Stress, Anxiety and Aggression

Question 1

Stress - what is it?:

Answer 1

• ‘Physiological reaction caused by perception of aversive or threatening situations’ - Walter Cannon (1871-1945)
  
  • Change that causes physical, emotional, or psychological strain
  • Physiological responses help prepare for ‘fight-or-flight’ situations
  • Episodic or continuous
• Adaptive, but also harmful

Question 2

Physiology of the stress response-SAM axis

Answer 2

• Threats require enhanced activity -> need to mobilise energy resources
  
  • Sympathetic-Adrenal-Medullary (SAM) system
  • Hypothalamus and sympathetic nervous system stimulate adrenal medulla (kidneys) to release the catecholamine transmitters epinephrine (high blood glucose) and norepinephrine (high blood pressure)
• Norepinephrine also secreted in brain during stress

Question 3

Physiology of the stress response-HPA axis

Answer 3

• Hypothalamic-Pituitary-Adrenal (HPA) axis
  
  • Paraventricular nucleus of the hypothalamus (PVN) releases the peptide corticotropin-releasing hormone/factor (CRH/CRF)
  • CRH stimulates anterior pituitary to release adrenocorticotropic hormone (ACTH)
  • ACTH enters general circulation and stimulates adrenal cortex to secrete glucocorticoids (e.g., cortisol) -> increases glucose, decrease pain sensitivity
  • CRH also secreted in brain during stress in limbic system

Question 4

Stress effects on the brain

Answer 4

• Stress can be neurotoxic
  
  • Hippocampus - involved in learning and memory
  • Chronic exposure to glucocorticoids destroys hippocampal neurons via decreased glucose entry and
  • Glutamate reuptake -> excessive Ca2+ influx and toxicity

Question 5

Evidence for stress-induced neurotoxicity - Uno et al, 1989

Answer 5

• Vervet monkey colonies in Kenya
  
  • Have a hierarchical society
  • Bottom rank monkeys subjected to continuous stress by upper rank
  • -> enlarged adrenal glands (excessive (nor)epinipherine production)
  • -> hippocampal degeneration

Question 6

Post-traumatic stress disorder (PTSD):

Answer 6

• Long-lasting psychological symptoms after traumatic event (e.g., natural disaster, experience of violence) is over
  
  • PTSD likelihood is increased if the traumatic event involves danger or violence from other people (assault, war)
  • Symptoms - flashbacks, hypervigilance, irritability, heightened reactions to sudden noises, detachment from social activities.
  • Often triggered by cues (e.g., helicopter sound) related to traumatic event (e.g., war)
  • Learned, conditioned response

Question 7

PTSD and brain changes:

Answer 7

• Reduced size of hippocampus in combat veterans and police officers with PTSD (Bremner et al, 1995; Gurvits et al, 1996; Lindauer et al, 2005)
  
  • Possible risk factor for PTSD:
  • Monozygotic twin study from Vietnam war (Gilbertson et al, 2002)
  • Smaller hippocampus in those with PTSD
  • Possible reason for hippocampus and PTSD:
  • Hippocampus plays a role in distinguishing contexts
• Inability in PTSD from detecting threatening vs safe contexts, ‘threat generalisation’

Question 8

Altered activity of the amygdala and medial prefrontal cortex in PTSD:

Answer 8

· Prefrontal cortex (PFC) involved in impulse control and thought to normally inhibit amygdala, involved in emotional expression (Rauch et al. 2006)
· PTSD associated with greater amygdala and reduced mPFC activation than controls to fearful face (opposite for happy face) (Shin et al. 2005)
· PTSD-related changes may indicate excessive emotional response and reduced inhibitory control

Question 9

PTSD treatments

Answer 9

· Psychotherapy: - associated with decreased amygdala activity and increased PFC, hippocampus activity (Thomaes et al., 2014)
· Antidepressants (SSRIs): increased hippocampal volume (Bossini et al., 2007; Vermetten et al., 2003)

Question 10

PTSD treatment - exposure therapy

Answer 10

· Learned associations (cue–stress) play a role in PTSD
- Cue alone induces a. conditioned fear response
· How can we reduce or extinguish this learned response?

Question 11

Pavlov - extinction learning reduces cue responding:

Question 12

PTSD treatment - exposure therapy 2:

Answer 12

· Cue exposure therapy is highly effective (Powers et al., 2010), borrows principles from extinction learning.
· Repeated cue presentation over weeks in safe therapy context reduces response to cue (learning of non-threat, reduction of fear/anxiety)

Question 13

Anxiety and anxiety disorders:

Answer 13

· Anxiety - apprehensive uneasiness or nervousness over an impending or anticipated ill (Merriam-Webster)
· Normal part of life, unlike stress may not have an identifiable trigger, but some similar responses (faster heartbeat, breathing)
· Anxiety disorder=more intense fear/anxiety inappropriate for circumstance.

Question 14

Anxiety disorders:

Answer 14

· Anxiety disorder - more intense fear/anxiety inappropriate for circumstance, more than a temporary worry
· Likely due to cumulative effects of stress, contributes to depressive and substance abuse disorders
· Women more likely than men to experience
· Many types, but panic disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder have known biological component

Question 15

Panic disorder:

Answer 15

· Episodic attacks of acute (seconds to hours) anxiety, terror
- Symptoms: hyperventilation (low CO2), irregular heart-beat, dizziness, faintness, fear of losing control and dying
- Cultural factors play a role as Asian, African, and Latin American Countries have lower rates than e.g. USA (American Psychiatric Association)

Question 16

Agoraphobia:

Answer 16

· Intense fear or anxiety about leaving home, being in open/public areas, being in lines/crowds, etc.
· Coping through avoidance of those situations due to disproportionate fear or anxiety
- Staying home for years, fear of panic attack

Question 17

GAD and social anxiety disorder:

Answer 17

· 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
· 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 to both (more prevalent in people of European descent than e.g. Asian, Latino, African descent)

Question 18

Brain changes linked to anxiety disorders:

Answer 18

· Functional imaging using PET and fMRI show changes in the prefrontal cortex, anterior cingulate cortex, and amygdala.
· Increased amygdala activity during panic attack (Pfleiderer et al., 2007) and in response to presentations of faces with anger, disgust, and fear in social anxiety disorder (Phan et al., 2005)
- Activation correlates with symptoms
· Adolescents with GAD exhibit increased amygdala and decreased ventrolateral prefrontal cortex activation (Monk et al., 2008)
· Lack of suppression of amygdala activation via ventromedial prefrontal cortex (vmPFC)
- vmPFC plays a role in inhibition of fear

Question 19

Treatments for anxiety disorders - GABAergic drugs:

Answer 19

· 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

Question 20

Treatments for anxiety disorders:

Answer 20

· BDZ administration reduces amygdala activity when looking at emotional faces (Paulus et al., 2005)
· Flumazenil (antagonist) disinhibits action at GABAA receptor and produces panic in panic disorder patients.
- Treats BDZ overdose, acute alcohol intoxication
· Abuse potential, withdrawal, sedation.
· Better compounds are needed with fewer side effects.

Question 21

Treating anxiety by increasing neurosteroid synthesis:

Answer 21

· Neuroactive steroids ‘neurosteroids’ (e.g. allpregnaolone) synthesized in periphery and CNS
· 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 (Nothdufter et al., 2011)

Question 22

Treatment for anxiety - compounds that affect the serotonin and glutamate system:

Answer 22

· The anti-depressant fluvoxamine, a SSRI, reduces panic attacks (Asnis et al., 2001).
· Similar findings for D-cycloserine (DCS) an indirect agonist of NMDA receptor (Ressler et al., 2004)
· Presumed action by facilitating ability of behavioural therapy to extinguish fear responses
· DCS facilitates extinction of conditioned fear in animals (Walker et al. 2002)

Question 23

Aggression:

Answer 23

· Common across many species
· Related to species survival, such as gaining access to mates, protecting offspring
· May involve behaviours related to threat (warning), defensive (attack), submission (accept defeat).

Question 24

Brain circuits of aggression:

Answer 24

· Programmed by brain stem
· Electrical stimulation of periaqueductal gray (PAG) elicited aggressive attack and predation in cats (Gregg and Siegel 2001)
· Medial Hypothalamus→Dorsal PAG: defensive rage
· Lateral Hypothamaus→Ventral PAG: Predatory attack
· Amygdalar nuclei control these pathways

Question 25

Aggression and serotonin - animal studies:

Answer 25

· Increasing serotonin transmission reduces aggression (Audero et al., 2013)
· Reducing serotonin transmission via destruction of serotonergic axons (Vergnes et al., 1988) or reducing serotonin synthesis increases aggression (Mosienko et al. 2012)
· Low levels of serotonin metabolite (5-HIAA) in cerebrospinal fluid in rhesus monkeys linked with high levels of aggression (Howell et al., 2007)
- Picking fights with bigger monkeys
- High risk taking (dangerous leaps)
- Suggests serotonin inhibits aggression and controls risky behaviours

Question 26

Aggression and serotonin - human studies:

Answer 26

· Some (mixed) evidence that serotonergic neurons play an inhibitory role (Duke et al., 2013) in aggression
· Low 5-HIAA in CSF linked with aggression and antisocial behaviour
· SSRI (fluoxetine) has shown to reduce aggressive behaviour in some cases

Question 27

Aggression as a reward:

Answer 27

· Reward: Objects, actions, experiences that attains a positive motivational property. (Increases the probability of actions that lead to these)
· “The sight of yellow police tape gives me a rush. My heart is beating, my hands sweating. I am not scared – I’m excited. My mind starts running. I want back in the game.”

Question 28

Aggression as a reward 2:

Answer 28

· Certain individuals exhibit ‘appetitive’ aggression, motivated by intrinsic reward (Elbert et al., 2010)
· Thought to be an adaptation to violent environments (Crombach et al., 2013)
- Remaining more functional in violent settings (war afflicted communities, e.g. Ugandan Child soldiers)
- Elevated social status
· Animal models allow us to study this behaviour (and brain mechanisms) under controlled conditions
- Conditioned place preference (CPP)
- Instrumental conditioning

Question 29

Examining aggression reward in animals-1:

Answer 29

· Conditioned Place Preference (CPP)
· Typically used with drug, food, social reward in mice/rats.
· Before conditioning - all chambers are neutral stimuli.
· Conditioning - One chamber is paired with reward (drug) where as the other one is not.
· After conditioning - After several reward- chamber pairings, reward-paired side acquires motivational significance and acts as a conditioned stimulus
· If a substance/experience is ‘rewarding’ then animals will spend more time in that chamber paired with that substance/experience, i.e. develop a preference.

Question 30

CPP with aggression reward - Golden et al, 2016:

Answer 30

· Resident vs intruder males
· Male rodents are very territorial after sexual experience and will attack the 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 mouse

Question 31

Operant/instrumental task for aggression reward:

Answer 31

· Animals will learn to lever press for food reward in operant ‘Skinner’ chamber.
· The reward sustains the lever press response or ‘reward self-administration’
· Once trained animals will press lever even in absence of reward or ‘reward seeking’
· Animals will learn to lever press for ‘intruder’ (aggression self-administration)
· Trained animals press lever even in absence (aggression-seeking)

Question 32

Does aggression SA and seeking activate the reward system in the brain?:

Answer 32

· 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’

Question 33

Immediate early genes (IEGs) as a proxy marker of activity:

Answer 33

· 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