Anxiety Disorders 2 Flashcards
What is extinction learning?
Proces by which repreated presentation of CS without US reduces expression of conditioned response
What are the different types of criterion that need to be met in PTSD diagnosis?
5 marks
- Had to have been exposed to a stressor
- Intrusion symptoms - re-experiencing the effect
- Avoidance - persistant avoidance of distressing trauma related stimuli
- Negative alterations in cognition and mood - persisten distorted blame of self or others for causing traumatic event
- Alteration in arousal and reactivity - hypervigilance, problems in concentration, irritable
(not quite criteria but also depersonalization and derealization)
List some risk factors of PTSD
4 marks
- Prior emotional disorder
- Prior history of abuse
- Genetics
- Event severity/ duration
Which axis is affected in PTSD/ attributes to it?
1 mark
Hypothalamic-pituitary- adrenal axis
What does teh HP adrenal axis do in response to stress?
4 marks
- Releases corticotropin releasing factor (CRF) into anterior pituitary gland
- CRF then binds to CRF type 1 receptor on pituitary corticotropes activating cAMP pathways
- This induces the release of adrenocorticotrophic hormone (ACTH)
- Glucocorticoids released by ACTH bind to MC2-R
What can be seen by an icnrease in cell signals of CRFH (corticotrophin releasing factor) and AVP (vasopressin) to the PVN (paraventricular nucleus)?
5 marks
- Increase in cardiovascular tone
- Increase in blood pressure
- Mobilization of stored energy to muscle
- Transient enhancement of immunity
- Inhibition of long term processes i.e. growth and reproduction
What are the stress markers in the brain?
Noradrenaline and cortisol
What is seen in the concentration of the stress markers in PTSD?
1 mark
Noradrenaline increases whereas cortisol decreases
What drug enhances the supression of plasma cortisol and ACTH?
3 marks
Dexamethasone - used to contorl cortiosl levels in pituitary as doesn’t go to brain but remains peripherally
Cortisol promotes negative feedback as it acts on the pituitary
Suggests PTSD patients have more sensitive inhibtion to blockage of cortical production
What is believed to be the result of cortisol levels being reduced in the brain in PTSD?
3 marks
- Believed to be an exaggerated feedback loop on HP axis
- Less cortisol production but somehow a compensatory effect at level of cortisol
- Hormones associated with decrease in glucocorticoid steroid signalling in hypothalamus and other structures
How does glucocorticoid receptor activation take place?
5 marks
- FKBP5 bound GR-complex (via hsp90) - causes GR lower affinity for cortisol. Binding by TPR domain that serves as docking station for several different co-chaperones
- Cortisol bound, FKPB5 is exchanged against FKBP4 which binds dynein - exchange of FKBP4 recruits dyneien and allows nuclear translocation and transcriptional activity
- GR complex translocated to the nucleus and DNA binding
- GR inreases FKBP5 transcription and translation
- Increased FKBP5 confers higher GR resistance
What are the chaperone proteins of glucocorticoids?
4 marks
- HSP90
- FK506 - participates in heat shock (hsp90) protein steroid receptor complex
- HSP70
- BAG1
- FK5B06 - important functional regulator of GR-complex protein
Do people with PTSD tend to have a higher or lower baseline level of FKBP5?
Higher - and also have higher stress induced expression of FKBP5
How can FKBP5 predict the emergence of PTSD?
2 marks
- Polymorphisms in FKBP5 interact with early trauma/ childhood abuse to predict adult PTSD
- Increased expression of FKBP5 - shows decreased stress coping, prolonged cortisol response and increased anxiety
What is the double hit hypothesis?
Environmental disruptions can cause an epigenetic change particularly in FKBP5 in early development, increasing GC resistance and stress
Outline briefly how environmental factors can cause an increase in the expression of FKBP5 in adulthood.
3 marks
- Stress in childhood causes demethylation of intron 7
- Reduced methylation leads to increased transcription
- Increased stress-induced FKBP5 expression in adult
What does FKPB5 actually do?
4 marks
Regulates:
GR activity
DNA methylation
ERK/ Akt signalling
Spine maturity
Explain how PTSD patients develop a resistance to glucorticoids.
4 marks
- early life adversity triggers an increase in circulating glucocorticoids (GCs) that act on GRE neat a TATAA sequence in intron 2 in a risk allele of FKBP5 in hippocampus
- TATAA sequence absent - activates transcription start site and a GRE intron 7 leads to demethylation of a methylated CpG site in intron 7 of risk allele
- causes persistent activation of FKBP5 throughout life
- so stress in life causes release of GC’s and then activates demethylation of FKBP5, suppressing GC receptor = resistance to GC’s in PTSD
What differences can be seen anatomically in a healthy patient and a patient with PTSD?
2 marks
- Amygdala of PTSD patient shows hyperresponsiveness to emotions than healthy patient
- Pre-frontal cortex shows major decrease in fearful response in PTSD compared to healthy patient
Learn info on next part
What molecule does the lateral amygdala show an increase in?
1 mark
Increase in noradrenaline in response to stress and glucocorticoids
How does the activity of the hippocampus change in response to stress?
2 marks
- Decrease in LTP in response to stress
- Increase in LTP in response to noradrenaline
- Increase in excitablity in response to GCs
How does muscimol affect extinction memory?
2 marks
- It is located prelimbicly so delays extinction
- Its a GABAA agonist so increases inhibition
Does the prelimbic cortex or the infralimbic cortex have a role in extinction memory?
2 marks
Infralimbic cortex does
- inhibits the expression of fear and controls the brain region involved in controlling negative extinction
Prelimib cortex is involved in the expression of fear - no role in extinction learning
How does stress affect the vmPFC?
Fear related memory can’t be properly distinguished
What are the 2 opposing nuclei in the PFC and what do they do?
2 marks
dACC (fear eliciting) and vmPFC (fear inhibting)
Theres two opposing nuclei in prefrontal cortex and are implicated
in modulation through amygdala in extinction process
How can you enhance extinction as a therapeutic strategy?
Proper behavioural training leads to extinction - those who can’t have anxiety/PTSD
What can be used as a partial NMDA receptor agonist?
2 marks
DCS - D-cycloserine
- It potentiates consolidation of extinction - and experimentally in mouse modles see decrease in percentage of freezing after DCS is administered
What is one way in enhancing extinction therapeutically?
Using sodium butyrate
or
HDAC inhibitors - maintains open chromatin so that transcription still occurs
