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.

2

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

6

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

7

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

8

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