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Neurobiology of Aggression and Violence: gy ggSystems, Intervention, and Impact
Neal G. Simon, Ph. D.ProfessorProfessor
Dept. of Biological SciencesLehigh University
Outline: Goals1 O i1. Overview
2. Regulatory Systemsa. hormonesb. neurotransmittersc. interactions
3. Intervention and Imaging3. Intervention and Imaging
4. Aggression as a Model for Disease
a. stress-related affective illness
5. Aging and Dieta. supplementsb impact on aggression and imp lsi itb. impact on aggression and impulsivityc. neurogenomics
6. Summary and Conclusions
Genetics: One Gene Models
Witkin et al (1976). Criminality in XYY and XXY men. Science
Saudou et al (1994). Enhanced aggressive behavior in mice lacking 5-HT1B receptor. Science
Nelson, et al. (1995) Behavioural abnormalities in male mice lacking neuronal nitric oxide synthase. Nature
Brunner et al. (1993) Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science
O (1997) B h i l ff t f t t di ti i l i PNASOgawa (1997). Behavioral effects of estrogen receptor gene disruption in male mice. PNAS
Merriman, Cameron (2007). Risk-taking: behind the warrior gene story. NZ Medical Journal
Complex Social Behaviors Integrate Multiple Gene Pathways: Neurogenomics
Economic Burden
• Violent Offenses: $70 billion
• Stress-Related Affective Illness: $125 billion
• Dementias $100 billion
TOTAL $295 billion
Biological Sciences
Aggression and Violence: A Systems Perspective
BEHAVIOR, LIFE EVENTS, & ENVIRONMENT
CIRCUITS
CELLS ADAPTATION
MOLECULES SIGNALS & TRANSDUCERS
GENES
Biological Sciences
Definitions
Conspecific Aggression
• Part of reproductionPart of reproduction
• Establishment of dominance status
• Access to Resources
Violence/Inappropriate Aggression
• Intent to harm and cause injury
Assault murder• Assault, murder
Sex Differences
Male Facilitation
T d M t b litT and Metabolites
Female Inhibition
DHEA
Female Inhibition
Biological Sciences
Target Systems
CHO
CH3
CH3
O
5-HT AVPOH
TESTOSTERONE
OH
GABA DHEA ESTRADIOL
Testosterone Steroid Dehydroepiandrosterone
Male Female
Testosterone Steroid Dehydroepiandrosterone(T) (DHEA)
Active
PREG S
E2 DHT T AE DHEAMetabolites
AndrogenReceptor GABA
TargetSystemSerotonin Vasopressin
INHIBIT ENHANCE ENHANCE ENHANCE
GABA AAndrogenSite of
5HT1A 5HT1 V1A AVP A
ReceptorRegulated
TranscriptionAction5HT1A, 5HT1B V1A, AVP
FACILITATION INHIBITIONEffect onAggression
MALES
HormonesHormones
• testosterone
• estradiol
NeurotransmittersNeurotransmitters
• serotonin
• vasopressin
www.about-charlotte-nc.com
Hormonal Hypothesesyp
• Causal: invariant and it’s all about testosterone
• Facilitative: a probabilistic model
• Neuromodulator: integrates endocrine, peptidergic, & neurochemical systems
Biological Sciences
Genomic Effects of TestosteroneMetabolism and Steroid Receptors Determine Effects in Target NeuronsMetabolism and Steroid Receptors Determine Effects in Target Neurons
aromataseSteroid Receptor Complexes
TER
AR
E2
T
DHT
ARARER
5α reductase ARDHT
mRNA
cofactorsGTFs
INTERACTINGAR AR
ARE ERE
RNA pol II
mRNA
DNA
INTERACTING
Enhancer Promoter
Neuroendocrine Regulatory Systems for Intermale Aggressiongg
Androgen Estrogen Combined or DirectAndrogen Estrogen Combined or Direct
Sensitive Sensitive Synergistic T
Male + + + + + + + ++ + high sensitivity + moderate sensitivity - insensitive
Biological Sciences
Androgenic Steroid Abuse: Roid Rage
www.byjamesraia.com phenomenaonbreak.wordpress.com
NeurotransmittersNeurotransmitters
5HT AVP
Serotonin System: Human Brain
Serotonin and Aggression
InhibitoryInhibitory
Pharmacology: 5HT1a and 5HT1b receptor
Genetics: Knockout Mouse
Human Impulsivity and HostilityHuman Impulsivity and Hostility
THERE IS AN INVERSE RELATIONSHIP BETWEENTHERE IS AN INVERSE RELATIONSHIP BETWEEN SEROTONIN FUNCTION AND AGGRESSION
Serotonin 1a Receptor
cnsforum.com
Serotonin 1a Receptor: A GPCR Second Messenger System
Signal Integration: Testosterone and Serotonin
Neuroendocrine Neurochemical
Serotonin (5-HT)Testosterone
5-HT1A/1B 5-HT TransporterAndrogenic Estrogenic
?Biological Sciences
Summary: Males
• Multiple Steroidal Pathways• Multiple Steroidal Pathways
• Androgenic Modulation: Permissive
• Estrogenic Modulation: Restrictive
Biological Sciences
Vasopressin: A Facilitator of Aggressiongg
• Established link to aggressionEstablished link to aggression
T t t D d t• Testosterone Dependent
• Interface with serotonin system
Biological Sciences
Sexual Dimorphism in Vasopressin Fibers in R t L t l S tRat Lateral Septum
Female Male
De Vries and Simerly, 2002
Vasopressin: Biological Diversity
Invertebrate & Vertebrate Vertebrate BehaviorPhysiology
fluid regulation
Vertebrate Behavior
communicationg
carbohydrate metabolism
thermoregulation
sexual behavior
pair bondingthermoregulation
reproductive function
pair bonding
paternal/maternal care
social memory
aggression
stress-related disorders
Brain Vasopressin System
• Vasopressin Neurons Localized to PVN, SON, Accessory Nuclei, BNST and Medial Amygdala
• V1a and V1b Receptors MediateV1a and V1b Receptors Mediate Behavioral Effects of AVP
V1B in Rat Pituitary CorticotrophsV1A Hamster
Patients with Violent Personalities Have Blunted Serotonin Activity and Elevated CSF Vasopressin
• Patients with history of “fighting & assault” show weak prolactin response to fenfluramine challenge.
Coccaro et al., 1998
• Prolactin levels are negatively correlated with CSF vasopressin levels.
Imaging and Intervention
fMRI: Imaging Aggression in Awake Animals
Piloerection is used as an indicator of autonomic activation
Social Arousal in the Imaging Environment
Vasopressin 1a Antagonism Blocks Aggression
Social Stress/Arousal in Response to an Intruder Male
Activated Pathway After Oral SRX251y
Vasopressin 1a Antagonism Blocks Aggression
Amygdala Cortex Hippocampus Thalamus
ntru
der
Mat
e &
Inm
ent
51 T
reat
mSR
X25
Summary
•Testosterone and its metabolites maintain AVP fibers and V1a receptor integrity
• Vasopressin receptor antagonists may represent a novel intervention strategy for inappropriate aggressionintervention strategy for inappropriate aggression and stress-related indications
Biological Sciences
Aggression as a Model for Stress-related Affective Illness
Hypothalamic-Pituitary-Adrenal Axis
STRESSCortex
STRESS
Hippocampus Amygdala Neurotransmitters
Hypothalamus
CRFAVP
Pituitary
CRF
CortisolAdrenal
AVP
Cortisol
ACTH
Adrenal Cortex
adapted from cnsforum.com
Normal and Atypical Responses to Stress: Allostatic Load
McEwen (2007) Physiol. Rev.
Social Subjugation/Chronic Defeat: Ph i l i l Eff t & CPhysiological Effects & Consequences
• Cortisol dysregulation
• Conditioned defeat • Depression
• Testosterone suppression
• AVP suppression
• Anxiety
• Cardiovascular DiseaseAVP suppression
• 5HT hyperactivity
Cardiovascular Disease
• Immune Compromise
• Biogenic amine changes
Biological Sciences
Vasopressin is Linked to Stress-related DisordersR. Landgraf (2006). Involvement of the vasopressin system in stress-related disorders. CNS
& Neurological Disorders – Drug Targets 5, 167-179
Synthesis, content, and release of AVP in PVN in HAB and LAB rats under basal and stress conditions
Panic Disorder and 5HT-1a Receptor
Statistically-analyzed PET scan data superimposed onStatistically analyzed PET scan data superimposed on structural MRI scan (front of brain is at right) shows areas in the anterior and posterior cingulate where panic disorder patients had nearly one third fewer serotonin 5-HT1A receptors compared to healthy
t l bj t Th li ht th l th t th
PET scan shows distribution of serotonin 5-HT1A receptors (front of brain is at top), which were reduced by about a third in the raphe (Ra) in panic disorder patients control subjects. The lighter the color, the greater the
difference between patients and controls.disorder patients.
Neumeister et al (2004) J Neurosci
Signal Processing in Depression
http://www.nimh.nih.gov/press/DeisserothDepressionCrossroadsBigger.mp4p gg p
Summary
• Chronic subjugation disrupts conspecific aggresssion
• Ph siological changes in hormone and ne rochemical• Physiological changes in hormone and neurochemical function mimic stress-related disorders
B l b t AVP/5 HT i iti l• Balance between AVP/5-HT is critical
• Testosterone and its metabolites maintain AVP fibers and V1A t i t itV1A receptor integrity
• Vasopressin receptor antagonists may represent a novel intervention strategy for inappropriate aggressionintervention strategy for inappropriate aggression and stress-related indications
Biological Sciences