# Presentation: 552827

## Targeting reconsolidation as a new therapeutic strategy 

- Karim Nader
- Alfred P. Sloan Fellow
- Dept. of Psychology
- McGill University
- Montreal Canada

**Notes:**
One of the defining feature of memories is that their nature changes with time.  We’ve known for over 100 years that new memories are very senitive to disruption while older memories are more resistant to disruption. An every day example phone number and distraction.  This change from a sensitive to a insensitive state is what current Memory consolidation describe.  What I am going to try and convince you of is that you can revert  insensitive memories to a sensitive state simply by remembering them.  Once in this state, they are subject to being changed in content or strength and I will show you that memories can be functionally erased. 

## Kinds of Consolidation

- Hippocampus Dependent

- weeks to years

- _LTM_

- _STM_

- seconds to hours

- seconds to hours

- _Remote_

- _STM_

- Systems Consolidation

- Cellular Consolidation

- Hippocampus Independent
- 	(Neocortex)

**Notes:**
CC refers to how individual cells stabilize the changes in synaptic efficacy that are thought to encode memories.  CC is a property of all neurons, not just cells in the hippo.  
Aplysia, PFC or spinal cord etc. 

## 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

**Notes:**
Consolidation is a one way street

## Cellular Consolidation of  Auditory Fear Memories in the Lateral Amygdala

## Fear Conditioning

**e.g. light or tone**

***Time***

**Natural Threat**

**CS**

- Amygdala

**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 hr***

- STM

- 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                 LTM

***20 hr***

***4 hr***

**Percent Freezing**

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

- _Consolidation:_

- _Reconsolidation:_

- 1 x Tone-Shock            STM             LTM

***20 hr***

***4 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.

## Protein synthesis inhibition in the LA blocks consolidation and reconsolidation.

- Schafe & LeDoux, 2000

- Nader, Schafe & LeDoux, 2000

- Consolidation

- Reconsolidation

## A Test of Whether Reconsolidation Depends on Reactivation of the Memory

- 1 x CS-US             No CS               Test 2

***24 hr***

***24 hr***

## Anisomycin’s behavioral effects are predicated on memory reactivation

- 1 x CS-US              No CS                Test

***24 hr***

***24 hr***

## 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*

## Percent Freezing

**Percent Freezing**

**Auditory fear conditioning- **_**Rats**_
**Intra-amygdala infusions**

**Percent Exploration**

**Object recognition-**_**Mice**_
**Transgenic Knockout**

**PR-STM**

**PR-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**

**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)_

## Constraints on Reconsolidation

## Memories are richly associated

- Cake

- Grandmother

- 6th Birthday

- 7th Birthday

- Friends

- Pets

- Gifts

**Notes:**
Bartlett’s classic work demonstrating that memories can change with each time you interact with them. Loftus who suggested that reconsolidation could be a mechanisms to mediate such changes.   

## 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: CS1********US**
**CS2: CS2********CS1   ********US**

- CS1US

- CS2CS1

**Notes:**
2nd order Conditioning 
1- small associative network
2- indirectly reactivated.

## 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 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**