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The Neurobiology of Social Recognition Approach and Avoidance


									The Neurobiology of Social
Recognition, Approach, and
       Larry J. Young
• Understanding how the brain processes
  social information and regulates social
  behavior helps us understand psychiatric
  disorders specifically affecting social
• 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
• not necessarily models of any specific
  human condition
• instead contribute to our understanding of
  the social brain.
• 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.
• The second model, prairie and montane
  voles, has been the focus of a decade of
  research in social approach behaviors, or
  affiliation, and proven particularly useful in
  understanding the role of neuropeptides in
  facilitating social interest and attachment.
• A third model uses conditioned defeat in
  hamsters to examine the neurochemical
  pathways involved in social avoidance as
  a consequence of adverse social
 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
• Studies in genetically engineered mice have provided a
  similar example of how the brain differentially processes
  social verses nonsocial information.
• Social recognition in mice, unlike primates, is primarily
  based on olfactory cues.
• During a brief social encounter, a male mouse will
  investigate a novel mouse by sniffing the head and
  anogenital region for approximately 1 min.
• Presumably during this investigation, the mouse is
  collecting and storing information regarding the identity
  of the novel mouse.
• 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
• This reduction in olfactory investigation after an
  initial exposure indicates that the male
  recognizes the stimulus mouse as familiar.
• That is, a social memory was stored during the
  initial encounter and retrieved during the second
• Behavioral studies using knockout mice
  have demonstrated that the neuropeptide
  oxytocin (OT) is essential for the
  expression of a social memory
• Young et al. have used mice genetically
  engineered to lack a functional OT gene to
  investigate the role of OT in social
• One of the most intriguing phenotypes of
  the OT knockout mouse is that they 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
• In addition, 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
• 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
• Young et al. have used Fos
  immunocytochemistry to determine the brain
  areas that are activated during a social
  encounter in normal and OT knockout
• Fos is the product of the immediate early gene
  c-fos, which is expressed when a neuron has
  been activated.
• Fos immunoreactivity has been used extensively
  as a marker of neuronal activation during the
  expression of behavior.
• In their experiment, normal and OT knockout
  mice were either left alone in their cages or
  presented with a social stimulus animal for 90
• During such an exposure, both wildtype and OT
  knockout mice engaged in similar levels of
  olfactory investigation and other behaviors, but
  only the wildtype mice formed a social memory
  during the exposure.
• One hour after the 90-sec exposure, the brains
  were harvested and processed for Fos
• Wildtype and knockout mice displayed similar
  levels of Fos induction in the olfactory pathway,
  including the main and accessory olfactory
  bulbs, the piriform cortex, and the cortical
• however, whereas wildtype mice exhibited a
  significant elevation of Fos staining in the medial
  amygdala, OT knockout mice had no induction
  of Fos immunoreactivity in this region.
• The bed nucleus of the stria terminalis and the
  medial preoptic area, which receive direct input
  from the medial amygdala, also failed to show a
  Fos induction in the OT knockout mice.
• The medial amygdala receives olfactory input
  directly from the olfactory bulbs and is rich in
• Together, these observations suggest that the
  amygdala differentially processes social and
  nonsocial information, and this differential
  processing is dependent on the presence of OT.
• The OT knockout mice displayed a robust
  induction of Fos immunoreactivity in the
  somatosensory cortex after the social exposure,
  whereas the wildtype mice did not.
• This altered pattern of neural activation is
  consistent with the hypothesis that in the
  absence of OT, the brain uses alternate neural
  circuits to process social information.
• 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
     The Neurobiology of Social
• 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
• 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
• 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
• 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
• It is not clear whether the avoidance of
  social interactions in montane voles is due
  to cognitive processes similar to social
  anxiety or simply a lack of interest in
  taking part in social interactions.
• 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
• Neuroanatomic, pharmacologic, and molecular
  studies have begun to provide clues as to why
  prairie voles seek out social contact whereas
  montane voles do not.
• Two neuropeptides, oxytocin (OT) and
  arginine vasopressin (AVP), appear to
  play a critical role in the social behavior of
  prairie 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
• Oxytocin is involved in promoting maternal
  behavior, sexual receptivity, and affiliative
• Infusions of OT into the brains of male rats
  increase the amount of social interactions
  with other male rats
• Vasopressin (or its nonmammalian
  homologue, vasotocin) modulates social
  communication in frogs, birds and
  hamsters and social recognition in rats
• In prairie voles, OT and AVP have been shown
  to modulate two specific aspect of social
• First, OT or AVP infusions increase the amount
  of time that a vole spends socially engaged with
  a stimulus vole.
• Specifically, these peptides increase the amount
  of time spent in olfactory investigation and
  huddling in a side-by-side posture with another
• Second, these peptides are involved in the
  formation of the pair bond. Mating facilitates the
  formation of the pair bond in the monogamous
  prairie vole.
• In the laboratory, pair bond formation is
  assessed in a threechambered testing arena by
  quantifying the amount of time the experimental
  animals spends during a 3-hour test with either
  the mate (tethered in one chamber) or with a
  novel animal (tethered 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 actually facilitate partner
  preference formation in the absence of mating
• Similar results have been obtained using AVP
  antagonists and agonists in male prairie voles
Neuropeptide Receptors and Social
• Both OT and AVP are present in all
  mammalian species, and prairie and
  montane voles appear to have similar
  levels of these peptides (Wang et al 1996).
• 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 have
  demonstrated that prairie and montane
  voles have dramatically different
  distributions of OT and AVP receptors
  within the brain
• prairie voles have high levels of OT receptor in
  the nucleus accumbens and the basolateral
  amygdala relative to montane voles,
• montane voles have high levels of receptors in
  the lateral septum.
• prairie voles have high densities of the V1a
  subtype of the AVP receptor in the ventral
  pallidum and the medial amygdala compared
  with montane voles,
• montane voles have much higher levels of
  receptors in the lateral septum than do prairie
• One might predict that differential
  localization of receptors in brain might lead
  to the activation of different circuits upon
  peptide release and ultimately to different
  behavioral responses.
• This appears to be the case.
• Male prairie and montane voles were given
  identical infusions of 1.0 ng of AVP, and their
  behavioral response in an affiliation test was
• Within 15 min after injection, prairie voles
  injected with AVP exhibited significantly higher
  levels of social interactions with a stimulus
  animal compared with prairie voles injected with
  artificial cerebrospinal fluid
• In contrast, the injection of AVP had no
  impact on social interactions in montane
• Instead montane voles respond to AVP
  injections by exhibiting increased levels of
  nonsocial behaviors such as autogrooming
• To demonstrate experimentally that there is a direct
  relationship between the behavioral response AVP and
  the specific pattern of V1a vasopressin receptors
  (V1aR), mice transgenic for the prairie vole vasopressin
  receptor were created
• The transgene contained 2.2 kb of the 5-prime flanking
  region, the coding sequence, the intron, and 2.4 kb of
  the 3. flanking region of the prairie vole V1aR gene.
• Young et al. included the 5-prime flanking region of the
  gene because this region is likely has the regulatory
  sequences that direct the expression of the gene in a
  region-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
• high levels of V1aR binding was detected in the olfactory
  bulb, thalamus, and cingulate cortex of both the
  transgenic mice and prairie voles, but not in the wildtype
• These mice were then cannulated and injected with 1.0
  ng of AVP into the lateral ventricles and tested in an
  affiliation test, as had been performed previously with the
• 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 (Young et al 1999;
  Figure 3).
• Nontransgenic littermates showed no
  increase in affiliative behavior after AVP
• The transgenic mice did 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.
• Nonetheless, 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.
   Neural Circuits of Affiliation
• Through what neural mechanisms do OT
  and AVP promote social interactions?
• The differential distribution of OT and AVP
  receptors in prairie and montane vole
  brains provide some interesting clues.
• Prairie voles have a high density of OT
  receptors in the nucleus accumbens,
  whereas montane voles have few
  receptors in this region (Figure 2).
• 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
  (McBride et al 1999).
• 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 (Gong
  et al 1996;
• Depletion of dopaminergic projections to
  these regions prevents cocaine self-
  administration 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 perhaps
  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. As a parvovirus, AAV typically infects
  cells and inserts its own DNA into the host cell’s
• 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
• 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
• Infusions of the dopamine D2 agonist
  quipirole into the nucleus accumbens of
  the female prairie vole facilitated partner
  preference formation in absence of
  mating, whereas similar 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
• 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.
   Genetic Mechanisms Affecting
        Affiliative Behavior
• Young et al. have investigated the
  molecular mechanisms that result in the
  species differences in OT and AVP
  receptor expression.
• The tissue-specific expression of a gene is
  determined by interactions of transcription
  factors with specific DNA sequences
  surrounding the gene, particularly in the 5-
  prime flanking region of the gene.
• The region of the V1aR that encodes the
  receptor 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 bp 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
• These studies suggest that individual differences
  in regulatory DNA sequence upstream of a gene
  may actually have a dramatic influence on both
  the pattern of receptor expression in the brain
  and in the social behavior of the organism.
Neurobiology of Social Anxiety and
     Avoidance in Rodents
• Pharmacologic studies of social defeat in
  hamsters may provide a useful model for
  understanding some of the neurobiological
  mechanisms leading to social avoidance
  behaviors and therefore may provide an
  animal model with relevance to psychiatric
  conditions such as social anxiety.
• Hamsters are territorial animals, and when
  allowed to establish a territory in a home cage, a
  male hamster will vigorously defend his territory
  with an aggressive attack.
• The social defeat model involves placing a male
  hamster into the cage of an aggressive resident.
  During the 5-min exposure, the experimental
  hamster is defeated in an aggressive encounter.
  The exposure may be repeated several times.
• This conditioned social defeat has a longlasting
  impact on the social behavior of the animal.
• When the defeated hamster is subsequently
  exposed, in its own home cage, to a smaller,
  nonaggressive hamster, the defeated hamster
  will flee and display submissive behavior.
• This submissive display lasts up to 30 days after
  the conditioned defeat training.
• This defeat–exposure paradigm has the
  potential for pharmacologic manipulations to
  investigate the role of specific neurotransmitters
  in both the acquisition and the expression of the
  conditioned defeat.
• In defeated animals, peripheral injection of
  a specific corticotropin releasing factor
  (CRF)1 receptor antagonist (CP-154,526)
  1 hour before the exposure to a
  nonaggressive intruder did not reduce the
  level of submissive or defensive behaviors
• Central infusions of a nonspecific CRF1/CRF2
  receptor antagonist (D-Phe CRF(12– 41))
  significantly reduced the display of submissive
  behavior to the small intruder.
• These studies are consistent with a role for CRF
  and the CRF2 receptor in the expression of the
  social avoidance–submis-sive behaviors in the
  conditioned defeat model.
• A large body of evidence suggests that
  CRF plays a key role in the regulation of
  the endocrine and behavioral responses to
  stress and has been implicated in the
  psychopathology of depression and
  anxiety disorders
• A recent primate study using the orally
  administered CRF1 antagonist antalarmin
  investigated the effects of blocking CRF1
  receptors on the behavioral response to a social
• Rhesus monkeys given the drug displayed a
  decrease in anxiety-and fear-related behaviors
  when placed in close proximity to an unfamiliar
  male separated only by a Plexiglas screen
• There is some evidence that specific
  neurotransmitter receptor systems may
  modulate social anxiety differently from other
  nonsocial forms of anxiety.
• For example, Gonzalez examined the effects on
  anxiety of 5-HT1a and benzodiazepine receptor
  agonists injected into the basolateral amygdala
  as measured by the social interaction test and
  the elevated plus maze in rats
• The social interaction test involves
  familiarizing a rat to a stimulus rat on 2
  consecutive days for 5 min, followed by a
  5-min exposure on the 3rd day, when
  social interactions were recorded.
• Increases in olfactory investigation,
  pursuit, or grooming are interpreted as
  decreased anxiety levels.
• In the elevated plus maze, the rat chooses
  between spending time in the closed, dark
  arms or the open, lighted arms.
• Increases in the amount of time spent in
  the open arms indicate decreased anxiety
• Bilateral infusions of 50 or 200 ng of the 5HT1a
  agonist 8-OH-DPAT into the basolateral nucleus
  of the amygdala produced a 50% reduction in
  social interaction but had no significant effect on
  time spent in the open arms of the plus maze.
• The effect of 8-OH-DPAT was blocked by the 5-
  HT1a receptor antagonist tertatolol.
• In contrast, infusions of the benzodiazepine
  receptor agonist midazolam into the same
  region resulted in a doubling of time spent
  interacting socially but had no effect of plus
  maze behavior.
• These results suggest that
  neurotransmitter systems acting on
  receptors in the basolateral amygdala may
  act preferentially to modulate social
  anxiety, but not nonsocial anxiety as
  measured by the elevated plus maze.

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