1. Anxiety Disorders, Autistic Disorder, Attention-Deficit/Hyperactivity Disorder, and Stress Disorders
Chapter 17

2. 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.

3. 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

4. Why Study Fear Memory?
500,000 excess cases of PTSD emerging in NYC as a result of September 11th, 2001 (Galea et al., 2002)

5. 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

6. 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

7. 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

8. 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

9. 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

10. Animal Models of Anxiety
Predator odor
Cat
Fox
Isolation stress
Singlely housed
Chronic unpredictable stress
Cold, warm, isolation, foot sock, etc….
Submersion stress
“drowning-like” experience
Fear conditioning
Social defeat

11. Predator Stress
Developed in the Adamec laboratory (Adamec & Shallow, 1993)
Unprotected exposure of a rat/mouse to a cat for 10 min
Cat
Entrance
Human
Rat Holding
Box

12. Dark/light Box
Acoustic Startle
Elevated Plus Maze
Adamec et al., etc

13. Fear Conditioning Protocol
TRAINING
Novel Context (CS) + Tone (CS) + Footshock(US)
Day 1
CONTEXT TEST
Training Context (CS)
Day 2
CUE TEST
Tone (CS)

14. Phases of Memory Reconsolidation
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)
von Hertzen & Giese, 2005
Train
Reactivate
Test
Evidence suggests that reactivation of a memory can return it to a labile state requiring reconsolidation via protein synthesis

15. 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

16. Rapamycin Blocks Reconsolidation of Shock-induced Fear Memories* **
Blundell et al., 2008

17. Corticosterone May Facilitate Extinction
Re-Exposure
Re-Exposure
Re-Exposure
Re-Exposure
Re-Exposure
24 h
24 h
24 h
24 h
24 h
Test
Train
Extinction Trials
A new memory is formed – context is no longer associated with
shock (reduction in freezing)

18. Corticosterone Augments Multiple-Trial Extinction in a Lasting Manner
Inject – 5 minutes
post-reactivation
7 days
Corticosterone can augment consolidation of fear memory extinction.
Thus, corticosterone could be given following therapeutic reactivation of traumatic memories.
However, this effect could spontaneously revert.
Can we make the effect longer lasting?
Blundell et al., 2011

19. Conclusion
Endogenous corticosterone surge following traumatic memory reactivation may be a natural mechanism to augment extinction of an associative fear memory (“prevent” PTSD?).

20. 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