Transcript Testosterone, Aggression, and Impulsivity

Testosterone, Aggression, and
Impulsivity in Rats
Erik Manke
March 7, 2014
Steroids vs. Water Bottle
http://www.youtube.com/watch?v=Yn5iIF95Qho
Arnold Visits Hans and Franz
http://screen.yahoo.com/pumping-hans-franzarnold-schwarzenegger-000000067.html
Defining Impulsivity
• Kerman et al. 2011
– Marked decreases in behavioral/emotional control,
lack of perception, brash decision making
• Batrinos 2012
– Lack of restraint, disuse of PFC, absence of inhibition,
and emotionality
• Wood et al. 2013
– Immediate disregard in decision making, impatience,
short term decisions, and reactive aggression
Testosterone and Impulsivity
• Kerman et al. 2011
– bHR rats (impulsive phenotype)  Increased
Aggression  Increased Testosterone x2 and
Corticosterone
• Batrinos 2012
– Testosterone  Activated Amygdala  Increased
Emotional Activity  Decreased Pre-frontal
Inhibition of Motor Control
• Wood et al. 2013
– Testosterone Increased Aggression but Reduced
CPu TH  Decrease Impulsivity
Questions/Themes/Hypotheses
• Kerman et al. 2011
• Hypothesis- bHR rats = higher aggression,
altered 5-HTergic cells in brainstem
• Compare/contrast bHR/bLR rats’ behaviors,
neurochemistry, and hormone levels
• Differential expression of Tph2 and Sert versus
c-fos in rats depending on brain region and
phenotype
Questions/Themes/Hypotheses (cont.)
• Batrinos 2012
• Relationship of Testosterone and Cortisol
• Testosterone  Activated Amygdala  Increased
Emotional Activity  Decreased Pre-frontal
Inhibition of Motor Control (increased
impulsivity)
• Cortisol  Increased Pre-frontal cortex control
(decreased impulsivity)
• Seratonin  Inhibits motor impulsivity
• Testosterone, cortisol, and serotonin form a triad
Questions/Themes/Hypotheses (cont.)
• Wood et al. 2013
• How do AAS affect impulsivity? Through DA?
– Acb, CPu, PFC, and VTA/SN
• AAS  Aggressive Behavior  DA from
Hypothalamus  Increased aggression and
Impulsivity
Kerman et al. 2011 High/Low Responder Rats
bHR and bLR Rats
• Selectively-bred high and low responder rats
• Many generations bred for distinct behaviors
• bHR rats = Phenotypically impulsive
– “…heightened novelty-induced exploration,
impulsivity, and increased sensitivity to drugs of
abuse.”
• bLR rats = Phenotypically non-impulsive
– “…exaggerated depressive and anxiety-like
behaviors.”
Serotonin
• Key role in aggressive responses
• Influx upon resident/intruder experiments
• Measured by Tph2 (synthesis) and Sert
(reuptake) gene expression
• Expression inhibits c-fos expression
• Expect high Tph2 and Sert in bHR rats
• Expect high c-fos in bLR rats
Figure 1: Behavioral differences between bHR and bLR rats
Figure 2: Relative
Testosterone/Corticosterone Levels in
bHR versus bLR rats before and after
intrusion
Figure 3: Serotonergic cell groups in rat
brainstem sections caudal (A) to rostral (T)
Figure 4: Tph2 (top) and Sert (bottom) expression differences between bHR rats (left) and
bLR rats (right)- Significance in B9 cell group and pontomesencephalic reticular formation
Figure 5: Greater Tph2 expression in bHR rats compared to bLR rats
Figure 6: Greater Sert expression in bHR rats compared to bLR rats
Figure 7: Sert expression (red)
and c-fos expresssion (green) and
overlay in bLR (left) versus bHR
(right)
Figure 8: c-fos expression greater in bLR rats compared to bHR rats in certain
regions
Batrinos 2012 Testosterone and (He?)Man
I Said Hey!
The triad
• Testosterone vs. Cortisol/Serotonin
• PET and fMRI allow locality and interactions to
be determined
• Ratios determine aggressiveness, anti-social
behavior, anger, and possibly impulsiveness
Testosterone
•
•
•
•
Associated with aggression/anti-social behavior
Violent vs. non-violent prisoners
Testosterone dosing
CAG repeats in human androgen receptor
promoter
• Testosterone  Amygdala  Reduced prefrontal cortex inhibition (higher impulsivity)
• Local brain testosterone > effect than circulatory
Cortisol
•
•
•
•
Antagonist to testosterone
Inhibits GnRH
Linked to submissive behavior
Cortisol  Testosterone  Decreased
Impulsivity
• Testosterone inhibits CRH
• Testosterone/Cortisol ratio may predict
impulsivity
Serotonin
• Counteracts testosterone
• Regulates impulsivity and aggressiveness
• Both activating and inhibitory neurons in prefrontal and subcortical areas
• High pre-frontal serotonin = low impulsivity
Wood et al. 2013 ‘Roid rage in rats?
Nose Poke Test
• Male rats trained for nose poke response to
light for potential fight
• Resident/Intruder Model (5 min)
• FI10 Schedule
• Measure operant response
• Measure acts of aggression
Figure 1: Operant Responses
Significant differences= *
-No difference between
testo/vehicle for operant
responses/rate
-Testo rats fought
more/earlier
-Vehicle rats in contact
more often/longer
-
Delayed-Discounting Procedure
•
•
•
•
•
2 retractable levers with control on sides
Light stimulus
70 s trial with 10 s response window
Initially equal rewards 1 forced trial
Large reward delay increased by 15 s
increments
• Impulsive = immediate reward (1 pellet)
• Not Impulsive = delayed reward (4 pellets)
Figure 2: Delay-Discounting
Impulsivity
-No significant differences
between Vehicle/Testo Rats
-Tested body weight (A)
-Food per session (B)
-Food per day (C)
-Unreinforced Trials per
session (D)
Figure 3: Large Reward Preference
-Small/Immediate reward=
impulsive preference
-Large/Delayed reward=nonimpulsive preference
-Only significant at 45 second
delay
-Trend
-Q: Why are testosterone
rats less impulsive?
A: Look at Immunoblots
Western Immunoblot
• 20 week old rat brains
• Measure target protein (TH) levels
– PFC, Acb, CPu, VTA/SN
• Primary Antibodies for TH and beta-tubulin
• Secondary Antibodies for fluorescence
• Ratio of TH to beta tubulin measured
Tyrosine Pathway
TH
Rate limiting enzyme
Figure 4: Western Immunoblot
(Top) and TH Levels (Bottom)
-Top-Caudate/Putamen TH
and beta tubulin protein
expression
-Bottom- Testo/Vehicle TH
levels only significantly differ
in the Caudate/Putamen
-Q: What does this mean?
A: CPu causes disinhibition
of thalamus increasing
impulsivity
Reactive vs Proactive Aggression
Chris Benoit 2007 Double Murder Suicide
Answering the Focal Questions
•
•
•
•
Kerman et al. 2011
Impulsive phenotype (bHR)
Increase in Aggression  increase 5-HT
Two fold increase in testosterone and
corticosterone
• Increased Tph2 and Sert expression
• Decreased c-fos expression
• bHR rats exhibit elevated gene expression
levels causing elevated aggression (possibly
impulsivity?)
Answering the Focal Questions (cont.)
• Batrinos et al. 2012
• Testosterone/cortisol ratio and serotonin
levels form impulsiveness regulatory triad
• Primary interaction = amygdala and prefrontal cortex
• Aggression and Impulsiveness closely tied
Answering the Focal Questions (cont.)
• Wood et al. 2013
• TH levels in Acb, VTA/SN, and PFC = same in
Immunoblot study for vehicle/testo
• CPu TH lower and delayed reward higher in
testo reflected lower impulsivity
• Testosterone does not  Greater impulsivity
• Testosterone may  Less impulsivity
Final Thoughts/Conclusions
• Three modes of thinking regarding testosterone
and impulsivity:
1. Phenotypic impulsivity  higher aggression 
higher testosterone
2. Increased testosterone  decrease pre-frontal
cortex motor control  increase impulsivity
3. Testosterone Increased Aggression but
Reduced CPu TH  Decrease Impulsivity
Works Cited
Batrinos, M. L. 2012. Testosterone and aggressive behavior in
man. International Journal of Endocrinology & Metabolism
10(3): 563-568.
Kerman, I. A., Clinton, S. M., Bedrosian, T. A., Abraham, A. D.,
Rosenthal, D. T., Akil, H., & Watson, S. J. 2011. High
novelty-seeking predicts aggression and gene expression
differences within defined serotonergic cell groups. Brain
Research 1419: 34-45.
Montoya, E. R., Terberg, D., Bos, P. A., & Van Honk, J. 2011.
Testosterone, cortisol, and serotonin as key regulators of
social aggression: A review and theoretical perspective.
Motivation and Emotion 36: 65-73.
Wood, R. I., Armstrong, A., Fridkin, V., Shah, V., Najafi, A., &
Jakowec, M. 2013. ‘Roid rage in rats? Testosterone effects
on aggressive motivation, impulsivity and tyrosine
hydroxylase. Physiology & Behavior 110- 111: 6-12.