Understanding the brain and
behavior
The Neurobiology of Social
Recognition, Approach, and Avoidance
Larry J. Young
Introduction
• Understanding how the brain processes
social information and regulates social
behavior helps us understand psychiatric
disorders specifically affecting social
behavior.
• Animal models provide an opportunity for
experimental manipulations that are not
possible in human patients.
• Several rodent model systems that have
proven particularly useful for
understanding how the brain processes
social information and regulates social
behavior.
• Not necessarily models of any specific
human condition
• Instead contribute to our understanding of
the social brain.
Gene knock-out mouse
From IDENTIGENE Mouse Genotyping ad
• The first model, the oxytocin knockout
mouse, demonstrates the role of the
neuropeptide oxytocin and the amygdala
in the differential processing of social
verses nonsocial information in the context
of social recognition.
Social Recognition and the Neural
Processing of Social Stimuli
• Several studies suggest that the brain has
specific neural circuits involved in processing
social information rather than nonsocial stimuli.
• Human brain imaging studies have
demonstrated that the brain processes social
visual stimuli differently from nonsocial stimuli.
• For example, the lateral fusiform gyrus is
activated to a greater degree when subjects
view faces than when viewing nonface objects
• Social recognition in mice, unlike primates,
is primarily based on olfactory cues.
• During the first social encounter, a male
mouse will investigate a novel mouse by
sniffing the head and anogenital region for
approximately 1 min.
• If the male encounters the same mouse
again, it will investigate the stimulus
mouse for only a few seconds and then
quickly engage in different behaviors.
Neuropeptide oxytocin
• Oxytocin is a neuropeptide
• Oxytocin induces maternal behavior,
uterine contraction and lactation
• Young et al. used mice genetically
engineered to lack a functional oxytocin
(OT) gene to investigate the role of OT in
social behavior
• OT knockout mouse fail to habituate to, or
recognize, a stimulus mouse even after
repeated exposures
• This deficit in social memory is not due to
problems with general olfactory processing
because these mice habituate normally to
nonsocial scents, such as a cotton ball
scented with lemon extract
• OT knockout mice appear to have normal
general learning and memory abilities because
they perform as well as normal mice in the
Morris water maze, which quantifies
performance on a spatial learning task.
• The specific deficit in social recognition suggests
that although general cognitive abilities and
olfactory processing are intact, the processing of
social stimuli is abnormal.
• Social recognition in the OT knockout
mouse can be fully restored by a single
infusion of 1.0 ng OT into the brain just
minutes before the initial social encounter.
• Infusion of a specific OT antagonist into
the brain of wildtype mice prevents the
expression of a social memory.
• Injection of the OT after the initial
exposure fails to restore social recognition,
demonstrating the OT must be present
during the initial processing of the social
information, rather than for the retrieval of
that information during subsequent
exposures
• What part of the brain controls social
recognition using OT?
• Use Fos staining to see which brain
neurons are activated
Experiment
• Normal and OT knockout mice were either
– left alone in their cages, or
– presented with a social stimulus animal for 90
sec.
Fos staining indicates neuron
activation
• Wildtype mice: amygdala activated
• OT knockout: amygdala not activated
• The medial amygdala receives olfactory
input directly from the olfactory bulbs and
is rich in OT.
• Suggest that the amygdala differentially
processes social and nonsocial
information,
• Differential processing is dependent on the
presence of OT.
• Brain imaging studies with high-functioning
autistic patients also suggest that the amygdala
is involved in processing social information.
• Functional magnetic resonance imaging (fMRI)
was performed on healthy and autistic subjects
to examine brain activity during the processing
of facial expressions
• Autistic subjects failed to display an activation of
the left amygdala during this task, whereas the
healthy subjects had significant activation of this
region.
Neuropeptides in social interest
and attachment
Montane vole
Elizabeth Hadly Stanford University
• Once the brain gathers and processes
social information, it must decide how to
react to the situation.
• In other words, should the individual
engage in social interactions, such as
grooming, or attack or flee?
• What is it about interacting with other
individuals in a social context that is
rewarding to most individuals?
• A rodent about the size of a golden
hamster known as a vole has provided an
excellent system for understanding
affiliative behavior as well as social
attachment
• There are several species of voles that
inhabit various regions of North America,
and these species display a range of
social behaviors.
• Prairie voles (Microtus ochrogaster), found
naturally in the Midwestern United States,
are highly social, form long-lasting social
attachments with their mates, and are
monogamous
• Like humans, prairie voles seek social contact.
In nature, these rodents live in colonial nests
consisting of a mating pair and several
generations of offspring.
• Prairie voles prefer to spend much of their time
in physical contact with another prairie vole,
typically in a side-by-side posture referred to as
huddling.
• In large, naturalistic enclosures, prairie voles
spend more than 50% of their time interacting or
huddling with another prairie vole
• In contrast to prairie voles, montane voles
(M. montanus), which inhabit the Rocky
Mountain region, appear to avoid social
contact except for the purpose of mating.
Montane voles do not form social
attachments between mates.
• Female montane voles rear their young in
isolated nests and abandon their offspring
after 2 to 3 weeks
• In a similar naturalistic enclosure as
described above, montane voles spent
only around 5% of the time socially
interacting with other montane voles
• Because prairie and montane voles are
genetically very similar, yet so different
socially, together they provide an excellent
comparative model system for examining
the brain mechanisms involved in
promoting social contact.
• Do oxytocin (OT) and arginine vasopressin
(AVP) explain the differences in social
behavior of voles?
• Vasopressin and OT are 9–amino acid peptides with a
ring structure connected by a disulfide bond.
• The peptides differ only at two amino acid residues and
the OT and AVP genes are located adjacent to each
other on the same chromosome
• Both peptides are synthesized in neurons in the
hypothalamus that project to the posterior pituitary and
are released into the peripheral blood supply where they
regulate functions such as blood pressure, urine
concentration, uterine contraction, and lactation
• These neuropeptides are also synthesized
in separate hypothalamic and
extrahypothalamic neurons that release
the peptides independently within the brain
to modulate a number of social behaviors
OT and AVP effects on social
interaction
• OT or AVP infusions increase the amount
of time that a vole spends in olfactory
investigation and huddling in a side-byside posture with another animal
OT and AVP effects on pair bonding
• The prairie vole, which is monogamous,
forms a permanent pair bond after mating.
• In the laboratory, pair bond formation is
assessed in a three chambered testing
arena by quantifying the amount of time
the experimental animals spends during a
3-hour test with either the mate (confined
to one chamber) or with a novel animal
(confined in separate chamber).
• Intracerebroventricular infusions of an OT
antagonist into a female prairie vole before
mating prevents the formation of a partner
preference (Insel and Hulihan 1995), whereas
OT injections facilitate partner preference
formation, even in the absence of mating
• Similar results have been obtained using AVP
antagonists and agonists in male prairie voles
• Both OT and AVP are present in all
mammalian species, and prairie and
montane voles appear to have similar
levels of these peptides
• So what explains the differences in
affiliative behavior in these species?
• The answer appears to lie within the
regional expression of the receptors for
these peptides within the brain.
• Receptor autoradiography studies show
that prairie and montane voles have
dramatically different distributions of OT
and AVP receptors within the brain
• prairie voles have higher levels of OT
receptor in the nucleus accumbens (the ‘s
brain“pleasure center”) and the basolateral
amygdala relative to montane voles
• prairie voles have higher densities of the
V1a subtype of the AVP receptor in the
ventral pallidum and the medial amygdala
compared with montane voles,
• Differential localization of receptors in
brain might lead to the activation of
different circuits upon peptide release and
ultimately to different behavioral
responses.
Experiment
• Male prairie and montane voles were
given either
– 1.0 ng of AVP in artificial cerebrospinal fluid
– artificial cerebrospinal fluid alone (control)
• Behavioral response: affiliation test
Prairie voles
• Prairie voles injected with AVP exhibited
significantly higher levels of social
interactions than control prairie voles
injected with artificial cerebrospinal fluid
Montane voles
• In contrast, the injection of AVP had no
impact on social interactions in montane
voles.
• Instead montane voles respond to AVP
injections by exhibiting increased levels of
nonsocial behaviors such as autogrooming
Do other species show the same
effects of vasopressin?
• Young et al. created transgenic mice
carrying the prairie vole vasopressin
receptor
• Test if there is a direct relationship
between the behavioral response to AVP
and the specific pattern of V1a
vasopressin receptors (V1aR)
• The transgene contained the regulatory
sequences that direct the expression of
the gene in a tissue-specific manner.
• Mice transgenic for the prairie vole V1aR
gene expressed the V1aR in a pattern that
was similar (but not identical) to that of
prairie voles, but markedly different from
that of nontransgenic mice
• The transgenic mice, which share some of
the regional distribution of AVP receptors
with the prairie vole, responded to the AVP
treatment by displaying increased
affiliative behavior (Figure 3, next slide).
• Nontransgenic littermates showed no
increase in affiliative behavior after AVP
injection.
• The transgenic mice did not respond to
vasopressin in exactly the same way as prairie
voles.
• Mice not display elevated V1aR binding,
compared with nontransgenic mice, in some of
the areas that may be critical specific aspects of
social behavior, such as the amygdala and
ventral pallidum.
• These mice also did not display partner
preferences as prairie voles do.
• This is the first study to demonstrate that
the regional distribution and density of a
neurotransmitter or neuropeptide receptor
is directly associated with the social
behavior displayed by an individual.
• How do the the differential distribution of
OT and AVP receptors in prairie and
montane vole brains promote social
interactions?
• Prairie voles have a high density of OT
receptors in the nucleus accumbens,
whereas montane voles have few
receptors in this region
• Vasopressin receptors are concentrated in
the ventral pallidum of the prairie vole but
not of the montane vole.
• Both the nucleus accumbens and the
ventral pallidum are components of the
mesolimbic dopamine reward system
• Both regions receive dopamine projections
from the ventral tegmental area and are
thought to mediate the rewarding, or
reinforcing, effects of both natural stimuli
and drugs of abuse.
• Infusions of psychostimulants into these
regions of rats produce a conditioned
place preference for the environment in
which they received the injections
• Depletion of dopaminergic projections to
these regions prevents cocaine selfadministration behavior in rodents
• The high density of OT and AVP receptors
in the dopamine reward systems of prairie
voles, and the virtual lack thereof in
montane voles, suggests that activation of
these regions during social interactions is
reinforcing for prairie voles, thus promoting
social contact.
• Young et al. tested this hypothesis using
viral vector gene transfer to increase V1aR
expression specifically in the ventral
pallidum of male prairie voles.
• Adeno-associated viral (AAV) vectors are an
efficient means by which gene expression can
be manipulated in the adult animal.
• AAV typically infects cells and inserts its own
DNA into the host cell’s genome.
• By deleting the AAV genes and replacing them
with a gene of interest, it is possible to place any
gene into the genome of the neurons
surrounding the injection site
• Young et al. constructed AAV vectors by placing
the prairie vole V1aR gene sequence
downstream of a neuron-specific enolase
promoter, which directs expression in all
neurons.
• By injecting small amounts of the virus into the
ventral pallidum, they were able to selectively
increase the level of expression of the V1aR in
this region
• These AAV infusions result in an approximately
100% increase in V1aR expression, which
persists for at least 4 months.
• Male prairie voles that had artificially
elevated V1aR in the ventral pallidum
displayed elevated levels of social
interactions with novel stimulus animals,
as measured by olfactory investigation and
huddling, compared with animals injected
with the same virus in a control region, the
caudate putamen
• Male prairie voles with increased V1aR
expression in the ventral pallidum, but not
in the caudate putamen, developed a
partner preference after cohabitating
overnight, without mating, with a female
• Thus V1aR activation in the ventral
pallidum both increases social contact and
facilitates social attachment.
• A separate study demonstrated that OT receptor
activation in the nucleus accumbens is
necessary for the formation of social
attachments in female prairie voles.
• Infusions of a selective OT receptor antagonist
into the nucleus accumbens prevented the
formation of a partner preference after mating,
but similar infusions into the caudate putamen
had no effect
• agonist increases activity of target
receptor
• antagonist lowers activity of target
receptor
• Infusion of the dopamine D2 agonist
quipirole into the nucleus accumbens of
the female prairie vole
– facilitated partner preference formation, even
in absence of mating
• Infusions of the D2 antagonist eticlopride
– prevented partner preference formation after
mating
• Although there is no direct evidence of a
dopamine– peptide interaction, these
studies are consistent with the hypothesis
that, in social species, OT and AVP may
enhance the hedonic value of social
interactions by activating the neural
circuitry involved in reward and
reinforcement.
• These studies suggest the possibility that
individual differences in neuropeptide
receptor expression in the dopamine
reward circuitry could underlie individual
differences in personality traits in humans
• There is some evidence to suggest that
individual differences in dopamine
systems are associated with social anxiety
• Tiihonen reported that striatal dopamine
reuptake site densities were markedly
lower in patients with social phobia
compared with age-and gendermatched
comparison subjects.
• A more recent brain imaging study used SPECT
to examine the dopamine D2 receptor binding
potential in the striatum of 10 subjects with
generalized social phobia and 10 healthy
comparison subjects (Schneier et al 2000).
• This study reported significantly lower D2
receptor binding potentials in subjects with
generalized social phobia compared with healthy
control subjects.
• What causes the species differences in OT
and AVP receptor expression?
• Young et al. investigated the molecular
mechanisms
• The tissue-specific expression of a gene is
determined by interactions of transcription
factors with specific DNA sequences
surrounding the gene, particularly in the 5prime flanking region of the gene.
• The region of the V1aR gene that encodes
the protein is 99% identical between the
prairie and montane vole
• However, in the 5-prime flanking region of
the prairie vole gene, there is a 428
nucleotide expansion of a highly repetitive
sequence located just over 700 bp
upstream of the transcription start site
• A similar sequence is also found in the
same region of the V1aR of another highly
social and monogamous species of vole,
the alpine vole (M. pinetorum); however,
the less social meadow vole (M.
pennsylvanicus) V1aR gene does not
contain this sequence.
• Highly repetitive DNA sequences are
unstable and subject to rapid mutation.
• The human V1aR gene also has a highly
repetitive sequence in the promoter that is quite
variable among individuals (Thibonnier et al
2000).
• These studies suggest that individual differences
in regulatory DNA sequence upstream of a gene
may have a dramatic influence on both the
pattern of receptor expression in the brain and in
the social behavior of the organism.