Aggressive Behavior

Neuroendocrinology Kevin Kelliher

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

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

Aggression and Testosterone

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

Testosterone levels don’t 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

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

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

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

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)

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

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

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

GABAs Bitonic Effects

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)

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

Aggression in V1bR-KO and WT mice

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Social Recognition

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

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

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….

Aggressive encounters in male TRPc2-KO mice

Number of male-male mount attempts in male TRPc-KO mice

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.?

Maternal Aggression

Endocrine Patterns of Pregnancy in Rodents

5 10 15 211 18 22

Progest erone

Placental Lactogens

Est radiolProlact in Surges

adapt ed f rom Bridges 1996 and Grat t an 2001

Day of Pregnancy

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

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)

Neural Correlates

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

OlfactoryBulb

BNST

MePD

VMH

mPOA

PPN

PVN

VentrolateralSeptum

cFos pCreb

CoA

Neural Correlates

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

OlfactoryBulb

Insularprefrontalcortex

Mediodorsalthalamicnucleus

MePD

VMH

mPOA

PPNPVN

Septalnucleus

Lesions decrease maternal aggression

Lesions increase maternal aggression

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

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

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 doesn’t effect maternal aggression

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

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)

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

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?)

Neurochemical CorrelatesDrug Function Effect on Maternal Behavior when given via

5-HTP 5-HT precurser Reduces Aggression Systemicfluprazine 5-HT1 receptor agonist Reduces Aggression Systemicfluvoxamine 5-HT reuptake inhibitor Reduces Aggression Systemicfluoxetine 5-HT reuptake inhibitor Reduces Aggression SystemicRU24969 nonspecific 5-HT1 agonist Reduces Aggression Systemiceltoprazine nonspecific 5-HT1 agonist Reduces Aggression SystemicTFMPP nonspecific 5-HT1 agonist Reduces Aggression/no effect Systemic

8-OH-DPAT 5-HT1A receptor agonistReduces Aggression/no effect/increases aggression

Systemic, ICV, cPAG,septum

isapirone 5-HT1A receptor agonist Reduces Aggression Systemic, ICVbuspirone 5-HT1A receptor agonist Reduces Aggression SystemicDOI 5-HT2A/C receptor agonist Reduces Aggression SystemicPCPA 5-HT Synthesis Inhibitor Reduces Aggression Systemicmianserin 5-HT receptor antagonist Reduces Aggression Systemicmethysergide 5-HT receptor antagonist Reduces Aggression Systemicmethiothepin 5-HT receptor antagonist Reduces Aggression Systemicrianserine 5-HT2A/C receptor antagonist no effect Systemicondansetron 5-HT3 receptor antagonist no effect SystemicMDL72222 5-HT3 receptor antagonist no effect Systemic

benzodiazepines (CDP, diazepam, oxazepam and alprazolam) GABA receptor agonists Increase Aggression SystemicCaffeine, FG7142, Pentylenetrazol benzodiazepine antagonists Reduces Aggression Systemic

Bicuculline GABA receptor antagonist Reduces AggressionInjected into VMH or MeA

Bicuculline GABA receptor antagonist no effect PAGmuscimol GABAA receptor agonists no effect PAG6-OH-DA Excititory lesion of DA system Increase Aggression ICV or VTA

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

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

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

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

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

Neuroanatomical aspects of aggression in cats

Neuroanatomical aspects of aggression in cats

Neuroanatomical aspects of aggression in cats

Neurochemical aspects of Defensive rage

Neurochemical aspects of Defensive rage

Neurochemical aspects of Defensive rage