Testosterone, Aggression, and Impulsivity in Rats

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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-franz-arnold-schwarzenegger-000000067.html. Defining Impulsivity.
Testosterone, Aggression, and Impulsivity in RatsErik MankeMarch 7, 2014Steroids vs. Water Bottlehttp://www.youtube.com/watch?v=Yn5iIF95QhoArnold Visits Hans and Franzhttp://screen.yahoo.com/pumping-hans-franz-arnold-schwarzenegger-000000067.htmlDefining 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 RatsbHR 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 ratsFigure 2: Relative Testosterone/Corticosterone Levels in bHR versus bLR rats before and after intrusionFigure 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 formationFigure 5: Greater Tph2 expression in bHR rats compared to bLR ratsFigure 6: Greater Sert expression in bHR rats compared to bLR ratsFigure 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?)ManI 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 pre-frontal 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 pre-frontal 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/longerDelayed-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=non-impulsive preference-Only significant at 45 second delay-Trend-Q: Why are testosterone rats less impulsive? A: Look at ImmunoblotsWestern 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 PathwayTH Rate limiting enzymeFigure 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 impulsivityReactive vs Proactive AggressionChris Benoit 2007 Double Murder SuicideAnswering 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 pre-frontal 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 testosterone2. Increased testosterone  decrease pre-frontal cortex motor control  increase impulsivity3. Testosterone Increased Aggression but Reduced CPu TH  Decrease ImpulsivityWorks CitedBatrinos, 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.
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