Behavioral Neuroscience II
BNST – Homosexuality & Transexuality
• Somatostatin innervation by the amygdala was neurons were quantified in the BNST in the 4
groups (42 subjects).
• Men had almost twice as many somatostatin neurons as women.
• The number of neurons in the BNST of male-to-female transsexuals was similar to that of the
Week 7, Class 1: Aggressive Behavior
• Aggression: from Latin, ad-gradior – “I move forward” (i.e. approach)
• Specific type of approach: approach with intent to harm
• ‘‘Behavior that inflicts harm and injury or threatens to do so’’ (Berkowitz, 1993)
• ‘‘Any form of behavior directed toward the goal of harming or injuring another living being
who is motivated to avoid such treatment’’ (Baron and Richardson, 1994)
Aggressive behavior can be critical for species survival (adaptive behavior)
• Can be used to obtain food, water, and other resources, including female mates in the case
of males, and to defend its territory, offspring, or social rank (Takahashi and Miczek, 2013)
o Aggressive behavior is sometimes essential for survival
• Carries the associated risks of injury or even death
o One has to judge whether to be aggressive or not
• The exercise of aggressive behavior is determined by a cost-benefit analysis
• When this balance is disrupted and an animal shows an exaggerated level of aggression, the
behavior is no longer adaptive, and it could be called maladaptive or pathological aggression
(i.e. escalated aggression)
o When aggression escalates to dangerous, uncontrollable levels.
Neural control of aggressive behavior: The Hypothalamus
• Electrical stimulation of the hypothalamus elicits aggressive behavior in cats
o Two forms of aggressive behavior in cats:
▪ Defensive rage (growling, meowing, yowling, hissing,..)
• Obtained when stimulating one particular area
▪ Predatory attack (upon stimulation, the cat will bite an anesthetised rat)
• Obtained when stimulating another area
• Sometimes called “Quiet Biting” Amygdala - Hypothalamus – PAG
• Electrical Stimulation Techniques have allowed us to identify different areas of the brain
involved in Aggressive behaviors.
o Amygdala, Hypothalamus, Periaqueductal Grey
o Responses are also mediated by input from the VTA and the mPFC (Medial Pre-
• Control of Defensive Rage:
o Central Nucleus & Basal Nucleus from the Amygdala send projections to Dorsal PAG
o Medial Nucleus sends projections through the Hypothalamus to the Dorsal PAG
o Stimulating the medial hypothalamus in cats thus induces Defensive Rage
• Predation Behavior
o Medial Hypothalamus projects to the Lateral Hypothalamus, from there, the signal
goes to the Ventral PAG which controls predation
o Stimulating the Lateral Hypothalamus in cats will induce Predatory Attack
• Impulsive, unplanned
• Planned, goal-directed
o Cat walks calmly
towards rat before
Neural control of aggressive behavior – Role of Dopamine and Serotonin
o The male ‘resident’ rats confronted a smaller naive ‘intruder’ male.
o Dopamine levels increase in the Nucleus Accumbens during and after an aggressive
▪ Resident Intruder Paradigm
o The extended duration of the DA response might reflect the expectation of /
preparation for the possibility of a second fight
• Study – 2:
o The male ‘resident’ rats confronted a smaller naive ‘intruder’ male.
o Dopamine levels increase in the prefrontal cortex after an aggressive episode
o The levels of serotonin decreased during and after the fight. Nucleus Accumbens – Dopamine reinforces aggressive behavior
• D1- and D2-like receptor antagonists were infused into the NAcc of male rats prior to the
• Goal-directed aggression Experimental set-up
o In this set-up male mice will nose-poke in a hole for an opportunity to fight an
o Mice were trained to nose- poke in the assigned active hole a certain number of
times after which the house light was turned on and an intruder is introduced into
o Fighting is allowed to take place for a certain period of time after which the house
light dimmed and the intruder Removed.
• Both antagonists reduced the motivation to fight in a dose-dependent manner
o However, the drug did not did not alter motor activity indicating that the effects were
not secondary to motor deficits.
o Less nose-pokes per minute with increasing antagonist concentrations
• D1- and D2-like receptor antagonists also reduced percent time spent aggressing the
intruder during the encounters.
o Less biting, Less tail-rattling.
Serotonin: Lesioning Midbrain Raphe Nuclei
• Raphe nuclei contains the cell bodies of serotonergic neurons which project to different
areas of the brain (hippocampus, amygdala, hypothalamus, …)
o RN is found in the brain stem
• Lesioning the midbrain Raphe in male rats decreases the levels of serotonin in the forebrain
and induces intraspecific aggressiveness (towards another male).
Serotonin and aggressive behaviour in non-human primates
• In this study, they measured the levels of the serotonin metabolite 5-HIAA in the CSF in male
• 4 categories of Aggressive behaviour were described:
2. Stationary threats
4. Physical assault.
• “Escalated Aggression” was defined as the percent of aggressive encounters that were
Chases (dangerous long leaps at great heights between treetops) or Physical Assaults
• Low CSF 5-HIAA was associated with an increased probability of initiating aggressive
behaviors that escalated to class 3 or 4.
• Serotonin and impulsivity
o Low CSF 5-HIAA was associated with a high proportion of spontaneous, unprovoked
long leaps (associated with impulsive aggressive behavior). Serotonin and social dominance
• Social dominance: the competent behaviour of one animal who dominates the others (non-
• Female rhesus monkeys study:
o A single piece of fruit is thrown into the group and 3 behaviors are scored:
▪ Displacements, threats and chases.
o A female was considered more dominant than another when it won more encounters
than it lost with another monkey.
• Low levels of 5-HIAA in the CSF was not associated with high social ranking but with low
• Serotonin and fight wounds
o The levels of 5-HIAA were also low in the CSF of excessively aggressive females that
had to be removed because of severe fighting (or for treatment of fight wounds).
Serotonin and Mortality
• The rate of mortality was measured over a 4-year period from 49, 2-year-old prepubertal
male rhesus monkeys. Aggressive behavior was also monitored.
• Low levels of 5-HIAA in the CSF were associated with high mortality.
o Dead subjects had initiated escalated aggression which has a high probability of
trauma or injury, at a higher rate than subjects that remained alive.
• Low CSF 5-HIAA concentrations quantified early in life is a powerful biological predictor of
future excessive aggression, risk taking, and premature death among non-human primate
Serotonin depletion and aggressive behavior
• Monkeys were separated in 3 groups receiving amino-
o T+ Tryptophan supplemented
o B Nutritionally balanced
o T- Acute tryptophan depleted.
▪ Recall, low tryptophan leads to low
• Acute tryptophan depletion increases both spontaneous
and competitive aggression in male monkeys.
• Tryptophan supplementation decreases competitive aggression in both males and females.
• Competitive aggression: aggressive behaviour displayed after food is newly placed in the
feeder. Sex hormones and aggressive behavior
• Castration of male mice reduces aggressiveness (no fighting) and injections of testosterone
• Testosterone in male rodents:
o Adult male rodents are more aggressive than females.
▪ This is also the case in other species, even humors!
o Adult males fight for territory or access to females.
o Racall: Androgen secretion occurs prenatally, decreases and then increases again
▪ Intermale aggressiveness also begins around puberty
Female Aggression facilitated by testosterone
• Female rodents are less likely to fight than males.
• Aggression between females is facilitated by testosterone
• Ovariectomized female rats were given daily injections of estradiol, testosterone or placebo
for 14 days.
• Animals were placed in a test cage and an unfamiliar female was introduced.
o Frequency of fighting was higher in the Testosterone group compared to Estradiol
Prenatal exposure to androgens increases female aggression
• Rodent foetuses share the uterus with brothers and sisters.
• A female may have:
o Zero (0M)
o 1 (1M), or
o 2 (2M) brothers adjacent to her.
• Being next to a male increases the female’s blood levels of androgens.
• When tested as adults, 2M females showed increased inter-female aggressiveness.
Testosterone and serotonin
• In this study, they measured the levels of testosterone in the CSF (Cerebro-Spinal Fluid) of
male rhesus monkeys.
• Testosterone concentrations were positively correlated with increased aggressivity
(competitive behavior) but not increased impulsivity.
• High CSF testosterone levels further increased the rates and intensity of aggression in
subjects with low CSF 5-HIAA. (Low Levels of serotonin)
• Ablation of Progesterone-Receptor-expressing neurons located in the ventromedial
hypothalamus (VMH) reduces aggression in male rats
o Less attacks, Shorter attacks, less bites, etc. Summary
• Dopamine levels increase in the nucleus accumbens and the prefrontal cortex during and
after an aggressive episode
• Dopamine reinforces aggressive behaviour.
• Serotonin levels decrease in the prefrontal cortexduring and after an aggressive episode.
• Low serotonin levels are associated with increased aggressiveness, increased impulsivity
(impulsive-aggressive behaviour), low social rankings and high mortality rate.
• Testosterone levels positively correlate with aggressive behaviour.
• In ovariectomized female rodents, fighting is facilitated by testosterone.
• Prenatal exposure to androgens increases inter-female aggressiveness.
• Destruction of progesterone-receptor expressing neurons in the VMH reduces aggressive
behaviour in male rats.
Aggressive Behavior Studies in humans
Serotonin and suicide (aggression-related behavior
• The incidence of suicidal acts was studied in 68 depressed patients and related to the level of
5-HIAA in the CSF.
• Patients in the low 5-HIAA mode (below 15 ng/ml) attempted suicide significantly more often
than those in the high mode, and they used more violent means.
Low CSF 5-HIAA and Aggression
• Two studies conducted in male military personnel referred to psychiatric services due to
• Histories of aggressive behaviours and suicide attempts were significantly associated with
each other and with low levels of CSF 5-HIAA.
ATD increases impulsivity
• ATD – Acute Tryptophan Depletion
• Go/No-Go task (eight 2 digit numbers)
o Subject must press the button at the Active numbers
▪ Correct responses were rewarded with a high-
pitched tone and presentation of the word
“Correct” on the computer screen, and the
addition of 10 cents to the participant’s
▪ Incorrect responses were punished by a low-
pitched tone, presentation of the word
“Wrong,” and subtraction of 10 cents from the
participant’s earnings. Go/No-Go continued:
o Commission errors: failures to inhibit responses to passive numbers
o Omission errors: failures to respond to active numbers.
• In young men (18-25yrs) with a multi-generational family history of alcoholism, acute
tryptophan depletion (ATD) increased commission errors on a Go/No-Go task, a measure of
• Results suggest that people who are at risk for alcoholism (and other impulsive behaviors)
have easily perturbed 5HT systems.
• One possibility is that their serotonin system is functioning at the bare minimum level for
normal functioning, but that if you lower it slightly, its ability to properly regulate impulse-
control is lost.
ATD increases aggression
• Male subjects:
1. Trp depleted beverage
3. Trp containing beverage
• ATD increased aggressive Responding in the Point Substraction Aggression Paradigm (PSAP).
• Aggressive responding was provoked only in subjects with high trait hostility levels,
(measured on a personality questionnaire Buss-Perry Aggression Questionnaire).
o Hostile men may be more prone to behavior change induced by the perturbation
ofthe 5-HT neurotransmitter system
• Point Substraction Aggression Paradigm
o Subjects are presented with 2 buttons A and B. They have to press button A to earn
money (100times = 20 point which they would be paid for at the end of the
o Every once in a while, they suddenly have money subtracted from their total, and
they are told that this was done by another subject who was doing the same task
next door. This is done to provoke aggressive behaviour.
o The real subject has a choice. He can press button A to keep earning or press B which
will subtract a point from his opponent (subject will not receive this point though in
order to prevent positive reinforcement).
o The number of times that the subject presses B, isthe measure of “aggressive
• Boys are generally more aggressive than girls
o Exposure to androgens, more socially acceptable.
• In boys, circulating levels of testosterone increase markedly at puberty.
o Increased circulating levels of testosterone are associated with an increase in non-
aggressive, antisocial / conduct disorder (CD) behaviors (e.g., vandalism, shoplifting)
but not physical violence.
o Supraphysiologic androgen administration to men (600 mg/wk intramuscular
injections) increased Point Subtraction Aggression Paradigm scores (PSAP).
▪ Agression was increased with androgen administration
o In a subpopulation of the subjects (~16%), the behavioral change was pronounced
including clinically relevant increases in manic symptoms (abnormally elevated or
irritable mood, arousal, and/or energy levels).
Athletes taking anabolic steroids
• Some athletes take anabolic steroids to increase their muscle mass and strength and
supposedly their competitiveness.
• This study characterized the relationship between testosterone levels and aggressivity
among weightlifters who are users (n=10) or nonusers (n=18) of anabolic steroids.
• Supranormal testosterone concentrations were associated with increased aggression.
• In humans, low 5HT levels are associated with increased suicide attempts and increased
• Acute tryptophan depletion increases impulsivity.
• Acute tryptophan depletion increases aggressiveness in hostile subjects.
• In boys 9-15 yrs of age, increased testosterone levels are associated with increased non-
aggressive conduct disorder symptoms.
• Supraphysiologic androgen administration increased Point Subtraction Aggression Paradigm
scores (PSAP) in men.
• Athletes taking anabolic steroids show increased aggression in the PSAP scores. Prefrontal Cortex Lesions (VMPFC & DLPFC)
• The story of Phineas Gage
o “He is fitful, irreverent, indulging at times in the grossest profanity, manifesting but
little deference for his fellows, impatient of restraint or advice when it conflicts with
his desires, at times pertinaciously obstinate, yetcapricious and vacillating, devising
many plans of future operation, which are no sooner arranged than they are
abandoned…In this regard his mind was radically changed, so decidedly that his
friends and acquaintances said that he was ‘no longer Gage.’” (Harlow HM. Recovery
from the passage of an iron bar through the head. Mass Med Soc Publ 1868;2:327)
o Rod entered from the bottom of the frontal lobe to the top.
▪ A lot of tissue was likely damaged.
vmPFC vs. amygdala lesions in decision making
• In this study, subjects with bilateral amygdala lesions or vmPFC lesions were examined for
decision making using “the gambling task”.
• Subjects chose cards from decks shown on a computer screen that provided either small
immediate rewards but big losses (bad decks) or from decks that provided fewer rewards but
also fewer losses (good decks).
o Controls learn to choose the good decks
o Patients with lesions in the amygdala of vmPFC chose the bad decks
Anticipatory SCR (skin conductance response)
• Electrodermal activity (SCR) is measured as an index of somatic state activation.
o High Conductance, High Sweating, High Stress.
• Normal subjects develop an anticipatory SCR which is higher for the bad decks than the good
• Patients with lesions in the amygdala or the vmPFC cortex fail to acquire anticipatory SCRs.
• SCRs to reward and punishment
o Patients with lesions of the ventromedial prefrontal cortex (vmPFC) have normal skin
conductance responses (SCR) to rewards and punishments.
o Patients with lesions to the amygdala do not show normal SCRs to rewards and
• Amygdala damage and vmPFC damage is associated with impairment in decision-making
• The roles played by the amygdala and vmPFC in decision-making are different.
• The impairment in decision-making after amygdala damage could be an indirect
consequence of the role of the amygdala in attaching affective attributes to stimuli.
• The poor decision-making associated with vmPFC damage is related to an inability to
integrate effectively all of the somatic state information triggered by the amygdala as well as
other somatic effectors such as the hypothalamus and brainstem nuclei. Volume of PFC in Antisocial Personality Disorder
• Subjects were grouped into:
1. 34 controls
2. 27 men with substance dependence
3. 21 men with diagnosis of APD.
• The APD group showed an 11% decrease in the PFC grey matter volume so a structural brain
• This deficit may underlie the low arousal, poor fear conditioning, lack of conscience and
decision-making deficits that characterize antisocial, psycopathic behaviour.
Antisocial Personality Disorder diagnosis
The Diagnostic and Statistical Manual of Mental Disorders (DSM):
A. There is a pervasive pattern of disregard for and violation of the rights of others occurring
since age 15 years, as indicated by three or more of the following:
o Failure to conform to social norms with respect to lawful behaviors as indicated by
repeatedly performing acts that are grounds for arrest;
o Deception, as indicated by repeatedly lying, use of aliases, or conning others for
personal profit or pleasure;
o Impulsivity or failure to plan ahead;
o Irritability and aggressiveness, as indicated by repeated physical fights or assaults;
o Reckless disregard for safety of self or others;
o Consistent irresponsibility, as indicated by repeated failure to sustain consistent work
behavior or honor financial obligations;
o Lack of remorse, as indicated by being indifferent to or rationalizing having hurt,
mistreated, or stolen from another;
B. The individual is at least age 18 years.
C. There is evidence of conduct disorder with onset before age 15 years.
D. The occurrence of antisocial behavior is not exclusively during the course of schizophrenia or
a manic episode.
Index of 5HT Synthesis Impulsive Personality Disorders
• PET study in which they used *α-[11C]Methyl-L-Tryptophan* (Serotonin Tracer) for assessing
rates of brain serotonin synthesis.
• 14 subjects with impulsive-aggressive behavior were scanned as well as 11 healthy controls.
• In people with a long history of impulsive-aggressive affectively labile behavior, serotonin
synthesis might be reduced in:
o The or