stress, anxiety, and aggression

what is stress?

what is stress?

• physiological reaction caused by perception of aversive or threatening situations; change that causes physical, emotional, or psychological strain

• physiological responses prepares ‘fight or flight’

• episodic or continuous

• adaptive but harmful

what is the sympathetic-adrenal-medullary (SAM) system?

• hypothalamus and sympathetic nervous system stimulate adrenal medulla (kidneys) to release the catecholamine transmitters epinephrine (increases blood glucose) and norepinephrine (increases blood pressure)

• norepinephrine also secreted in brain during stress

what does the hypothalamic-pituitary-adrenal (HPA) axis do?

• paraventricular nucleus of the hypothalamus (PVN) releases the peptide corticotropin-releasing hormone/factor (CRH/CRF)

• CRH stimulates anterior pituitary to release ACTH

what are the effects of stress on the brain?

• can be neurotoxic

• chronic exposure to glucocorticoids destroys hippocampal neurons via decreased glucose entry

• glutamate reuptake → excessive Ca2+ influx and toxicity

describe Diamond et al.’s (1999) study

• rat exposed to cat smell for 75min

• blood glucocorticoids increased

• impaired primed-burst potentiation (PBP) in hippocampus

• impaired in spatial task

describe the study by Uno et al. (1989)

what is PTSD?

• long-lasting psychological symptoms after traumatic event is over

• likelihood is increased if the traumatic event involves danger or violence from other people

• learned, conditioned response

symptoms of PTSD

• flashbacks

• hypervigilance

• irritability

• heightened reactions to sudden noise

• detachment from social activities

• often triggered by cues related to traumatic event

how does PTSD affect the hippocampus?

• reduced size of hippocampus in combat veterans and police officers with PTSD

• twin study shows possible genetic risk factor

• Gilbertson et al. - smaller hippocampus in those with PTSD from the Vietnam war

what are the possible reasons for why PTSD affects the hippocampus?

• hippocampus plays a role in distinguishing contexts

• inability in PTSD from detecting threatening vs safe contexts; threat generalisation

how does PTSD affect the amygdala and medial prefrontal cortex?

• PFC involved in impulse control and thought to inhibit the amygdala; involved in emotional expression

• PTSD associated with greater amygdala and reduced mPFC activation compared to control group

• PTSD related changes may indicate excessive emotional response and reduced inhibitory control

how is PTSD treated?

• psychotherapy - associated with decreased amygdala activity and increased PFC hippocampus activity

• antidepressants (SSRIs) - increased hippocampal volume

• exposure therapy - borrows principles from extinction learning; repeated cue presentation over weeks in safe context reduces response to cue

what is anxiety?

• apprehensive uneasiness or nervousness over an impending or anticipated ill

what is an anxiety disorder?

• more intense fear/anxiety that is inappropriate for the context

• likely due to cumulative effects of stress, contributes to depressive and substance abuse disorders

• women more likely to experience than men

• many types have a biological component

what is a panic disorder?

• episodic attacks of acute (seconds to hours) anxiety/terror

• cultural factors play a role as Asian, African, and Latin American countries have lower rates than countries like the USA

what are the symptoms of a panic disorder?

• hyperventilation (low CO2)

• irregular heartbeat

• dizziness

• faintness

• fear of losing control/dying

what is agoraphobia?

• intense fear or anxiety about leaving home, being in open/public areas, being in crowds etc.

• coping through avoidance of those situations due to disproportionate fear or anxiety

what is generalised anxiety disorder (GAD)?

• excessive, uncontrollable worrying and anxiety from a wide range of situations and difficulties controlling these symptoms

• Sense of impending danger, sweating, trembling, difficulty concentrating

• More prevalent in women than men

• cultural component

what is social anxiety disorder/phobia?

• Persistent, excessive fear of being exposed to the scrutiny of others (e.g.
  public speaking, group conversations), appearing incompetent

• Sweating, blushing

• Equally likely in men and women

• cultural component

what are the brain changes linked to anxiety disorders?

• PET and fMRI show changes in the prefrontal cortex, anterior cingulate cortex and amygdala

• increased amygdala activity during panic attacks

• adolescents with GAD exhibit increased amygdala and decreased ventrolateral prefrontal cortex activation

how are GABAergic drugs used to treat anxiety disorders?

• Benzodiazepines (BDZ) reduces anxiety and anxiety-like behaviours in animals

• Less time spent on the ‘anxiogenic’ open arm on the elevated plus maze (EPM)

• Binds to the inhibitory GABAA receptor as ‘agonist’
  • Increases Cl- influx
  • hyperpolarisation

what are treatments for anxiety disorders?

• BDZ administration reduces amygdala activity when looking at emotional faces

• flumazenil (antagonist) disinhibits action at GABAa receptor and produces panic but treats BDZ overdose and acute alcohol intoxication

treating anxiety by increasing neurosteroid synthesis

• neurosteroids increase activity of GABAa receptor

• during anxiety attacks, neurosteroid synthesis is suppressed, resulting in suppression of GABAa receptor function

• XBD173 enhances neurosteroid synthesis and reduces panic in absence of sedation and withdrawal symptoms

treatment for anxiety - compounds that affect the serotonin and glutamate system

• fluvoxamine (anti-depressant and SSRI) and D-cycloserine (indirect agonist of NMDA) reduces panic attacks

key characteristics of aggression

• common across many species

• related to species survival (access to mates, protecting offspring)

• may involve behaviours related to threat, defensive, submission

brain circuits of aggression

• programmed by the brain stem

• electrical stimulation of periaqueductal grey (PAG) elicited attack in cats

• medial hypothalamus → dorsal PAG (defensive rage)

• lateral hypothalamus → ventral PAG (predatory attack)

• amygdalar nuclei control these pathways

aggression and serotonin: animal studies

• increasing serotonin transmission reduces aggression

• reducing serotonin transmission via destruction of serotonergic axons or via reducing serotonin synthesis increases aggression

aggression and serotonin: human studies

• mixed evidence that serotonergic neurons play an inhibitory role in aggression

• low levels of serotonin metabolite (5-HIAA) in CSF linked with aggression and antisocial behaviour

• SSRI has shown to reduce aggressive behaviour in some cases

aggression as a reward

• some individuals exhibit ‘appetitive’ aggression, motivated by intrinsic reward

• thought to be an adaptation to violent environments

describe a conditioned place preference (CPP) animal model

• before conditioning - all chambers are neutral

• conditioning - one chamber is paired with a reward and the other is not

• after conditioning - reward-paired chamber acquires motivational significance and acts a conditioned stimulus

describe CPP with aggression reward

• resident vs intruder males; males rodents are very territorial after sexual experience and will attack an unfamiliar intruder

• during conditioning - resident attacks the intruder in the ‘paired’ side; no intruder on the ‘unpaired’ side

• after conditioning - resident mouse that exhibited aggression spends more time on the paired side in the absence of the intruder

operant/instrumental task for aggression reward

• animal put in a skinner chamber

• animals will learn to press lever for ‘intruder’ (aggression self-administration)

• trained animals press lever even in absence of an intruder (aggression seeking)

does aggression SA and seeking activate the reward system in the brain?

• The nucleus accumbens (NAc) plays a key role in reward and motivated actions together with the VTA.

  • e.g. Food and drug-seeking

• Activated by rewarding experiences, e.g. drugs of abuse, food, water, and sex.

• Measured by the activity-sensitive protein ‘Fos’

• Artificial stimulation using ‘optogenetics’

immediate early genes (IEGs) as a proxy marker for activity

• Strong activity induces ‘immediate early genes’ (IEGs) which are rapidly transcribed to mRNA (20- 45 min) and translated to protein product (90-120 min)

• c-Fos or Fos is an IEG, it’s protein product ‘Fos’ is used often as a neuronal activity marker

• Detect Fos protein post- mortem in prepared brain tissue slices via immunohistochemistry

what are optogenetics?

Light-induced neuronal activity manipulations using viruses