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Simon_090507
Course: BIOS 95, Spring 2008School: Lehigh
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of Neurobiology Aggression and Violence: gy gg Systems, Intervention, and Impact Neal G. Simon, Ph. D. Professor Dept. of Biological Sciences Lehigh University Outline: Goals 1. Overview 1 O i 2. Regulatory Systems a. hormones b. neurotransmitters c. interactions 3. Intervention and Imaging 4. Aggression as a Model for Disease a. stress-related affective illness 5. Aging and Diet a. supplements b. b impact on...
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of Neurobiology Aggression and Violence: gy gg Systems, Intervention, and Impact
Neal G. Simon, Ph. D. Professor Dept. of Biological Sciences Lehigh University
Outline: Goals
1. Overview 1 O i 2. Regulatory Systems a. hormones b. neurotransmitters c. interactions 3. Intervention and Imaging 4. Aggression as a Model for Disease a. stress-related affective illness 5. Aging and Diet a. supplements b. b impact on aggression and impulsivity imp lsi it c. 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 Ogawa (1997). B h i l effects of estrogen receptor gene disruption in male mice. PNAS O (1997) Behavioral ff t f t t di ti i l i 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:
Stress-Related Affective Illness: Dementias
TOTAL
$70 billion $125 billion $100 billion
$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 reproduction Establishment of dominance status Access to Resources
Violence/Inappropriate Aggression Intent to harm and cause injury Assault murder Assault,
Sex Differences
Male
T and Metabolites d M t b lit
Facilitation
DHEA
Female
Inhibition
Biological Sciences
Target Systems
O CH3 CH3
O
5-HT
AVP
TESTOSTERONE
OH
OH
GABA
DHEA
ESTRADIOL
Male
Testosterone (T)
Female
Steroid
Dehydroepiandrosterone (DHEA)
Active
E2 DHT T AE DHEA
Metabolites
PREG S
Serotonin
Vasopressin
Target System
Androgen Receptor
GABA
INHIBIT
ENHANCE
ENHANCE
ENHANCE
5HT1A, 5HT1 1B
V1A, AVP
Site of Action
Androgen Regulated Transcription
GABA A Receptor
FACILITATION
Effect on Aggression
INHIBITION
MALES
Hormones testosterone estradiol Neurotransmitters serotonin vasopressin
www.about-charlotte-nc.com
Hormonal Hypotheses yp
Causal: invariant and it's all about testosterone Facilitative: a probabilistic model Neuromodulator: integrates endocrine, peptidergic, & neurochemical systems
Biological Sciences
Genomic Effects of Testosterone
Metabolism and Steroid Receptors Determine Effects in Target Neurons Steroid Receptor Complexes E2 T
5 reductase
DHT
aromatase
ER AR AR
ER
AR
AR
T
cofactors
AR AR
GTFs INTERACTING RNA pol II mRNA
DNA
ARE ERE
Enhancer
Promoter
Neuroendocrine Regulatory Systems for gg Intermale Aggression
Androgen Sensitive Male
Estrogen Sensitive
Combined or Synergistic
Direct T
++
+
++
moderate sensitivity
++
-
++
insensitive
+ + high sensitivity
Biological Sciences
Androgenic Steroid Abuse: Roid Rage
www.byjamesraia.com
phenomenaonbreak.wordpress.com
Neurotransmitters
5HT
AVP
Serotonin System: Human Brain
Serotonin and Aggression
Inhibitory Pharmacology: 5HT1a and 5HT1b receptor Genetics: Knockout Mouse Human Impulsivity and Hostility THERE 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
Testosterone
Androgenic Estrogenic
Neurochemical
Serotonin (5-HT)
5-HT1A/1B 5-HT Transporter
Biological Sciences
?
Summary: Males
Multiple Steroidal Pathways Androgenic Modulation: Permissive Estrogenic Modulation: Restrictive
Biological Sciences
Vasopressin: A Facilitator of Aggression gg
Established to link aggression T t t Testosterone Dependent D d t Interface with serotonin system
Biological Sciences
Sexual Dimorphism in Vasopressin Fibers in Rat Lateral Septum R tL t lS t
Female
Male
De Vries and Simerly, 2002
Vasopressin: Biological Diversity
Invertebrate & Vertebrate Physiology
fluid regulation g carbohydrate metabolism thermoregulation reproductive function
Vertebrate Behavior
communication sexual behavior 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 Mediate
Behavioral Effects of AVP V1A Hamster V1B in Rat Pituitary Corticotrophs
Patients with Violent Personalities Have Blunted Serotonin Activity and Elevated CSF Vasopressin
Patients with history of "fighting & assault" show weak
fenfluramine challenge.
prolactin response to
Prolactin levels are negatively correlated with CSF vasopressin levels.
Coccaro et al., 1998
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 y
After Oral SRX251
Vasopressin 1a Antagonism Blocks Aggression
Amygdala
Mate & In ntruder
Cortex
Hippocampus
Thalamus
SRX25 Treatm 51 ment
Summary
Testosterone and its metabolites maintain AVP fibers and
V1a receptor integrity
Vasopressin receptor antagonists may represent a novel
intervention strategy for inappropriate aggression and stress-related indications
Biological Sciences
Aggression as a Model for Stress-related Affective Illness
Hypothalamic-Pituitary-Adrenal Axis
STRESS
Cortex
Hippocampus
Amygdala
Neurotransmitters
Hypothalamus CRF AVP Pituitary
AVP
Adrenal Cortex
Cortisol
ACTH
adapted from cnsforum.com
Normal and Atypical Responses to Stress: Allostatic Load
McEwen (2007) Physiol. Rev.
Social Subjugation/Chronic Defeat: Physiological Eff t Ph i l i l Effects & Consequences C
Cortisol dysregulation Conditioned defeat Testosterone suppression AVP suppression 5HT hyperactivity Biogenic amine changes
Biological Sciences
Depression Anxiety Cardiovascular Disease Immune Compromise
Vasopressin is Linked to Stress-related Disorders
R. 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
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 patients.
Statistically analyzed Statistically-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 control subjects. The lighter the color, the greater the t l bj t Th li ht th l th t th difference between patients and controls.
Neumeister et al (2004) J Neurosci
Signal Processing in Depression
http://www.nimh.nih.gov/press/Deisser othDepressionCrossroadsBigger.mp4 p gg p
Summary
Chronic subjugation disrupts conspecific aggresssion Ph siological changes in hormone and neurochemical Physiological ne rochemical
function mimic stress-related disorders
B l Balance b t between AVP/5-HT i critical AVP/5 HT is iti l Testosterone and its metabolites maintain AVP fibers and
V1A receptor i t t integrity it
Vasopressin receptor antagonists may represent a novel
intervention strategy for inappropriate aggression and stress-related indications
Biological Sciences
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