Fear incubation leads to generalized avoidance in an animal model of PTSD

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Fear incubation leads to generalized avoidance in an animal model of PTSD

  1. 1. Fear incubation leads to generalized avoidance in an animal model of PTSD AG Wotjak Data Presentation – December 2008 Fabrício Pamplona, Dr. AG Wotjak Max Planck Institute of Psychiatry - Munich
  2. 2. Avoidance is a natural defensive response
  3. 3. Avoidance is a natural defensive response
  4. 4. Anxiety disorders from an ethological perspective Adapted from Gray J.A. & McNaughton N., The Neuropsychology of Anxiety (2001), Oxford press. DANGER TO AVOID TO APPROACH avoidable unavoidable avoidable unavoidable Phobia flight escape avoidance Panic fight freeze Anxiety risk assessment behavioral inhibition Depression behavioral supression
  5. 5. Post-traumatic stress disorder <ul><li>PTSD includes (DSM-IV): </li></ul><ul><li>Traumatic event </li></ul><ul><li>Long-lasting symptoms </li></ul><ul><li>Fear responses to trauma stimuli </li></ul><ul><li>Avoidance of trauma stimuli </li></ul><ul><li>Increased arousal and hypervigilance </li></ul><ul><li>Social impairment </li></ul><ul><li>Depression-like symptoms </li></ul>
  6. 6. PTSD mouse model Siegmund A & Wotjak CT., J Psychiatr Res. (2007) 41:848-60. Slide kindly provided by Yulia Golub
  7. 7. Develop a behavioral task to investigate avoidance behavior and fear generalization in the PTSD mouse model. Objective
  8. 8. 30 cm 30 cm 30 cm 30 cm 10 cm 10 cm 10 cm C.OD.A. apparatus Conditioned Odor Avoidance (C.OD.A.)
  9. 9. Home cage bedding (Safety signal) Odor stimulus (Acetate 1%) Odor stimulus (Ethanol 70%) Conditioned Odor Avoidance (C.OD.A.)
  10. 10. Home cage bedding (Safety signal) Guillotine doors Guillotine doors Odor stimulus (Acetate 1%) Odor stimulus (Ethanol 70%) Conditioned Odor Avoidance (C.OD.A.)
  11. 11. Home cage bedding (Safety signal) Guillotine doors Guillotine doors Odor stimulus (Acetate 1%) Odor stimulus (Ethanol 70%) Mouse at the Starting point Conditioned Odor Avoidance (C.OD.A.)
  12. 12. <ul><li>Behavioral Parameters: </li></ul><ul><li>1) Habituation phase </li></ul><ul><li>Time in the nest (s) </li></ul><ul><li>Latency to leave the nest (s) </li></ul><ul><li>Immobility time (s) </li></ul><ul><li>2) Exploratory phase </li></ul><ul><li>Time in each compartment (s) </li></ul><ul><li>Entries in each compartment </li></ul><ul><li>Latency to the 1st entry (s) </li></ul>C.OD.A. protocol
  13. 13. Experiment 1: Establishment of the conditioned ethanol avoidance 0.7mA, 2s C.OD.A. EtOH EtOH vs Acetate 7 days
  14. 14. Experiment 2: C.OD.A. in PTSD mice (fear incubation) 1.5mA, 2s C.OD.A. EtOH EtOH vs Acetate 2 or 28 days
  15. 15. Experiment 2: C.OD.A. in PTSD mice (fear incubation) 1.5mA, 2s C.OD.A. EtOH EtOH vs Acetate 2 or 28 days
  16. 16. Experiment 2: C.OD.A. in PTSD mice (corticosterone release) 1.5mA, 2s EtOH EtOH vs Acetate exposure 28 days
  17. 17. Experiment 3: Role of safety component (nest) in C.OD.A. Evaluation of the first 5 min (habituation) 1.5mA, 2s C.OD.A. EtOH EtOH vs Acetate 28 days
  18. 18. Experiment 4: Relation with trauma intensity 0, 0.5, 0.75, 1.5mA, 2s C.OD.A. EtOH EtOH vs Acetate 28 days
  19. 19. Experiment 5: Role of context memory – High and Low freezers 1.5mA, 2s C.OD.A. EtOH EtOH vs Acetate 28 days 1 day 3 min LF/HF
  20. 20. Experiment 6: Relation with other PTSD parameters Parameters selected for bivariate correlations and PCA: Freezing: - Chamber (trauma context) - Cylinder (new environment) - Tone (sensitization) - Hexagon (grid) Startle: - Baseline startle (105 dB, 115 dB) - Tone-enhanced startle (%TES) CODA: - Latency to the first entry -Time in EtOH, Acetate and Nest compartments
  21. 21. Intra-task bivariate correlations Experiment 6: Relation with other PTSD parameters
  22. 22. Experiment 6: Relation with other PTSD parameters Principal components analysis
  23. 23. Experiment 7: Understanding avoidance: Preventive Extinction 1.5mA, 2s C.OD.A. EtOH EtOH vs Acetate 25 days Day 2-4: 3 or 30 min 1 day 3 min
  24. 24. Experiment 7: Understanding avoidance: Preventive Extinction 1.5mA, 2s C.OD.A. EtOH EtOH vs Acetate 25 days Day 2-4: 3 or 30 min 1 day 3 min
  25. 25. Experiment 9: Understanding avoidance: Apparatus habituation
  26. 26. Experiment 9: Understanding avoidance: Apparatus habituation
  27. 27. Experiment 10: Understanding avoidance: Habituation + Extinction
  28. 28. Experiment 10: Understanding avoidance: Habituation + Extinction
  29. 29. Experiment 11: Pharmacological validation: Diazepam effects
  30. 30. Experiment 12: Pharmacological validation: Fluoxetine effects
  31. 31. Conclusions <ul><li>Conditioned avoidance to odor cues can be established in mice. </li></ul><ul><li>Avoidance does not correlate with other behavioral ´PTSD symptoms´, putatively representing a distinct emotional dimension. </li></ul><ul><li>A “generalized” avoidance develops after fear incubation, which seems to involve associative and non-associative components. </li></ul><ul><li>Pharmacological validation suggests that generalized avoidance is part of a depression-like phenotype, rather than an anxiety one. Note: SSRI are first choice treatment for PTSD. </li></ul>
  32. 32. Fabricio Pamplona People directly involved in the experiments Vincenzo Micale Yulia Golub Cristoph Thoeringer Kathrin Henes Wolfgang Plendl Carsten Wotjak Cristoph Mauch

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