targeting reconsolidation as a new therapeutic strategy

Targeting reconsolidation as a new therapeutic strategy

Karim Nader

Alfred P. Sloan Fellow

Dept. of Psychology

McGill University

Montreal Canada

Kinds of Consolidation

Hippocampus Dependent

weeks to years

LTMSTM

seconds to hours seconds to hours

RemoteSTM

Systems Consolidation

Cellular Consolidation

Hippocampus Independent(Neocortex)

Cellular Memory Consolidation Theory

Short-Term Memory (STM)• Seconds to Hours• ”Labile” (sensitive to disruption)• Does not require new RNA & protein synthesis

Long-Term Memory (LTM)• Days, Weeks, lifetime• Consolidated (insensitive to disruption)• Does require new RNA & protein synthesis

Cellular Consolidation of Auditory Fear Memories in the Lateral

Amygdala

Conditioned Stimulus (CS)e.g. light or tone

Time

defensive behavior

autonomic arousal

hypoalgesia

reflex potentiation

adrenal activation

Natural ThreatCS

Amygdala

Fear Conditioning

Unconditioned Stimulus (US)e.g. footshock

Does the Consolidation of Auditory Fear Conditioning Require Protein Synthesis in the LA?

1 x Tone-Shock 4 hr

Anisomycin (62.5 g/0.5 l/side) into the Lateral (LA)

Amygdala

Basic Paradigm:

20 hrSTM LTM

Schafe & LeDoux, 2000

Protein synthesis inhibition in the LA blocks the induction of long term memory.

Schafe & LeDoux, 2000

1 x CS-US STM LTM20 hr4 hr

STM LTM

0

20

40

60

80

100

Control

Anisomycin

Per

cen

t F

reez

ing

Consolidation:

Reconsolidation:

Do Consolidated Memories Return to a Labile State When Retrieved or Reactivated?

1 x Tone-Shock STM LTM20 hr4 hr

1 x CS-US CS PR-STM PR-LTM20 hr4 hr24 hr

Nader, Schafe & LeDoux, 2000

Schafe & LeDoux, 2000

Anisomycin (62.5 g/0.5 l/side) infusions into the Lateral amygdala (LA)

Predictions

1- If reactivation of a consolidated memory causes it to undergo another time-dependent memory stabilization process then post-reactivation anisomycin infusions should block PR-LTM but not PR-STM.

2- If consolidated memories remain fixed in the brain, then post-reactivation anisomycin should have no detrimental effect on the memory.

Tone-Shock CS PR-STM PR-LTM20 hr4 hr24 hr

Protein synthesis inhibition in the LA blocks consolidation and reconsolidation.

Schafe & LeDoux, 2000

STM LTM

0

20

40

60

80

100

Control

Anisomycin

Per

cen

t F

reez

ing

PR-STM PR-LTM

0

20

40

60

80

100

Control

AnisomycinP

erce

nt

Fre

ezin

g

Nader, Schafe & LeDoux, 2000

Consolidation Reconsolidation

A Test of Whether Reconsolidation Depends on Reactivation of the Memory

1 x CS-US No CS Test 224 hr 24 hr

Anisomycin’s behavioral effects are predicated on memory reactivation

1 x CS-US No CS Test 24 hr 24 hr

1 2 30

20

40

60

80

100

Trial

Summary• By definition;

– Given that anisomycin had no effect on the memory when the memory was not reactivated demonstrates it was in a consolidated state.

– Given that anisomycin impaired the memory when the memory was reactivated demonstrates it was in a labile state.

• Therefore, the reactivation of consolidated auditory fear memories returns them to a labile protein synthesis dependent state in the LA.

Lewis’ Memory Model

Active Memory• Seconds to Hours• ”Labile” (sensitive to disruption)•Does not require new RNA & protein synthesis

Inactive Memory• Days to Weeks• Consolidated (insensitive to disruption•Does require new RNA & protein synthesis

PR-STM PR-LTM0

20

40

60

80

100

Control

Anisomycin

Per

cen

t F

reez

ing

Auditory fear conditioning- RatsIntra-amygdala infusions

PR-STM PR-LTM0

20

40

60

80

100

Control

Zif286KO

Per

cen

t E

xplo

rati

on

Object recognition-MiceTransgenic Knockout

PR-STM PR-LTM

-80

-60

-40

-20

0

20

40

60

Control

Interference

Per

cen

t C

han

ge

Fro

m R

eac

tiva

tio

n

Motor sequence learning- Human

Per

cen

t F

reez

ing

Contextual fear conditioning-Mice Inducible dominant negative

PR-STM PR-LTM0

20

40

60

80

100

Control

CREBI

Ch

ang

es

in B

od

y L

eng

th

Conditioned malaise- Sea Slugs

PR-STM PR-LTM-4-3-2-10123456

Control

aniso

Per

cen

t F

reez

ing

PR-STM PR-LTM0

10

20

30

40

50

60

70

80

90

100

Vehicle

Anisomycin

Context fear conditioning- RatsIntra-hippocampus infusions

(Nader et al, 2000) (Debiec et al, 2002) (Kida et al, 2001)

(Bozon et al, 2003) (Child et al, 2003)(Walker & Stickgold, 2003)

Constraints on Reconsolidation

5th Birthday Cake

Grandmother

6th Birthday

7th Birthday

Friends

Pets Gifts

Memories are richly associated

Does reactivation of one component of a memory return associated

memories to a labile state?

Debiec, Doyer, Nader & LeDoux

Using Second Order Conditioning to Create a Small Associative Network

Protocol• Phase 1

– CS1-US

• Phase 2– CS2-CS1

• Phase 3– CS2

• Expression of these memories

CS1: CS1US

CS2: CS2CS1 US

CS1US

CS2CS1

Direct reactivation of the first order memory causes it to undergo reconsolidation.

When the first order memory is indirectly reactivated it does not return to a labile state.

Summary

• The findings that direct, but not indirect, reactivation of CS1 induced reconsolidation of the first order memory suggests that reconsolidation may be restricted to those aspects of a memory or memories that are directly reactivated.

A General Characterization of Reconsolidation

1-Reconsolidation is a fundamental process.

2-Reconsolidation is not ubiquitous. There are boundary conditions such as strength of training, pure space, and in some paradigms extinction.

3- Reconsolidation is not a carbon copy of consolidation.

Reconsolidation as a therapeutic target for the treatment of PTSD

• Collaboration between;

– Roger Pitman & Scott Orr, Harvard University

– Karim Nader & Alain Brunet, McGill University

Experiment: Reactivate old consolidated traumatic memories and treat patients with beta-adrenergic blocker propranolol.

•Propranolol blocks the mechanisms that modulate the strength of traumatic memories but not the content of the memory itself. •Post-trauma propranolol administration decreases the probability of PTSD being established.

•Prediction: Post-reactivation propranolol should decrease the intensity of the traumatic memory, while leaving the memory intact.

Acknowledgements

New York UniversityCenter for Neural science

New YorkUSA

• G. Schafe• S. Duvarci• J. Debiac

• J.E. LeDoux

McGill University

Montreal, Quebec

Canada

• E. Einarsson

• S.H. Wang

• C. Ben Mamou

• O. Hardt

• M. Pompeiano