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