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.

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

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

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

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

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 Cat Entrance Human Rat Holding Box

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

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

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

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 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)

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

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