1 / 25

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. Hippocampus Independent (Neocortex). STM. LTM. STM. Remote. Cellular Consolidation.

swann
Download Presentation

Targeting reconsolidation as a new therapeutic strategy

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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 Hippocampus Independent (Neocortex) STM LTM STM Remote Cellular Consolidation seconds to hours seconds to hours Systems Consolidation weeks to years

  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. d e f e n s i v e b e h a v i o r a u t o n o m i c a r o u s a l h y p o a l g e s i a r e f l e x p o t e n t i a t i o n a d r e n a l a c t i v a t i o n Fear Conditioning Conditioned Stimulus (CS) e.g. light or tone Unconditioned Stimulus (US) e.g. footshock Time Natural Threat Amygdala CS

  6. Does the Consolidation of Auditory Fear Conditioning Require Protein Synthesis in the LA? Basic Paradigm: 4 hr 20 hr STM LTM 1 x Tone-Shock Anisomycin (62.5 mg/0.5 ml/side) into the Lateral (LA) Amygdala Schafe & LeDoux, 2000

  7. 100 80 60 40 Control 20 Anisomycin 0 STM LTM Protein synthesis inhibition in the LA blocks the induction of long term memory. 4 hr 20 hr 1 x CS-USSTM LTM Percent Freezing Schafe & LeDoux, 2000

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

  9. 24 hr 20 hr Tone-Shock CSPR-STMPR-LTM 4 hr 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.

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

  11. A Test of Whether Reconsolidation Depends on Reactivation of the Memory 24 hr 24 hr 1 x CS-USNo CS Test 2

  12. Anisomycin’s behavioral effectsare predicated on memory reactivation 24 hr 24 hr 1 x CS-US No CSTest

  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. 100 80 60 40 Control 20 Anisomycin 0 PR-STM PR-LTM 100 90 80 70 60 50 40 30 Vehicle 20 Anisomycin 10 0 PR-LTM PR-STM 100 80 60 40 Control 20 CREBI 0 PR-STM PR-LTM Auditory fear conditioning- Rats Intra-amygdala infusions Context fear conditioning- Rats Intra-hippocampus infusions Contextual fear conditioning-Mice Inducible dominant negative Percent Freezing Percent Freezing Percent Freezing (Kida et al, 2001) (Nader et al, 2000) (Debiec et al, 2002) Object recognition-Mice Transgenic Knockout Motor sequence learning- Human Conditioned malaise- Sea Slugs 60 40 20 Percent Change From Reactivation Changes in Body Length Percent Exploration 0 PR-STM PR-LTM -20 -40 Control -60 Interference -80 (Bozon et al, 2003) (Walker & Stickgold, 2003) (Child et al, 2003)

  16. Constraints on Reconsolidation

  17. Memories are richly associated Pets Gifts Friends 5thBirthday Cake 6th Birthday Grandmother 7th Birthday

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

  19. Protocol Phase 1 CS1-US Phase 2 CS2-CS1 Phase 3 CS2 Expression of these memories CS1: CS1US CS2: CS2CS1 US Using Second Order Conditioning to Create a Small Associative Network 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. 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 Acknowledgements

More Related