Neuroendocrine basis of social recognition
James T Winslow1 and Thomas R Insel2
Studies conducted in the past two years have yielded several
new insights about neuroendocrine regulation of social
recognition. The social recognition deficits seen in oxytocin
knockout mice have now been demonstrated in both males and
females, as well as in female estrogen receptor knockout mice.
The male vasopressin V1A receptor knockout mouse (but not
V1B) has a profound social recognition deficit. Preliminary
evidence suggests that female V1B receptor knockout mice
could also have social memory deficits. Several lines of evidence
have emerged that indicate that neuropeptide regulation is
significantly modulated by gonadal and corticosteroid activation.
Addresses
1
National Institute of Mental Health, National Institutes of Health Animal
Center, Building 110, 9000 Rockville Pike, Bethesda, MD 20892, USA
2
National Institute of Mental Health, 6001 Executive Boulevard,
Room 8235, Mail Stop Code 9669, Bethesda, MD 20892, USA
e-mail: [email protected]
Current Opinion in Neurobiology 2004, 14:248–253
This review comes from a themed issue on
Cognitive neuroscience
Edited by John Gabrieli and Elisabeth A Murray
0959-4388/$ – see front matter
ß 2004 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.conb.2004.03.009
Abbreviations
AVP
vasopressin
LSD
dorsolateral septum
OT
oxytocin
OTKO OT null mutant knockout
WT
wild type
Introduction
The development of social familiarity is perhaps the
earliest stage in the process of developing social relations
and consequently is crucial to normal social development.
The past decade has seen a growing appreciation of
unique biological systems for, as well as disorders of,
social cognition.
On the basis of both anecdotal reports and experimental
findings, a variety of dual process models have emerged to
differentiate between social identity recognition and a
sense of familiarity [1]. In humans and other primates,
individual recognition is achieved using visual and auditory cues. Converging evidence indicates that in the
human brain, the superior temporal sulcus and the lateral
fusiform gyrus interact in the processing of identity
information from the face [2]. Patients with lesions of
Current Opinion in Neurobiology 2004, 14:248–253
these regions have prosopagnosia, the inability to recognize faces, but show few if any other visual or memory
deficits [2]. Familiarity appears to recruit separate systems [3]. An additional layer of complexity is suggested
by evidence that the interpretation or perception of
emotional information in the face appears to depend
on activity in the amygdala [4].
In most non-primate mammals, a predominant source of
information necessary for social recognition is encoded
by olfactory or pheromonal signals. Kin recognition, pair
bond formation, selective pregnancy termination, territoriality and dominance hierarchies all depend on the
capacity of individuals to differentiate olfactory signatures in the long-term among familiar previously encountered conspecifics. Consequently, individual recognition
is crucial for reproduction and species survival.
In addition to these forms of long-term social recognition
(Figure 1; [5–7]), rodents are also known to form transient
short-term memories of recently encountered individuals
[8]. The behavioral aspects of social recognition and social
memory have been reviewed elsewhere [9,10]. In this
article, we describe the neuroendocrine basis of social
recognition, particularly focusing on the neuropeptides
vasopressin (AVP) and oxytocin (OT), with a summary of
recent transgenic studies that have identified specific
neural pathways mediating the effects of these neuropeptides on social recognition in rodents.
Neural regulation of social recognition
Among conventional neurotransmitter systems, dopaminergic and noradrenergic mechanisms have been implicated in social recognition [11–14], as have N-methyl
D-aspartate (NMDA)- and non-NMDA-mediated glutamatergic systems [15]. As might be expected, muscarinic
acetylcholine receptor activation, important for various
kinds of learning, has also been implicated in the formation of social memories necessary for recognition [16,17].
Central pathways for both AVP and OT have been
implicated in various forms of memory and learning as
well as complex social behaviors in a range of mammals.
For a more comprehensive treatment of the central nervous system effects of these neuropeptides on learning
and memory, see the 1993 review by de Wied et al. [18]. In
addition, several lines of evidence converge to support
the hypothesis that these neuropeptides might represent
an important link in the evolution and development of
social behavior [19,20]. Indeed, a recent report suggests
that even aspects of the role of OT in synaptic plasticity
and long-term memory could be intimately linked to its
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Neuroendocrine basis of social recognition Winslow and Insel 249
Figure 1
Olfactory investigation in mice. A predominant source of information
necessary for social recognition in mice is encoded by olfactory or
pheromonal signals.
role in the maintenance of maternal social behavior [21].
A key question has been whether or not these peptides,
implicated in learning and memory as well as social
behavior, might have a specific role in social recognition
either through modulation of conventional neurotransmitters or by acting through novel mechanisms.
Neuropeptide pharmacology
Until recently, studies of the neuroendocrine regulation
of social recognition have focused on pharmacological
manipulation of OT and AVP in male rats. The limited
bioavailability of peptides through the blood-brain barrier
has compelled most researchers to examine central efficacy following intracerebral administration. Intracerebroventricular injections of AVP in nanogram (ng) doses
enhance recognition responses in normal male rats [22].
Furthermore, the ventricular administration of a selective
vasopressin receptor V1A antagonist [23] or anti-AVP
serum [24] inhibits the recognition.
The social-memory-enhancing effects of AVP in males
appear to be dependent on specific neuroanatomical
structures, including the dorsolateral septum (LSD),
which is enriched with V1A receptors. Local injections
of low doses of AVP into the LSD enhance social memory, whereas local injections of the V1a antagonist [25] or a
V1a antisense oligonucleotide [26] block the speciestypical response. AVP innervation of the LSD is sexually
dimorphic [27,28] and sensitive to gonadectomy [29]. The
efficacy of V1A antagonist blockade of social recognition
in the LSD is also sensitive to gonadectomy [30]. Moreover, testosterone replacement restored the dependence
of social recognition on LSD AVP in castrated males [31].
The potential role of septal vasopressin receptor mediation of social recognition in the rat was recently examined
www.sciencedirect.com
using viral vector mediated delivery of the prairie vole
V1A receptor [32]. Landgraf et al. [32] demonstrated
that increased V1A expression in the septum after vector
administration improved social recognition compared to
controls receiving a vector without the V1A receptor
transgene. Taken together, these data suggest that endogenous AVP in the lateral septum acting through local
V1A receptors is linked to the processing of social olfactory information in rats.
Additional studies have implicated AVP activity within
the dorsal hippocampus [24] and the olfactory bulbs [33].
Vasopressin effects in the bulb may be mediated by
norepinephrine as the improvement in social memory
requires an intact projection from the locus coeruleus
[34] and local application of AVP facilitates noradrenalin
release.
Whereas AVP has been demonstrated to facilitate social
recognition across a range of doses and routes of administration, OT has been reported to have more complex
and often contradictory effects in the rat [34,35]. The
effects of OT injected into the ventricles [36] and OTrelated peptides and derivatives in the medial preoptic
area (MPOA) [37] were found to both facilitate and
attenuate social recognition depending on the dose or
peptide administered.
As was the case for AVP, injections of OT into the LSD
enhance social recognition in the rat. But, the lowest
effective dose in this nucleus is several orders of magnitude higher than that required to facilitate recognition
when OT is injected into the ventricles, making it unlikely
that the effect observed is mediated through local OT
receptors in the LSD. Conversely, injections of very low
doses of OT but not AVP appear to enhance the typical
male recognition response when administered in the
MPOA, a region in which OT receptors are present [37].
Unlike the differential effects of the two peptides in the
LSD and the MPOA, when injected into the olfactory
bulbs both OT and AVP appear to enhance the ability of a
male to recognize a familiar juvenile [33]. The effects of
both peptides are dependent on the presence of an intact
noradrenergic projection from the locus coeruleus to the
olfactory bulbs [34].
In contrast to the results with OT, injections of a selective
OT antagonist are unable to inhibit normal recognition
in the olfactory bulb, the lateral septum, or the medial
preoptic area [38]. Disparities between agonist and
antagonist effects are worth noting because agonists are
much less selective for the OT receptor. It is possible that
OT effects in the bulb or the limbic system are mediated
through V1a rather than OT receptors. Interestingly, the
central administration of an OT antagonist has been
reported to inhibit species typical recognition in females
Current Opinion in Neurobiology 2004, 14:248–253
250 Cognitive neuroscience
but not males. This implies that there are sexual dimorphisms in the sensitivities and possibly mechanisms for
memory enhancing properties of both AVP and OT
[39]. Although little is known about the mechanisms of
either OT or AVP effects, pharmacological studies have
established that the effect of OT on social recognition
in the bulbs is mediated through the activation of aadrenergic receptors [40].
Targeted mutations
Oxytocin mutations
In contrast to the inconsistent findings using OT antagonists in rats, transgenic techniques have demonstrated
OT to be a crucial mediator of social memory in mice.
Using OT null mutant knockout (OTKO) mice, we
established that OT was both necessary and sufficient
for short-term social recognition in the male mouse [41].
These animals completely failed to recognize familiar
conspecifics even after repeated encounters. This deficit
does not represent an abnormality in sensory processing
or a generalized impairment of learning and memory
because OTKO and wild type (WT) mice do not differ
on their ability to locate hidden food, learn spatial cues for
the Morris water maze, or habituate to an acoustic startle
(Figure 2).
Recently, a comparative study of OT and estrogen receptor knockouts [42] examined social recognition perfor-
mance of female OT, a-estrogen-receptor knockout
and b-estrogen-receptor knockout mice. Choleris et al.
[42] describe disturbed social recognition in all three
knockouts comparable to deficits characterized previously only in male OTKO mice. The authors propose
that social recognition depends on an intact OT system
in both male and female mice, but that this system may
also be crucially sensitive to gonadal steroid control
possibly through the interaction of four genes: oxytocin,
oxytocin receptor, a-estrogen receptor, and b-estrogen
receptor genes.
This proposal is consistent with findings from earlier
pharmacological studies, which also implicated a role
for gonadal steroids in neuropeptide regulation of social
recognition [43]. Recent studies have also implicated
corticosteroid hormones as potential modulators of social
memory. In particular, Tang et al. [44] demonstrated that
stimulation early in life resulted in significant enhancement of adult rat social recognition associated with a
significant decrease in basal corticosterone. Furthermore,
across rearing histories, recognition was highly negatively
correlated with basal corticosterone levels, which indicates that elevated basal corticosterone could impair an
individual’s social recognition performance. Interestingly, OT is an important modulator of hypothalamicpituitary-adrenal axis (HPA) activity, and this influence
might represent a key mechanism by which social behavior and experience interact in an individual’s response to
stress [45,46].
Figure 2
Additional pharmacological studies in male OTKO mice
have demonstrated that intracerebroventricular injections
of very small doses of OT (at least 1 pg), but not AVP, can
fully rescue the social recognition deficit [41]. But, in
contrast to the effects of AVP in rats, OT was only
effective in mice when present during the initial social
exposure. Oxytocin administered 10 min before the first
social encounter fully restored species-typical recognition
responses to the OTKO mice, whereas injections of OT
10 min after the first exposure did not differ significantly
from injections of artificial cerebrospinal fluid. Central
injections of a specific OT antagonist in WT mice also
caused deficits in social recognition.
Olfactory investigation
60
Duration (sec)
50
40
*
30
*
20
*
OTKO
WT
10
0
1
2
3
Encounter
4
New
female
Current Opinion in Neurobiology
OT null mutation and social amnesia. OT immunoreactivity in the
paraventricular and the supraoptic nuclei was reduced in
heterozygous (HET) and absent in homozygous (HOM) mice
compared to that of wild type (WT) siblings (Adapted from [56]). Time
allocated to olfactory investigation of an ovariectomized mouse
during repeated 1 min encounters. Male WT (open symbol) mice show a
rapid decline in investigation with renewed interest in a new female.
OTKO mice (closed symbol) showed no decline in interest in a
female (Adapted from [41]).
Current Opinion in Neurobiology 2004, 14:248–253
Oxytocin knockout and WT mice appear to differ in the
neural pathways they use to process social information.
Following a 90 s social encounter, WT and OTKO mice
showed different patterns of Fos induction in the brain
[47]. Although both genotypes activated Fos in the olfactory bulbs, lateral septum, pyriform cortex, and dorsolateral septum, OTKO males failed to induce Fos activation
in the medial amygdala and in several downstream projections of its nucleus, including the bed nucleus of the
stria terminalis and the medial preoptic area. In addition
to these areas of hypoactivation, the OTKO males
showed a massive hyperactivation in the somatosensory
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Neuroendocrine basis of social recognition Winslow and Insel 251
cortex and in several regions of the hippocampus, including CA1, CA3, and the dentate gyrus. Although the
significance of this increased activation remains unclear,
these males could be compensating for the absence of
activation in the medial amygdala by recruiting alternative neural pathways.
The medial amygdala, which failed to become activated
in the OTKO males, is enriched with OT receptors. To
determine if OT acting on receptors within the medial
amygdala was both necessary and sufficient for social
recognition, we injected OT and an OT antagonist into
this region [47]. Very low doses of OT (0.1 pg) administered directly into the medial amygdala prior to the first
encounter restored normal recognition to the OTKO
animals. Identical injections into the olfactory bulbs
failed to restore social recognition. Moreover, site-specific
injections of an OT antagonist (0.01 ng) into the medial
amygdala of WT mice reduced their ability to recognize
previously encountered individuals. Injections of an OT
antagonist into the olfactory bulbs of wild type animals
were without effect, effectively replicating the findings
previously reported in rats.
Vasopressin mutations
Brattleboro rats are Long Evans rats with a spontaneous
single base pair deletion in the gene that encodes vasopressin. This genetic defect is transmitted according to an
autosomal recessive pattern, and rats homozygous for the
defect completely lack the ability to synthesize vasopressin [48]. The phenotype for this mutation includes a
syndrome of polyuria and polydipsia, which is analogous
to central diabetes insipidus.
Engelmann and Landgraf [49] conducted the only study
to date on the social recognition of the Brattleboro rat, and
found it to be impaired. Conversely, using microdialysis
techniques they report significantly improved social
recognition in Brattleboro rats following administration
of synthetic AVP into the septum.
Knockout mice for both the V1A receptor (V1ARKO) and
V1B receptor (V1BRKO) have recently been produced,
and initial studies indicate a crucial role for vasopressin in
mouse social recognition dependent primarily on the V1A
receptor subtype [50,51]. Wersinger et al. [51] describe
a pronounced reduction of aggressive behavior but only
mild impairment of social recognition in V1BRKO mice
evident primarily under demanding memory conditions.
Bielsky et al. [50] describe a profound disruption of social
memory in male V1ARKO mice, which, similar to the
situation in the OTKO mice, did not appear to be related
to global memory or olfactory deficits. Temple et al. [52]
provide preliminary evidence that social memory deficits
in V1BRKO and OTKO mice extend to disruption of
strange-male mediated pregnancy block (Bruce Effect)
in females, although apparently by different mechanwww.sciencedirect.com
isms. Intriguingly, V1A receptor knockout mice appeared
to be significantly less anxious than WT mice in some
tasks — a phenotype similar to that described in OT
knockout mice [53].
Conclusions
Oxytocin and AVP are members of a large group of
ancient neuropeptides with conserved effects on a variety of mnemonic and social processes. Among their
established roles in mammals, both peptides control an
organism’s ability to remember individuals that they
have previously encountered. This form of social recognition is essential for all complex relationships, including
the development of lifelong pair bonds in monogamous
mammals.
The mechanisms by which AVP and OT facilitate social
memory remain unclear. At a cognitive level, AVP
appears more important for consolidation (in rats),
whereas OT appears essential for acquisition (in mice).
At this point, it is not clear whether the differences in
AVP and OT effects are related to the species tested or
the cognitive mechanism. The neuroanatomical distribution of receptors for both OT and AVP show profound
species differences, so one might expect that these peptides will have unique cognitive and behavioral effects
depending on their species-specific targets. Additional
studies with AVP in mice (including mice with null
mutations of AVP) as well as OT in rats should clarify
the extent to which AVP and OT have unique effects on
social recognition.
A related question regards the cellular mechanism for
these effects. Noradrenergic innervation of the bulb
appears crucial for social recognition. Kendrick and coworkers have described a cellular model for social recognition in the mouse that involves increased mitral cell to
granule cell activity in the bulb, dependent on noradrenergic input [54]. Whereas AVP effects might influence
this process in the bulb, OT effects on social recognition
appear to be mediated through the medial amygdala.
Nevertheless, OT effects might also be mediated by
modulating noradrenergic activity, not only in the rat
olfactory bulb [34,40] but also in the medial amygdala
of the OTKO mouse. Thus, AVP and OT might be
important primarily as modulators of noradrenergic
release in select neural pathways.
Now that we have two important candidates (AVP and
OT) and we know some of the sites of action (i.e. medial
amygdala for OT), a major area for future research will be
a more careful investigation of how these neuropeptides
influence cellular activity to permit social recognition.
The development of transgenic mice with specific deficits
in social memory provides an excellent opportunity to
discover the genes, proteins, and neural circuits necessary
for social recognition. Recent neuroimaging studies have
Current Opinion in Neurobiology 2004, 14:248–253
252 Cognitive neuroscience
begun to delineate specific ‘modules’ for social information in the human and nonhuman primate brain. What is
extraordinary about the emerging data with AVP and OT
is that specific neuroendocrine modulators might have
evolved early in phylogeny to organize social cognition
and social behavior in the brain.
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This is a solid, comprehensive examination of the behavioral phenotype of
V1A receptor knockout mice. The authors describe deficits in social
recognition comparable to those previously described in OTKO mice.
V1ARKO mice also showed changes in emotionality comparable to OTKO
mice.
51. Wersinger SR, Ginns EI, O’Carroll AM, Lolait SJ, Young WS III:
Vasopressin V1b receptor knockout reduces aggressive
behavior in male mice. Mol Psychiatry 2002, 7:975-984.
This is also a solid, comprehensive examination of the behavioral phenotype of V1B receptor knockout mice. The authors describe very
modest deficits in social recognition and pronounced changes in aggressive behavior. The profile obtained contrasts with that of the V1ARKO
mouse and provides interesting insights regarding the functional specificity of AVP receptor subtypes.
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either oxytocin or vasopressin 1b [abstract]. Society for
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53. Winslow JT, Hearn EF, Ferguson J, Young LJ, Matzuk MM,
Insel TR: Infant vocalization, adult aggression, and fear
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54. Kendrick KM, Da Costa AP, Broad KD, Ohkura S, Guevara R,
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Increased affiliative response to vasopressin in mice
expressing the V1a receptor from a monogamous vole.
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56. Nishimori K, Young LJ, Guo Q, Wang Z, Insel TR, Matzuk MM:
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