Transcript Chapter 17c

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
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a 450% increase in the incidence of PTSD
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 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
PREDATOR STRESS
Developed in the Adamec laboratory (Adamec & Shallow, 1993)
Unprotected exposure of a rat/mouse to a cat for 10 min
Human
Entrance
Cat
Entrance
Rat Holding
Rat
BoxHolding
Box
Dark/light Box
Acoustic Startle
Elevated Plus Maze
Adamec et al.,
etc
Fear Conditioning Protocol
TRAINING
Day 1
Novel Context (CS) + Tone (CS) + Footshock(US)
CONTEXT TEST
CUE TEST
Day 2
Training Context (CS)
Tone (CS)
Phases of Memory
Reconsolidation
Acquisition - the pairing of the
context/cue to the aversive stimuli
Consolidation—blocked by protein synthesis
Reconsolidation—blocked by protein
inhibitors (anisomycin)
synthesis inhibitors (anisomycin)
3-4 hours
3-4 hours
24 hours
24 hours
Train
Reactivate
Test
von Hertzen & Giese, 2005
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 Shockinduced Fear Memories
*
**
Blundell et al., 2008
Corticosterone May Facilitate
Extinction
Re-Exposure
24 h
24 h
Re-Exposure Re-Exposure Re-Exposure
24 h
24 h
Re-Exposure
24 h
Test
Train
Extinction Trials
A new memory is formed – context is no longer associated with
shock (reduction in freezing)
Corticosterone Augments Multiple-Trial
Extinction in a Lasting Manner
Reminder
Shock
Inject Inject Inject Inject
Train
Reactivate
Reactivate Reactivate Reactivate
80
% Freezing
Probe Probe
Probe
Vehicle
Cort
7 days
60
* *
*
40
*
Inject – 5 minutes
post-reactivation
*
20
0
0
2
4
6
Days
8
10
12
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