Aggressive Behavior

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Aggressive Behavior

• Neuroendocrinology Kevin Kelliher

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Aggression

• Aggressive Behavior - An Overt behavior with the
  intention of inflicting damage or other
  unpleasantness on an other individual (Moyer
  1971) (Brain 1979)
• Self defense (defensive rage and fear mediated
  attack)
• Maternal Aggression
• Predatory aggression
• Pup Killing
• Social Aggression

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Aggression

• Agonistic Behaviors - interrelated behaviors
  related to physical conflict between adult
  members of the same species (social aggression)
• Fighting
• Escape
• Defensive postures
• Dominance and Subordination
• Patrol and marking behaviors

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Aggression and Testosterone

• In a number of species increases in aggression
  have been correlated with rises in testosterone
• Seasonal changes
• Puberty

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Testosterone levels dont always correlate with
aggression

• High T and aggression in females are not
  correlated
• Male hamsters that are no longer in breeding
  condition will not increase aggressive bouts when
  injected with T
• Changes in(or the presence of) Androgen receptors
  are required for aggression

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Organization and Activation of Aggression in Mice

• In mice T is required both during development
  and in adulthood for the display of aggressive
  behavior.
• Females treated with T shortly after birth
  will display high levels of aggression in
  adulthood

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The 5-HT Hypothesis

• In general reduced levels of 5-HT are correlated
  with increased aggression
• 5-HT or its metabolites collected from CSF are
  found to be lower in more aggressive males
• Microdialysis can measure changes in 5-HT in
  specific brain areas at specific times
  surrounding aggressive episodes

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5-HT and Fighting

• 5-HT is decreased in the Prefrontal cortex after
  fighting
• Correlates with decreases in 5-HT in the CSF in
  more aggressive individuals
• 5-HT increases slightly in the NA after fighting
• In some instances when 5-HT agonists increase or
  antagonists decease instances of aggression this
  is believed to take place in the striatum

• 5-HT

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Caveat to Pharmacology

• Most drugs are not as specific as we would like
  (act on various receptors)
• Effects may be secondary to other effects
  (sedation, motor control)

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5-HT1B

• Most direct link between 5-HT and Aggression
• Agonists with a high affinity for anpirtoline
  5-HT1B (anpirtoline, CP-94,253 and zomitritan)
  reduce aggression.
• 5-HT1B Knockout mice have an aggressive phenotype

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Dopamine

• By contrast dopamine exerts permissive effects on
  aggressive behavior
• Changes in mesocorticolimbic can DA occurs
  before during and after aggressive episodes
• Changes in dopamine may reflect motivational
  aspects
• Acts via mesocorticolimbic pathway but not
  striatal
• Changes in DA are not found in striatum in
  response to aggressive episodes

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GABA

• GABA is believed to tonically inhibit aggressive
  behavior
• Acting via the GABAA receptor complex
• GABA levels are inversely correlated with levels
  of aggression
• However GABA agonists have bitionic effects on
  aggression
• Low doses increase aggression
• High doses decease aggression
• GABA likely mediates alcohol induced aggression
• Alcohol at low concentrations appears to
  specifically effect GABAA receptors
• Alcohols effects on aggression mimic the effects
  of benzodiazepines
• Low doses tend to increase aggressive behavior
  whereas high doses decrease aggression (and have
  sedative effects

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GABAs Bitonic Effects
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Vasopressin and Social Aggression

• Vasopressin has been implicated in a number of
  agonistic behaviors
• Scent-marking
• Patrolling
• Social fighting
• There are three known types of vasopressin
  receptors
• V2R - in the periphery
• V1aR and V1bR - Brain receptors (also located in
  the periphery as well)

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V1bR and Social Aggression

• Male V1bR-KO mice have significantly reduced
  instances of aggressive behavior
• Both Latency and number of attacks during a
  resident intruder test are decreased

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Aggression in V1bR-KO and WT mice
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Social Recognition
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Social Preferences in V1bR-KOs

• Social preferences are also altered in V1bRKO
  mice
• Male KOs fail to exhibit normal social
  preferences
• KOs appear to have reduced motivation for social
  interaction

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Olfactory Discrimination in V1bRKOs

• Decreased aggression in V1bRKOs is not due to a
  deficit in Olfactory Discrimination
• Mice have no apparent olfactory defects
• KOs can still discriminate between male and
  female urine

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Olfactory influences on Aggression

• In general an intact olfactory system is needed
  for full expression of social aggression
• One caveat about bulbectomy studies is that
  removal of olfactory bulbs have many non
  olfactory related consequences
• Is social aggression mediated by the VNO?
• Lets check.

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Aggressive encounters in male TRPc2-KO mice
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Number of male-male mount attempts in male
TRPc-KO mice
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Vomeronasal influences on aggression

• It appears that aggressive behavior is inhibited
  in TRPc2-KO mice based on number of fighting
  episodes vs number of mounting episodes
• Things to think about
• Fighting is not eliminated (if intruder is not
  submissive fighting occurs)
• Is mounting behavior always sexual?
• If sex discrimination is not altered what other
  agonistic behaviors may overall mediate so
  social aggression in these mice.?

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Maternal Aggression
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Endocrine Patterns of Pregnancy in Rodents
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Ovarian hormones and Maternal aggression

• Ovarian hormones can modulate Maternal Aggression
• Can differ depending on the species
• Rats E Increases maternal aggression both before
  and especially after parturition
• Mice E delays maternal aggression withdrawal
  facilitates it.
• P increases aggression prior to parturition no
  effect after.
• It is possible that the primary actions of these
  hormones are in the periphery facilitating
  sensory mechanisms

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Sensory input

• Olfactory
• Pup odors are facilitory to maternal aggression
• Intruder odors are required for maternal
  aggression
• Somatosensory
• Nipple stimulation is critical for the display of
  maternal aggression
• Auditory
• Questionable role however ultrasounds from male
  rats intruders can inhibit aggression (and
  facilitate mating)

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Neural Correlates

• Markers for neuronal activity label familiar
  neural circuits during maternal aggression

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Neural Correlates

• Lesions of various neural circuits alter the
  expression of maternal aggression

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Neural Circuitry

• Olfactory bulb -- Sensory (olfactory) cues from
  both pups and intruder
• Amygdala -- Integration of sensory cues from both
  pups and intruder and central responses
• Peripeduncular nucleus (PPN) -- Somatosensory
  cues from pups
• Septum-- Maternal responsiveness in general
  (Motivation?) in decreased
• mPOA-- Unknown exact extent but is known to
  decrease aggression in general
• VMH-- thought to be critical site for critical
  site for transmitting to motor output regions
• PAG-- Tonical inhibits maternal aggression
  however not part of output since lesions after
  removal of pups is not effective

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Neurochemical Correlates

• 5-HT - jury is still out hypothesized to
  decrease maternal aggression based on effects in
  males on general aggression
• Some studies found this some did not
• Equally interesting correlation between low 5-HT
  in CSF and aggression may be a male phenomena
• Likely acting at PAG, Raphe Nuclei or Amygdala to
  inhibit aggression
• Actions in the septum increase aggression

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5-HT and Maternal Aggression

• In general 5-HT reduces maternal aggression in
  rats
• In mice results of 5-HT agonists and antagonists
  have been mixed
• And while 5-HT decreases aggresssion in male
  praire voles (those that are highly paternal) it
  doesnt effect maternal aggression

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Neurochemical Correlates

• GABA -
• GABA receptor activity suppresses maternal
  aggression
• Actions are likely in the VMH and MeA
• Interestingly PAG activity inhibits maternal
  aggression but GABA not involved
• Maternal Aggression could involve an inhibition
  of GABA transmission in the amygdala and VMH
• Dopamine -
• DA tonically inhibits Maternal aggression
• Lesions of Dopamine Neurons in VTA results in
  increased maternal aggression
• 6-OH-DA injected into striatum is unaffected
  thus likely not involved (in context of DA)
• Site of action would thus be MH and VMH

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Neurochemical Correlates

• Oxytocin
• Hypothesized that OT from PVN inhibits aggression
  but no real evidence.
• By contrast OT in Central amygdala increases
  maternal aggression in hamsters
• OTs importance for social recognition (olfactory)
  is most crucial factor
• Vasopressin
• Although no specific studies on maternal
  aggression believed to have similar functions as
  with male aggression
• Vasopressin in lateral septum therefore should
  increase aggressive behavior
• Unpublished data reports V1bR-KO mice have
  reduced maternal aggression (but reduced
  aggression in general)

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Neurochemical Correlates

• CRH
• Peripheral infusions of ATCH or ICV injection of
  CRH reduce maternal aggression
• Since CRH elevates fear and anxiety it is thought
  that decreases would be needed to express
  maternal aggression
• Opioids
• Opioids generally decrease maternal aggression
• Likely mechanism is indirect altering animals
  general activity/pain sensation or olfactory
  ability

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Neurochemical Correlates

• Nitric Oxide
• Male nNOS-KO mice are highly aggressive
• By contrast knocking out nNOS in females
  eliminates attacks
• Increases in citulline (the byproduct of NO
  synthesis is observed in the mPOA, SCN and
  subparaventricular zone in association with
  maternal aggression
• How NO is acting is unknown (5-HT ? CRH? AVP?)

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Neurochemical Correlates
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NO and Male Aggression

• Male nNOS-KO mice are highly aggressive
• There is a link between nNOS and 5-HT turnover
• This may be related to a hypo functioning of the
  5-HT1A and 5-HT1B receptors
• 5-HT agonists can decrease aggression in nNOS
  mice but significantly higher doses are required
• Reducing 5-HT turnover in the brain of WT mice
  mimics aggressive phenotype found in KO mice

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Predatory Aggression
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Predatory Aggression

• A simplified model of the neural circuitry the
  mediates predatory aggression in the cat
• Electrophysiological studies suggest monosynaptic
  projections from the LH to the midbrain tegmentum
  are responsible for attack behavior
• Projections from tegmentum connect to motor
  pathways, trigeminal and facial nerves

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Modulatory Pathways

• A number of sites modulate attack behavior
• Amygdala (annoyingly abbreviated ME here)
• BNST - often thought to be part of the extended
  amygdala
• PAG feeds back to the lateral hypothalamus
• Also Hippocampus, septum and just about any other
  limbic area you can think of

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Defensive rage

• The Medial Hypothalamus is the critical site for
  the initiation of defensive rage in cats
• The primary circuit being MH to the PAG
• PAG excites brain stem and spinal neurons causing
  autonomic and motor cascade resulting in behavior
• Amygdala modulates activity but is not critical
  for initiation of behavior

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VMH and AMH

• Interestingly while the VMH has historically been
  the site for initiation of defensive rage the
  source of efferents is the AMH
• The VMH stimulates the PAG via the AMH

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Neuroanatomical aspects of aggression in cats
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Neuroanatomical aspects of aggression in cats
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Neuroanatomical aspects of aggression in cats
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Neurochemical aspects of Defensive rage
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Neurochemical aspects of Defensive rage
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Neurochemical aspects of Defensive rage