Brain Chemicals Involved In Aggression Identified

From ScienceDaily (Nov. 7, 2007) — School shootings. Muggings. Murder. Road rage. After decreasing for more than a decade, the rate of violent crime in the United States has begun to inch up again. According to the FBI’s Uniform Crime Reporting Program, violent crime rose 2.3 percent in 2005 and 1.9 percent in 2006, the first steady increase since 1993.

And new studies are helping scientists gain deeper insight into the neurobiology of aggression and violence. One analysis of brain imaging studies has revealed that brain structures involved in making moral judgments are often damaged in violent individuals. Another study involving teenage boys suggests that disruptions in a brain region linked to impulsive, aggressive behavior may underlie a certain type of violent, reactive behavior.

Still other research has shed new light on the role that certain brain chemicals play in aggressive behavior, including in maternal aggression. And new animal studies reveal that aggressive encounters cause changes in the brains of aggressors as well as their victims that increase vulnerability to depression and immune-related illnesses.

“Violence in our society is a major concern, indeed, a national health problem,” says Craig Ferris, PhD, of Northeastern University in Boston. “Understanding the confluence of events, both environmental and biological, that trigger a violent act has been the focus of educators, health professionals, and scientists for decades.

“New imaging technologies and animal models have helped neuroscientists
identify changes in brain neurobiology associated with inappropriate
aggressive behavior,” he says. “This information may help in the
development of new psychosocial and psychotherapeutic intervention
strategies.” Ferris is a stockholder in Azevan Pharmaceuticals, which is
developing drugs to stop self-injurious behavior.

After analyzing data from 47 independent brain imaging studies,
researchers at the University of Pennsylvania have found that the
rule-breaking behavior common to people with antisocial, violent, and
psychopathic tendencies may result partly from damage to the neural
circuitry in the brain that underlies moral decision-making.

“This finding supports other studies that may force society to question
its attitude toward the nature of crime and punishment,” says Adrian
Raine, PhD. “For example, should psychopaths be punished if, for reasons
beyond their control, they do not have the appropriate brain circuitry
to process moral dilemmas?”

Scientists have long known that damage to certain regions of the brain,
most notably the prefrontal cortex, can result in violent behavior. More
recently, imaging studies have identified the neural circuits that
become activated in the brains of normal, healthy individuals during
moral decision-making.

The analysis was undertaken to see if the brain regions compromised in
antisocial populations include the newly identified brain regions
involved in moral decision-making. Raine and his colleagues compared the
brain images of 792 antisocial individuals with 704 control subjects.
They found that antisocial individuals also tended to have overlapping
damage in brain structures involved in making moral judgments, most
notably the dorsal and ventral prefrontal cortex, the amygdala, and the
angular gyrus.

“If offenders are not fully responsible for the source of the brain
dysfunction that impairs their moral-decision making, this raises a
significant neuroethical issue regarding the appropriate level of
punishment for those who perpetrate morally inappropriate acts,” Raine
says.

New studies from the University of California, San Diego, are helping
scientists better understand what goes on in the brains of some teenage
boys who respond with inappropriate anger and aggression to perceived
threats. Preliminary findings from these studies suggest that such
behavior is associated with a hyperactive response in the amygdala, an
area of the brain that processes information regarding threats and fear,
and with a lessening of activity in the frontal lobe, a brain region
linked to decision-making and impulse control.

“This work will provide significant neurobiologic insight into why some
adolescents become aggressive and violent,” says Guido Frank, MD.
“Eventually, it may lead to more effective therapies for helping
adolescents overcome excessively aggressive behaviors that are harmful
to themselves as well as to others.”

Aggressive behavior can be divided into two types: proactive and
reactive. Proactive aggressors plan how they’re going to hurt and bully
others. Reactive aggression, however, is not premeditated; it occurs in
response to an upsetting trigger from the environment.

“Reactively aggressive adolescents — most commonly boys — frequently
misinterpret their surroundings, feel threatened, and act
inappropriately aggressive,” Frank says. “They tend to strike back when
being teased, blame others when getting into a fight, and overreact to
accidents. Their behavior is emotionally ‘hot,’ defensive, and
impulsive.”

The term “reactive-affective-defensive-impulsive” (RADI) has recently
been created to describe such behavior. Research suggests that
adolescents with RADI behavior are at an increased risk for a lifetime
of problems associated with impulsive aggression. “A major problem in
researching this topic is stigma and a notion that children will grow
out of aggressive behaviors,” Frank says. “It’s often difficult to
recruit such youngsters and their families to participate in research.”

Little is known about how the brain works in reactive aggression. In
their most recent studies, Frank and his colleagues recruited two groups
of male adolescents: one group diagnosed with RADI behavior and the
other group without any history of mental illness or aggression
problems. While being scanned by a brain imaging machine, both sets of
teenagers were asked to perform tasks that involved reacting to
age-appropriate, fear-inducing images. The tasks also tested the
teenagers’ impulsivity.

Preliminary data reveal that the brains of RADI teenagers exhibited
greater activity in the amygdala and lesser activity in the frontal lobe
in response to the images than the brains of the teenagers in the
control group. In a related study, Frank and his colleagues are
investigating whether these changes in brain activity are associated
with an abnormal increase in cortisol levels, a marker of the stress
response.

The brain chemical serotonin has long been known to play an important
role in regulating anger and aggression. Low cerebrospinal fluid
concentrations of serotonin have even been cited as both a marker and
predictor of aggressive behavior.

New studies from the Netherlands, however, indicate that this
serotonin-deficiency hypothesis of aggressiveness may be too simple.
“Serotonin deficiency appears to be related to pathological, violent
forms of aggressiveness, but not to the normal aggressive behavior that
animals and humans use to adapt to everyday survival,” says Sietse de
Boer, PhD, of the University of Groningen.

Furthermore, research now suggests that unchecked aggressive behavior
can eventually change the brain in ways that cause serotonin activity to
decrease-and, perhaps, violent behavior to increase.

To perform their most recent studies, de Boer and his colleagues
engendered violent characteristics of aggressive behavior in feral mice
and rats by permitting them to physically dominate other rodents
repeatedly. With such positive reinforcement, the animals’ initially
normal aggressiveness gradually became transformed into a more
pathological form-the kind also seen in pathologically violent people.

During this transformation, de Boer studied the chemical changes that
occurred in the rodents’ aggression-related brain circuits, particularly
those circuits involved with serotonin. They found that serotonin
activity decreased as a result of the animals experiencing repeated
victorious episodes of aggression but not as a result of normal,
functional acts of aggression.

“Our findings support meta-analyses of serotonin activity in aggressive
humans,” says de Boer. “That data showed that serotonin deficiency is
most readily detected in people who engage in impulsive and violent
forms of aggressive behavior rather than in individuals with more
functional forms of aggression.”

More recently, de Boer and his colleagues have found that the transition
from normal, adaptive aggressive behavior into abnormal forms that
inflict harm and injury is due to functional, but not structural,
changes in certain serotonin receptors in the brain. In animal studies,
treatment with selective serotonin receptor agonist compounds has been
found to restore the normal function of these receptors-and suppress
aggressive behavior, including its escalated forms. These findings may
one day lead to more effective treatments for violent behavior in
humans.

Researchers have identified, for the first time, that the release of a
neurotransmitter called arginine-vasopressin (AVP) in an area of the
brain called the amygdala helps regulate maternal aggression-a behavior
that ensures the survival of the offspring. Although the study was
conducted using rat dams, maternal aggression occurs in all mammals,
including humans.

“By understanding the brain pathways underlying maternal aggression in
rodents, we’re also gaining deeper understanding of regulation of
maternal behavior in general,” says Oliver Bosch, PhD, of the University
of Regensburg, in Germany.

Much of the past research into the neurobiology of maternal aggression
has focused on oxytocin, a neurotransmitter released in the brain during
birth and breastfeeding. Oxytocin reduces anxiety and fear, a factor
that is believed to enable new mothers to more aggressively face
intruders that might harm their offspring.

In his new study, Bosch investigated whether AVP also plays a role in
the regulation of maternal aggressiveness. Found in all mammals, AVP is
synthesized in the brain and then released to the kidneys, where it
helps regulate the body’s retention of water. More recently, AVP has
been implicated in male aggression and other social behavior,
particularly pair-bonding between sexual partners.

Using tiny probes that enabled the real-time collection of samples of
brain fluid, Bosch and his colleagues measured the release of AVP within
the amygdala, an area of the brain associated with both maternal anxiety
and aggression, while rat dams moved around their cages with their pups.
Some of the dams had been selectively bred for high anxiety-related
behavior; others had been bred for low anxiety-related behavior.
High-anxiety dams are not only more anxious, but also show more maternal
aggression towards intruders. In addition, they spend more time nursing
and in direct contact with their pups.

During the study, the rat dams were sometimes left undisturbed and were
at other times confronted for 10 minutes with an intruder. The more
aggressive, high-anxiety dams released more AVP within the amygdala
while defending their offspring from the intruder than did the less
aggressive, low-anxiety dams-a finding that strongly suggests a role for
AVP in maternal aggression.

The researchers also found they could use the brain’s AVP system to
manipulate the aggression shown by the dams. When the animals were given
an AVP receptor antagonist, which blocks the brain’s receptors for AVP,
the dams became less anxious and less aggressive. When synthetic AVP was
infused into the animals’ brains, however, the dams became more anxious
and increasingly aggressive.

“While AVP’s effects on maternal aggression are similar to what we found
earlier for oxytocin, these neuropeptides act differently on anxiety,”
Bosch says. “So it’s the brain’s AVP system itself, not AVP acting on
oxytocin receptors, that causes these changes in maternal behavior.”

Being the recipient of an aggressive social encounter can cause changes
in the brain that lead to depression, anxiety, and susceptibility to
immune-related illnesses, according to new animal studies from Carleton
University in Ottawa. Surprisingly, some of these negative effects
appear to be as strong in animals that successfully dominate social
situations as in those that react with submission.

“It seems that aggression, which is clearly deleterious to the
well-being of the victim, also has several negative repercussions for
the aggressor as well,” says Marie-Claude Audet, PhD.

Social stressors and negative relationships are believed to contribute
to stress-related disorders, including depression and anxiety. Stressful
events have a profound influence on the neuroendocrine and neurochemical
systems, causing chemical changes in many areas of the brain, including
several that are strongly involved in emotions: the prefrontal cortex,
the hippocampus, and the amygdala. Among the neurotransmitters and
hormones altered by stress are dopamine, serotonin, noradrenalin, and
corticotropin-releasing hormone (CRH) (which affects blood levels of
corticosterone). Recent research also has suggested a link between
stress and cytokines (signaling molecules within the immune system).
Cytokines may inform the brain of the presence of pathogens in the body,
thus triggering a stress-like response.

To more precisely determine how a social stressor disturbs
neuroendocrine, neurochemical, and cytokine function as well as
behavior, Audet and her colleagues designed a study in which naive mice
(ones not previously exposed to any social situation) were introduced to
the home cage of dominant mice for 15 minutes on either a single day or
on three consecutive days. As a control, some mice were not exposed to
any social stressor. The animals’ basal motor activity was monitored,
and blood and brain samples were taken and analyzed either 3 minutes or
75 minutes after the end of the stressor.

The study found that aggressive social interactions caused both dominant
and submissive mice to become hyperactive relative to the controls.
However, although motor activity remained high in dominant mice,
particularly in those that engaged in vigorous behavior, it declined
gradually in the submissive mice. Corticosterone levels-a marker of
stress-were significantly increased soon after the end of the stressor
session, and those levels remained elevated for protracted periods over
the course of the experiment. The increase was similar in both
submissive and dominant mice. Some cytokines also became elevated in the
prefrontal cortex of both groups of mice, and this effect was greater
after the stressful social encounters were repeated.

Measurements of stress-related neurotransmitters and hormones, however,
revealed some significant differences between the dominant and
submissive animals. For example, brain levels of the neurotransmitter
noradrenaline, which may help mediate the effects of stress on the body,
fell in the hippocampus of the dominant mice, but increased in the
central amygdala of the submissive mice. The expression of CRH also fell
in the prefrontal cortex of the dominant mice, but only after repeated
encounters with an intruding mouse.

In further studies, Audet observed that chronic exposure to social
stress increased the sensitivity to a bacterial challenge and that this
effect was more apparent in dominant mice.

“Our findings suggest that stressful social experiences, by affecting
central neurotransmitters and cytokines, may influence vulnerability to
depression and susceptibility to immune-related illness,” says Audet.
“Moreover, it appears that in addition to markedly affecting the
victim’s existence, aggression may have detrimental consequences also
for the one that dominates the interaction.”

Source: Society For Neuroscience