1. Targeting reconsolidation as a new therapeutic strategy Karim Nader Alfred P. Sloan Fellow Dept. of Psychology McGill University Montreal Canada

2. Kinds of Consolidation Hippocampus Dependent weeks to years LTM STM seconds to hours Remote STM Systems Consolidation Cellular Consolidation Hippocampus Independent (Neocortex)

3. 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

4. Cellular Consolidation of Auditory Fear Memories in the Lateral Amygdala

5. Conditioned Stimulus (CS) e.g. light or tone Time defensivebehavior autonomicarousal hypoalgesia reflexpotentiation adrenalactivation Natural Threat CS Amygdala Fear Conditioning Unconditioned Stimulus (US) e.g. footshock

6. 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 hr STMLTM Schafe & LeDoux, 2000

7. Protein synthesis inhibition in the LA blocks the induction of long term memory. Schafe & LeDoux, 2000 1 x CS-US STM LTM 20 hr4 hr STMLTM 0 20 40 60 80 100 Control Anisomycin Percent Freezing

8. Consolidation: Reconsolidation: Do Consolidated Memories Return to a Labile State When Retrieved or Reactivated? 1 x Tone-Shock STM LTM 20 hr4 hr 1 x CS-US CS PR-STM PR-LTM 20 hr 4 hr 24 hr Nader, Schafe & LeDoux, 2000 Schafe & LeDoux, 2000 Anisomycin (62.5  g/0.5  l/side) infusions into the Lateral amygdala (LA)

9. 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-LTM 20 hr 4 hr 24 hr

10. Protein synthesis inhibition in the LA blocks consolidation and reconsolidation. Schafe & LeDoux, 2000 STMLTM 0 20 40 60 80 100 Control Anisomycin Percent Freezing PR-STMPR-LTM 0 20 40 60 80 100 Control Anisomycin Percent Freezing Nader, Schafe & LeDoux, 2000 Consolidation Reconsolidation

11. A Test of Whether Reconsolidation Depends on Reactivation of the Memory 1 x CS-US No CS Test 2 24 hr

12. Anisomycin’s behavioral effects are predicated on memory reactivation 1 x CS-US No CS Test 24 hr

13. 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.

14. 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

15. PR-STMPR-LTM 0 20 40 60 80 100 Control Anisomycin Percent Freezing Auditory fear conditioning- Rats Intra-amygdala infusions Percent Exploration Object recognition- Mice Transgenic Knockout PR-STMPR-LTM -80 -60 -40 -20 0 20 40 60 Control Interference Percent Change From Reactivation Motor sequence learning- Human Percent Freezing Contextual fear conditioning- Mice Inducible dominant negative PR-STMPR-LTM 0 20 40 60 80 100 Control CREBI Changes in Body Length Conditioned malaise- Sea Slugs Percent Freezing Context fear conditioning- Rats Intra-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)

16. Constraints on Reconsolidation

17. 5 th Birthday Cake Grandmother 6th Birthday 7th Birthday Friends PetsGifts Memories are richly associated

18. Does reactivation of one component of a memory return associated memories to a labile state? Debiec, Doyer, Nader & LeDoux

19. 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: CS1  US CS2: CS2  CS1  US CS1  US CS2  CS1

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

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

22. 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.

23. 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.

24. 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.

25. Acknowledgements New York University Center for Neural science New York USA 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