fear incubation leads to generalized avoidance in an animal model of ptsd
TRANSCRIPT
![Page 1: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/1.jpg)
Fear incubation leads to generalized avoidance in Fear incubation leads to generalized avoidance in an animal model of PTSDan animal model of PTSD
AG Wotjak Data Presentation – December 2008AG Wotjak Data Presentation – December 2008
Fabrício Pamplona, Dr.Fabrício Pamplona, Dr.AG WotjakAG Wotjak
Max Planck Institute of Psychiatry - MunichMax Planck Institute of Psychiatry - Munich
![Page 2: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/2.jpg)
Avoidance is a natural defensive responseAvoidance is a natural defensive response
![Page 3: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/3.jpg)
Avoidance is a natural defensive responseAvoidance is a natural defensive response
![Page 4: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/4.jpg)
Anxiety disorders from an ethological perspectiveAnxiety disorders from an ethological perspective
DANGER
TO AVOID TO APPROACH
avoidable unavoidable avoidable unavoidable
Phobiaflight
escapeavoidance
Panicfight
freeze
Anxietyrisk assessment
behavioral inhibition
Depressionbehavioral supression
Adapted from Gray J.A. & McNaughton N., The Neuropsychology of Anxiety (2001), Oxford press.
![Page 5: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/5.jpg)
Post-traumatic stress disorderPost-traumatic stress disorder
PTSD includes (DSM-IV):
- Traumatic event
-Long-lasting symptoms
- Fear responses to trauma stimuli
- Avoidance of trauma stimuli
- Increased arousal and hypervigilance
- Social impairment
- Depression-like symptoms
![Page 6: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/6.jpg)
PTSD mouse modelPTSD mouse model
Siegmund A & Wotjak CT., J Psychiatr Res. (2007) 41:848-60. Slide kindly provided by Yulia Golub
![Page 7: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/7.jpg)
Develop a behavioral task Develop a behavioral task
to investigate avoidance behavior to investigate avoidance behavior
and fear generalization and fear generalization
in the PTSD mouse model. in the PTSD mouse model.
ObjectiveObjective
![Page 8: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/8.jpg)
30 cm 30 cm 30 cm
30 cm10 cm10 cm 10 cm
C.OD.A. apparatusC.OD.A. apparatus
Conditioned Odor Avoidance (C.OD.A.)Conditioned Odor Avoidance (C.OD.A.)
![Page 9: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/9.jpg)
Home cage beddingHome cage bedding(Safety signal)(Safety signal)
Odor stimulusOdor stimulus(Acetate 1%)(Acetate 1%)
Odor stimulusOdor stimulus(Ethanol 70%)(Ethanol 70%)
Conditioned Odor Avoidance (C.OD.A.)Conditioned Odor Avoidance (C.OD.A.)
![Page 10: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/10.jpg)
Home cage beddingHome cage bedding(Safety signal)(Safety signal) Guillotine doorsGuillotine doorsGuillotine doorsGuillotine doors
Odor stimulusOdor stimulus(Acetate 1%)(Acetate 1%)
Odor stimulusOdor stimulus(Ethanol 70%)(Ethanol 70%)
Conditioned Odor Avoidance (C.OD.A.)Conditioned Odor Avoidance (C.OD.A.)
![Page 11: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/11.jpg)
Home cage beddingHome cage bedding(Safety signal)(Safety signal) Guillotine doorsGuillotine doorsGuillotine doorsGuillotine doors
Odor stimulusOdor stimulus(Acetate 1%)(Acetate 1%)
Odor stimulusOdor stimulus(Ethanol 70%)(Ethanol 70%)
Mouse at theMouse at theStarting pointStarting point
Conditioned Odor Avoidance (C.OD.A.)Conditioned Odor Avoidance (C.OD.A.)
![Page 12: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/12.jpg)
Behavioral Parameters:
1) Habituation phase- Time in the nest (s)- Latency to leave the nest (s)- Immobility time (s)
2) Exploratory phase-Time in each compartment (s)- Entries in each compartment- Latency to the 1st entry (s)
C.OD.A. protocolC.OD.A. protocol
![Page 13: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/13.jpg)
0.7mA, 2s C.OD.A.EtOH EtOH vs Acetate
7 days
Experiment 1:Experiment 1: Establishment of the conditioned Establishment of the conditioned ethanol avoidanceethanol avoidance
![Page 14: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/14.jpg)
Experiment 2:Experiment 2: C.OD.A. in C.OD.A. in PTSD micePTSD mice (fear incubation) (fear incubation)
1.5mA, 2s C.OD.A.EtOH EtOH vs Acetate
2 or 28 days
![Page 15: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/15.jpg)
Experiment 2:Experiment 2: C.OD.A. in C.OD.A. in PTSD micePTSD mice (fear incubation) (fear incubation)
1.5mA, 2s C.OD.A.EtOH EtOH vs Acetate
2 or 28 days
![Page 16: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/16.jpg)
Experiment 2:Experiment 2: C.OD.A. in C.OD.A. in PTSD micePTSD mice (corticosterone release) (corticosterone release)
1.5mA, 2sEtOH
EtOH vs Acetateexposure
28 days
![Page 17: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/17.jpg)
Experiment 3:Experiment 3: Role of Role of safety component safety component (nest)(nest) in C.OD.A.in C.OD.A.
1.5mA, 2s C.OD.A.EtOH EtOH vs Acetate
28 days
Evaluation of the first 5 min (habituation)
![Page 18: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/18.jpg)
Experiment 4:Experiment 4: Relation with Relation with trauma intensitytrauma intensity
0, 0.5, 0.75, 1.5mA, 2s
C.OD.A.
EtOHEtOH vs Acetate
28 days
![Page 19: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/19.jpg)
Experiment 5:Experiment 5: Role of context memory – Role of context memory – High and Low freezers High and Low freezers
1.5mA, 2s C.OD.A.EtOH EtOH vs Acetate
28 days 1 day 3 minLF/HF
![Page 20: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/20.jpg)
Experiment 6:Experiment 6: Relation with other Relation with other PTSD parametersPTSD 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
![Page 21: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/21.jpg)
Intra-task bivariate correlations
Experiment 6:Experiment 6: Relation with other Relation with other PTSD parametersPTSD parameters
![Page 22: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/22.jpg)
Experiment 6:Experiment 6: Relation with other Relation with other PTSD parametersPTSD parameters
Principal components analysis
![Page 23: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/23.jpg)
1.5mA, 2s C.OD.A.EtOH EtOH vs Acetate
25 days
Day 2-4: 3 or 30 min
1 day 3 min
Experiment 7:Experiment 7: Understanding avoidance: Preventive Extinction Understanding avoidance: Preventive Extinction
![Page 24: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/24.jpg)
Experiment 7:Experiment 7: Understanding avoidance: Preventive Extinction 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
![Page 25: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/25.jpg)
Experiment 9:Experiment 9: Understanding avoidance: Apparatus habituation Understanding avoidance: Apparatus habituation
![Page 26: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/26.jpg)
Experiment 9:Experiment 9: Understanding avoidance: Apparatus habituation Understanding avoidance: Apparatus habituation
![Page 27: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/27.jpg)
Experiment 10:Experiment 10: Understanding avoidance: Habituation + Extinction Understanding avoidance: Habituation + Extinction
![Page 28: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/28.jpg)
Experiment 10:Experiment 10: Understanding avoidance: Habituation + Extinction Understanding avoidance: Habituation + Extinction
![Page 29: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/29.jpg)
Experiment 11:Experiment 11: Pharmacological validation: Diazepam effects Pharmacological validation: Diazepam effects
![Page 30: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/30.jpg)
Experiment 12:Experiment 12: Pharmacological validation: Fluoxetine effects Pharmacological validation: Fluoxetine effects
![Page 31: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/31.jpg)
ConclusionsConclusions
Conditioned avoidance to odor cues can be established in mice.Conditioned avoidance to odor cues can be established in mice.
Avoidance does not correlate with other behavioral Avoidance does not correlate with other behavioral
´PTSD symptoms´, putatively representing a ´PTSD symptoms´, putatively representing a
distinct emotional dimension. distinct emotional dimension.
A “generalized” avoidance develops after fear incubation, A “generalized” avoidance develops after fear incubation,
which seems to involve associative and non-associative which seems to involve associative and non-associative
components.components.
Pharmacological validation suggests that generalized Pharmacological validation suggests that generalized
avoidance is part of a depression-like phenotype, rather than an avoidance is part of a depression-like phenotype, rather than an
anxiety one. Note: SSRI are first choice treatment for PTSD.anxiety one. Note: SSRI are first choice treatment for PTSD.
![Page 32: Fear incubation leads to generalized avoidance in an animal model of PTSD](https://reader033.vdocuments.us/reader033/viewer/2022052903/55767a1fd8b42aa6108b4a5d/html5/thumbnails/32.jpg)
Yulia Yulia GolubGolub
Fabricio Fabricio PamplonaPamplona
Cristoph Cristoph ThoeringerThoeringer
Kathrin Kathrin HenesHenes
Wolfgang Wolfgang PlendlPlendl
Carsten Carsten WotjakWotjak
Cristoph Cristoph MauchMauch
People directly involved in the experimentsPeople directly involved in the experiments
Vincenzo Vincenzo MicaleMicale