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
Avoidance is a natural defensive responseAvoidance is a natural defensive response
Avoidance is a natural defensive responseAvoidance is a natural defensive response
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.
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
PTSD mouse modelPTSD mouse model
Siegmund A & Wotjak CT., J Psychiatr Res. (2007) 41:848-60. Slide kindly provided by Yulia Golub
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
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.)
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.)
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.)
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.)
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
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
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
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
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
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)
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
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
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
Intra-task bivariate correlations
Experiment 6:Experiment 6: Relation with other Relation with other PTSD parametersPTSD parameters
Experiment 6:Experiment 6: Relation with other Relation with other PTSD parametersPTSD parameters
Principal components analysis
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
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
Experiment 9:Experiment 9: Understanding avoidance: Apparatus habituation Understanding avoidance: Apparatus habituation
Experiment 9:Experiment 9: Understanding avoidance: Apparatus habituation Understanding avoidance: Apparatus habituation
Experiment 10:Experiment 10: Understanding avoidance: Habituation + Extinction Understanding avoidance: Habituation + Extinction
Experiment 10:Experiment 10: Understanding avoidance: Habituation + Extinction Understanding avoidance: Habituation + Extinction
Experiment 11:Experiment 11: Pharmacological validation: Diazepam effects Pharmacological validation: Diazepam effects
Experiment 12:Experiment 12: Pharmacological validation: Fluoxetine effects Pharmacological validation: Fluoxetine effects
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.
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