Targeting reconsolidation as a new therapeutic strategy Karim Nader Alfred P. Sloan Fellow Dept. of...
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Transcript of Targeting reconsolidation as a new therapeutic strategy Karim Nader Alfred P. Sloan Fellow Dept. of...
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