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

2. Lecture Preview  Anxiety Disorders  Autistic Disorder  Stress Disorders

3. 1.Stressor 2.Response: Fight/Flight 3. Escape from stressor 4. Return to normal Normal Catherine’s potential stress level during lecture Coping with stress

4. Stress Disorders Stressor – physiological reaction caused by the perception of aversive or threatening situations Fight/flight response – physiological reactions that prepare us for the strenuous efforts of fighting or fleeing Once threat is over, physiological state returns to normal (acute response) 4

5. Norepinephrine Pathway

6. Norepinephrine Stressful situations increase release of NA in hypothalamus, frontal cortex, lateral basal forebrain Controlled by a pathway from central nucleus (CN) of amygdala to locus coeruleus (LC) 6

7. Hypothalamic- Pituitary- Adrenal (HPA) Axis Stress increases glucocorticoid (cortisol) release PVN CRH

8. Glucocorticoid (cortisol) Hormone of the adrenal cortex that are important in protein and carbohydrate metabolism, secreted especially in times of stress.

9. Corticotrophin-Releasing Hormone (CRH) ICV injections of CRH decrease the amount of time a rat spends in the center of open field, enhances acquisition of a conditioned fear response, increases startle response elicited by a sudden loud noise ICV injections of CRH antagonist reduces anxiety 9

10. Negative Feedback of HPA Axis Due to glucocorticoid receptors at level of: hippocampus hypothalamus pituitary gland Prolonged stress disrupts negative feedback system

11. Effects of Stress on the brain -Long-term exposure to glucocorticoids destroys CA1 of hippocampus Stress exacerbates excitotoxic neuron loss 11 Stein-Behrens et al., 1994 CA1 CA3

12. Prenatal Stress – Increases in volume in Amygdala in Adulthood Salm et al., 2004

13. Effects of stress on the brain Prenatal stress causes learning and memory problems by interfering with development of hippocampus Stress (confine) pregnant mother Offspring have abnormal LTP and deficits on spatial learning task Prenatal stress causes changes in amygdala Pregnant moms injected with saline (last week of gestation) Volume of lateral amygdala in adulthood was increased (30%) Increased fearfulness to novel environment (pups) 13

14. Response to Restraint Stress in Adult Offspring Barbazanges et al, 1996

15. Effects of stress on brain Effects of prenatal stress on fetus are mediated by secretion of glucocorticoids Stressed pregnant moms, observed the effects of this stressor on their offspring once they grew up Prenatally stressed rats showed a prolonged secretion of glucocorticoids when they were stressed in adulthood If mom’s adrenal glands were removed so glucocorticoids were not increased during stressor, offspring reacted normally in adulthood 15

16. Effects of stress on the brain (Human Studies) Brain degeneration in CT scans of people who were tortured More mild forms of stress early in life also appear to affect brain development Episodes of emotional maltreatment during childhood was associated with an average 7.2 reduction in volume of the dmPFC 16

17. Acute Stress Discrete episodes (single exposure in experiments) Results in: Increase of glucocorticoid levels Deficits in spatial memory Deficits in LTP Increase of hyperarousal and anxiety-like behaviour (Diamond et al., 1999, Adamec et al., 2006)

18. Hyperarousal (startle ) Anxiety-like Behaviour : Elevated Plus Maze & Light/Dark Box

19. Animal Models of Anxiety  Predator odor  Cat  Fox  Isolation stress  Singlely housed  Chronic unpredictable stress  isolation, foot shock, etc….  Submersion stress  “drowning-like” experience  Fear conditioning  Social defeat

20. 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

21. 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 21

22. Hippocampal volume may predate exposure to stress Gilbertson et al., 2002

23. 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 23

24. PTSD individuals have higher activation in amygdala compared to frontal gyrus Shin et al., 2005

25. 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 25

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

27. Phases of Memory Reconsolidation ReactivateTest 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

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

29. Corticosterone Augments Multiple-Trial Extinction in a Lasting Manner Inject – 5 minutes post-reactivation 7 days Blundell et al., 2011

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

31. Acute stress and Neurogenesis General Consensus: Acute stress reduces hippocampal neurogenesis DISCREPANCIES: -Increase of neurogenesis in dorsal hippocampus using restraint stress (Kirby et al., 2010) -No change in neurogenesis using predator odor (Thomas et al., 2006)

32. Subgranular Zone of Dentate Gyrus

33. Predator Stress Predator Odour: Activates hypothalamic-pituitary-adrenal (HPA) axis and produces anxiety-like behaviour in rats Examples Trimethylthiazoline (TMT) = Fox feces (Hill et l., 2006) Soiled cat litter (Cohen,2004) Cat fur (Munoz-Abellan et al, 2010)

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

35. Research Question Predator stress (cat exposure) Anxiety-like behaviour seen up to 3 weeks after exposure (Adamec, 1999) How do the effects of predator stress influence adult hippocampal neurogenesis? Acute stress affects neurogenesis

37. (n= 4) (n= 6)

38. PTSD Treatments Current treatments – CBT, SNRIs, TMS Ongoing research to uncover underlying mechanisms involved –Increase neurogenesis?