Anxiety Disorders, Autistic Disorder, Attention- Deficit/Hyperactivity Disorder, and Stress Disorders Chapter 17
Dec 27, 2015
Anxiety Disorders, Autistic Disorder, Attention-Deficit/Hyperactivity
Disorder, and Stress Disorders
Chapter 17
• In March of 2001, in what was likely a suicide attempt, Corporal Christian McEachern drove his SUV directly into the headquarters building at CFB Edmonton. Corporal McEachern had served with Canada’s peacekeeping forces in Croatia and Uganda and had been diagnosed with PTSD upon his return. He was eventually tried for this action and found guilty, but was given no jail time. His complaint about the lack of proper services for Canadian Forces personally struggling with PTSD was investigated by Canada’s parliamentary ombudsman. The ombudsman found many cases of PTSD among Canada’s military personal were going unidentified and untreated (Marin, 2001). A follow-up report in 2008 found that 18 of the 31 recommendations in the original report had not yet been implemented (McFadyen, 2008). Clearly there is still more work to do in dealing with PTSD issues within the Canadian Forces.
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Posttraumatic Stress Disorder
A psychological disorder caused by exposure to a situation of extreme danger and stress
• Symptoms include: • Traumatic event persistently re-experienced
• Avoidance of stimuli associated with trauma
• Increased arousal
• Women > men
Why Study Fear Memory?
500,000 excess cases of PTSD emerging in NYC as a result of September 11th, 2001 (Galea et al., 2002)
PTSD Risk Factors Following Trauma
• Earlier age at the time of traumatic event
• Exposure to more than one traumatic event
• Father with a depressive disorder
• Low educational level
• Poor social support
• Pre-existing conduct disorder, panic disorder, GAD or depressive disorder
PTSD• Genes as possible risk factors for developing
PTSD• D2 receptors • DA transporters• 5-HT transporters
• Short allele for the promoter for the 5-HT transporter (5-HTT)• Kilpatrick et al., 2007 studied people living in Florida during the 2004
hurricane season• People at risk for PTSD (high hurricane exposure and low social
support) • The presence of the short allele was associated with a 450%
increase in the incidence of PTSD
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PTSD and brain damage
• Hippocampal damage in veterans with combat-related PTSD• 20% decreased in hippocampal volume • Loss was proportional to the amount of
combat exposure
• Police officers with PTSD had a smaller hippocampus
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PTSD• A smaller hippocampus may be a predisposing
factor in the acquisition of PTSD• Part of the reduction in hippocampus may predate the
exposure to stress• 40 pairs of monozygotic twins – 1 went to Vietnam
• Almost half the men who experience combat developed PTSD
• Smaller hippocampus in those that developed PTSD
• Smaller hippocampus was associated with more severe PTSD
• Hippocampal volumes of the twin brothers of PTSD patients who stayed home also showed smaller hippocampal volumes
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PTSD
• Most people exposed to a potentially traumatic event can suppress their emotional reaction.
• PFC can inhibit amygdala (facilitate extinction)• In PTSD
• fMRI study found that when shown picutres of faces with fearful expressions, people with PTSD show greater activation of amygdala and smaller activation of PFC than controls
• Symptoms of PTSD were positively correlated with activation of amygdala and negatively correlated with activation of mPFC
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Animal Models of Anxiety
Predator odorCatFox
Isolation stressSinglely housed
Chronic unpredictable stressCold, warm, isolation, foot sock, etc….
Submersion stress“drowning-like” experience
Fear conditioning Social defeat
Developed in the Adamec laboratory (Adamec & Shallow, 1993)
Unprotected exposure of a rat/mouse to a cat for 10 min
CatCatEntranceEntrance
HumanHumanEntranceEntrance
Rat HoldingRat HoldingBoxBox
Dark/light Box
Elevated Plus Maze
Acoustic Startle
Adamec et al., etc
Fear Conditioning Protocol
CUE TEST
Tone (CS)
TRAINING
Novel Context (CS) + Tone (CS) + Footshock(US)
Day 1
CONTEXT TEST
Training Context (CS)
Day 2
Phases of MemoryPhases of MemoryReconsolidationReconsolidation
Reactivate Test
Acquisition - the pairing of the context/cue to the aversive stimuli
24 hours
Consolidation—blocked by protein synthesis inhibitors (anisomycin)
3-4 hours
Reconsolidation—blocked by protein synthesis inhibitors (anisomycin)
3-4 hours
24 hours
von Hertzen & Giese, 2005
Train
Evidence suggests that reactivation of a memory can return it to a labile state requiring reconsolidation via protein synthesis
Blocking Reconsolidation?• mTOR is a serine/threonine protein kinase that regulates cell
growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription
• mTOR is known to be involved in various forms of synaptic plasticity.
• Few studies have examined the role of mTOR inhibition in learning and memory
Rapamycin Blocks Reconsolidation of Shock-induced Fear Memories
***
Blundell et al., 2008
Corticosterone May Facilitate Extinction
Train Test
24 h
Extinction Trials
24 h 24 h24 h24 h
Re-Exposure Re-Exposure Re-Exposure Re-Exposure Re-Exposure
A new memory is formed – context is no longer associated with shock (reduction in freezing)
Corticosterone Augments Multiple-Trial Extinction in a Lasting Manner
0 2 4 6 8 10 120
20
40
60
80 Vehicle
Cort
*
Train
Inject Inject Inject Inject
***
Probe
*
Probe
ReminderShock
Probe
Reactivate Reactivate Reactivate Reactivate
Days
% F
reez
ing
Inject – 5 minutes post-reactivation7 days
Blundell et al., 2011
Conclusion
Endogenous corticosterone surge following traumatic memory reactivation may be a natural mechanism to augment extinction of an associative fear memory (“prevent” PTSD?).
Summary: Genes & Mental Illness
• There are no genes for psychiatric disorders in the sense that there are genes for eye color.
• No known gene is either necessary or sufficient to produce mental illness.– However, this is different for one particular
neurological disorder.
• Instead, there are many susceptibility genes