Stress, Anxiety and Aggression Flashcards
Stress - what is it?:
- ‘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
Physiology of the stress response-SAM axis
- 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
Physiology of the stress response-HPA axis
- 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
Stress effects on the brain
- 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
Evidence for stress-induced neurotoxicity - Uno et al, 1989
- 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
Post-traumatic stress disorder (PTSD):
- 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
PTSD and brain changes:
- 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’
Altered activity of the amygdala and medial prefrontal cortex in PTSD:
· 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
PTSD treatments
· 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)
PTSD treatment - exposure therapy
· 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?
Pavlov - extinction learning reduces cue responding:
PTSD treatment - exposure therapy 2:
· 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)
Anxiety and anxiety disorders:
· 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.
Anxiety disorders:
· 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
Panic disorder:
· 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)
Agoraphobia:
· 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
GAD and social 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
· 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)
Brain changes linked to anxiety disorders:
· 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
Treatments for anxiety disorders - GABAergic drugs:
· 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
Treatments for anxiety disorders:
· 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.
Treating anxiety by increasing neurosteroid synthesis:
· 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)
Treatment for anxiety - compounds that affect the serotonin and glutamate system:
· 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)
Aggression:
· 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).
Brain circuits of aggression:
· 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
Aggression and serotonin - animal studies:
· 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
Aggression and serotonin - human studies:
· 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
Aggression as a reward:
· 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.”
Aggression as a reward 2:
· 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
Examining aggression reward in animals-1:
· 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.
CPP with aggression reward - Golden et al, 2016:
· 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
Operant/instrumental task for aggression reward:
· 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)
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 of 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
