Stress, anxiety and aggression

What is stress?

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* Walter Cannon → “physiological reaction caused by perception of aversive or threatening situations” 
* Change that causes physical, emotional or physiological strain 
* Physiological responses help prepare for “fight-or-flight” situations 
* Episodic or continuous 
* Adaptive but also harmful

Sympathetic-adrenal-medullary (SAM) system

hypothalamus and sympathetic nervous system stimulate the adrenal medulla (in the kidneys) to release the catecholamine transmitters (epinephrine and norepinephrine)

Epinephrine

catecholamine transmitter, increased blood glucose

Norepinephrine

catecholamine transmitter, increased blood pressure , which is also secreted in the brain during stress

Hypothalamic-pituitary-adrenal (HPA) axis

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1. The CRH stimulates the **anterior pituitary to release adrenocorticotropic hormone** (ACTH)
2. ACTH enters general circulation and stimulates the adrenal cortex to secrete **glucocorticoids → increases glucose, decreases pain sensitivity**
3. CRH also secreted in the brain during stress in the lymbic system

Neurotoxicity

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* **Chronic exposure to glucocortico**ids destroys hippocampal neurons via decreased glucose entry and glutamate reuptake → excessive calcium influx and toxicity 

Evidence for stress-induced neurotoxicity (Diamond et al., 1999)

– rat exposed to cat smell and presence for 75 min → blood glucocorticoids increased 

* **Impaired primed-burst potentiation in hippocampus** 
* **Impaired in spatial task** 

Evidence for stress-induced neurotoxicity (Uno et al., 1989)

– vervet monkey colonies in Kenya → bottom rank monkeys subjected to continuous stress by upper rank 

**→ enlarged adrenal glands = excessive norepinephrine production**

**→ hippocampal degeneration** 

PTSD

* Long-lasting psychological symptoms after event is over
* PTSD likelihood is increased if the traumatic event involves danger or violence from other people 
* Flashbacks, hypervigilance, irritability, detachment from social activities 
* Often triggered by cues reated to traumatic event → conditioned response 
* Hippocampus plays a role in distinguishing contexts → which PTSD struggles with as they can’t tell threatening vs safe contexts apart 

Effect of PTSD on the brain (Brenmer et al., 1995)

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

Effect of PTSD on the brain (Gilbertson et al., 2002)

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monozygotic twin study from vietnam war, smaller hippocampus in those with PTSD 

PTSD effect on the amygdala and medial prefrontal cortex

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* PTSD associated with greater amygdala and reduced Medial Prefrontal Cortex activation than controls to fearful face
* PTSD-related changes may indicate excessive emotional response and reduced inhibitory control 

Psychotherapy for PTSD

associated with decreased amygdala activity and increased PFC, hippocampus activity

SSRIS for PTSD

show increased hippocampal volume

Exposure therapy for PTSD

* works in the way coditioning does – as the cue alone induces conditioned fear response
* borrows principles from extinction learning, highly effective, repeated cue presentation over weeks in safe therapy context reduces response to cue

Anxiety

* apprehensive uneasiness or nervousness over an impending or anticipated ill
* May not have an identifiable trigger , but some similar responses → faster heartbeat, breathing 

Anxiety disorder

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* more intense fear inappropriate for circumstance, more than a temporary wory , likely due to cumulative effects of stress , contributes to depressive and substance abuse disorders
* Many types → panic disorder, agoraphobia, GAD and social anxiety disorder have known biological component

Panic disorder

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* Episodic attacks of acute anxiety or terror 
* Hyperventilation, irregular heart-beat, dizziness, faintness, fear of losing control and dying 
* Cultural factors play a role as well

Agoraphobia

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* Intense fear or anxiety about leaving home, being in public areas , crowds…
* Coping through avoidance of those situations due to disproportionate fear or anxiety 

General Anxiety Disorder

* Excessive, uncontrollable worrying and anxiety from a wide range of situations
* Sense of impending danger, sweating, trembling, difficulty concentrating 
* More prevalent in women than men 

Social Anxiety Disorder

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* Persistent, excessive fear of being exposed to the scrutiny of others or appearing incompetent 
* Sweating, blushing 
* Equally likely in men and women 

Brain changes linked to anxiety disorders

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* **Changes in the PFC, anterior cingulate cortex and amygdala** 
* **Increased amygdala activity** during panic attack + in response to representations of faces with anger, disgust and fear (for SAD)
* Lack of suppression of amygdala activation via ventromedial prefrontal cortex, which plays a role in the inhibition of fear 

**GABAergic drugs** 

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* BDZ reduces anxiety in animals , binds to the inhibitory GABAa receptor as agonist → increases CI- influx + hyperpolarisation 
* Flumazenil (antagonist) disinhibits action at GABAa receptor and produces panic in panic disorder patients → treats BDZ overdose

Increasing neurosteroid synthesis (as treatment)

* they are synthesised in periphery and CNS
* they increase the activity of GABAa receptors
* synthesised is suppressed during panic attacks
* XBD173 enhances neurostroid synthesis and reduces panic!!

Compounds that affect the serotonin and glutamate systems (as treatment)

* fluvoxamine (antidepressant) reduces panic attacks
* D-cycloserine as an indirect agonist of NMDA receptor
* DCS facilitates extinction of conditioned fear in animals

Brain circuits of aggression

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* Programmed by brain stem 
* Electrical stimulation of periaqueductal gray (PAG) elicited aggressive attack and predation in cats 
* Medial hypothalamus → dorsal PAG: defensive rage 
* Lateral hypothalamus → ventral PAG: predatory attack 
* Amygdalar nuclei control these pathways

Animal studies on aggression and setoronin

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* Increasing serotonin transmission reduces aggression
* Reducing serotonin transmission (destruction of serotonergic axons) or synthesis increases aggression
* Low levels of serotonin metabolite in cerebrospinal fluid in rhesus monkeys linked with high levels of aggression (Howell et al., 2007)

Human studies on aggression and serotonin

* Some mixed evidence that serotonergic neurons play an inhibitory role in aggression (Duke et al., 2013)
* Low 5-HIAA in CSF linked with aggression and antisocial beaviour 
* Fluoxetine has shown reduced aggressive behaviour

Aggression as a reward

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* This is thought to be an adaptation to violent envirionemnt → reamining more functional. Elevated social status 
* Animal models allow us to study this behaviour → conditioned place preference, instrumental conditioning 

Conditioned place preference

* typically used with drug, food and social rewards in mice/rats
* conditioning: one chamber has a reward the other does not
* after conditioning : reward-paried side aquicres motivational significance and acts as a conditioned stimulus
* if a substance is rewarding then animals will develop a preference for it -- i.e.: spend more time with it

Operant/instrumental task for aggression reward

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

trained animals press lever even in abscence (aggression seeking)

Does aggression activate the reward system in the brain?

* the nucelus accumbens plays a key role in reward and motivated actions (with the VTA)
* it is measured by the activity-sensitive protein “Fos”
* artificial stimulation using optogenetics

Optogenetics

light-induces neruonal activity manipulaton using viruses

Immediate early genes as a proxy marker of activity

* Fos is an immediate early genes -- used often as a neuronal activity marker