. In addition,
sex differences in the brain may allow for the display of similar
behaviors between males and females despite their different phy-
siologies . In other words, sexually dimorphic neurochemical
systems may allow males and females to have compensatory
mechanisms that work in concert with their physiologies to
produce similar behavioral outcomes. This suggestion is consistent
with studies in the prairie vole demonstrating that sexually
dimorphic systems, such as the AVP pathways from the MeA and
BNST to the LS , enable the display of parental behaviors in
males  while OT systems enable the same behaviors in fe-
10. Conclusions and future directions
Although study of the bonds formed between prairie vole pairs
cannot possibly allow us to fully understand the intricacies of hu-
man relationships, they can certainly offer insights into the basic
neural mechanisms underlying adult attraction and attachment.
The literature reviewed above has implicated a variety of neuro-
peptide, neurotransmitter, and hormonal systems in the regulation
of pair bonding in prairie voles. Accordingly, preliminary work in
humans has implicated many of these same systems in human so-
cial behaviors. For example, recent research utilizing functional
magnetic resonance imaging to measure real-time brain activation
in humans has suggested that DA neurotransmission may underlie
human mate choice and attachment . These studies found that
DA-rich areas, such as the VTA, were activated when participants
in either early stages of intense romantic relationships or in
long-term deeply-loving relationships viewed a photograph of
their beloved but not when they viewed pictures of other familiar
individuals [12,20,21]. Recent studies have also implicated the OT
system in human couple interactions. In a placebo controlled
experiment, for example, intranasal administration of OT—a meth-
od of delivery that readily allows the neuropeptide access to the
brain—significantly increased positive communication between
couples, as indexed by eye-contact, curiosity/care, and agreement
scores . Additionally, OT has been found to increase trust
K.A. Young et al./Frontiers in Neuroendocrinology 32 (2011) 53–69
among humans—a prerequisite to social affiliation . Further,
AVP has been implicated in human aggressive behavior, as levels
of AVP in the cerebrospinal fluid of men and women were posi-
tively correlated with a life history of aggressive behaviors . Ta-
ken together, these studies highlight the possibility that similar
neural mechanisms may mediate social behaviors in humans and
A relatively high degree of conservation between the behavioral
and neurobiological aspects of prairie vole and human social
behaviors suggests that the prairie vole model may be ideal for ba-
sic and translational research investigating the neurobiology of so-
cial behavior. Accordingly, research in prairie voles may not only
allow us to learn more about the factors that underlie normal so-
cial behaviors, but may also enable us to explore the underlying
causes of social deficits noted in several mental health disorders.
A noteworthy example involves the use of the prairie vole model
for the study of autism spectrum disorders [147,157], in which
AVP, OT, and DA have already been implicated [111,115,156,236].
Additionally, the prairie vole has recently been established as an
animal model for depression, specifically depression induced by
social loss in adulthood [29,103]. Finally, prairie voles have most
recently been utilized to study the effects of drugs of abuse on pair
bonding, and these studies have demonstrated that dysregulation
of the mesolimbic DA system may be involved in the drug-induced
impairment of social behavior [151,238]. These and other studies
 demonstrate the utility of this animal model for the investiga-
tion of neural mechanisms underlying normal and abnormal social
behaviors, and their related processes.
We would like to thank C. Lieberwirth, K. Lei, M.M. Martin and
A.S. Smith for their critical reading of the manuscript. We also
thank A.S. Smith for his helpful discussions during the writing of
this manuscript and for his photographic contributions. We grate-
fully acknowledge C. Badland and J. Chalcraft for their assistance
with the figures. Funding for this work was provided by National
Institutes of Health Grants DAF31-25570 to KAY, MHF31-79600
to KLG, and MHR01-58616, MHR21-83128, DAR01-19627, and
DAK02-23048, to ZW.
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