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Predicting not to predict too much:How the cellular machinery of the brain
may anticipate the uncertain future
Yadin DudaiDepartment of Neurobiology
The Weizmann Institute of Science
Consolidation
STM
LTM
Time
(The dual-trace hypothesis)
Storage
(Combining Ribot 1882, Muller & Pilzecker 1900, Hebb 1949, McGaugh 2000, Dudai 2004)
The textbook account of the biography of a memory: Items mature from a short-term into a long-term, stable state,
via consolidation, which occurs just once per item.
(The consolidation hypothesis)
Active Memory Inactive Memory
(After Lewis 1973, Dudai 2004, Nader 2005)
An alternative account:
(The recurrent phases hypothesis)
(The reconsolidation hypothesis)
What do the data indicate?
0
20
40
60
80
100
Ave
rsio
n I
nd
ex
LiCl ip
NaCl ip
An Experimental System: Conditioned Taste Aversion (CTA)
Taste CS Toxicosis US Aversion CR
Hrs Hrs - Yrs
Central gustatory area, insular cortex
(Same magnitude of memoryeven if first test performed
after several months)
The algorithm for the formation of long-term memory in cortex and its molecular implementation
(Berman, Lamprecht, Rosenblum, Naor, Bahar, Kobilo, Shema & Dudai, 1996-2009)
consolidation
consolidation
I will now demonstrate 4 ways to alter long-term CTA memory in cortex
Prima facie, this model fits the classic, unidirectional, account of LTM
But do the data support such ‘deterministic’ interpretation?
Triggering memory encoding
Taste memory consolidates in the insular cortex
Time
Mem
ory
STM
LTM
Consolidation
(Fits, but does not prove,the dual-trace hypothesis)
(A, taste exposure; B, CTA training. Data compiled from Rosenblum et al. 1993, Naor& Dudai 1996, Berman et al. 1998, Kobilo-Moav & Dudai unpublished, Elkobi et al. 2008)
180 240
ERK1/2Elk-1 PSD95
90 1206030
ScopolamineAnisomycin
Time after training (min)
Mag
nit
ude o
f obse
rved e
ffect
0.5
0.5
B. Blockade of long-term memory in cortex
A. Molecular changes in cortex following encoding
96h
Method No. 1: Disruption of consolidation
(Note time windows of consolidation)(Note time windows of consolidation)
Long-term taste memory extinguishes with use in the insular cortex
Time
Mem
ory
STM
LTM
Consolidation
(Agnostic to thedual-trace hypothesis)
Non-reinforced retrieval
1 54 6Days
Retr
ieval
Tra
inin
g
Days
(untested control doesn’t decline in 4 months)
(Eisenberg et al. 2003, Stehberg & Dudai unpublished)
Method No. 2: Experimental ‘extinction’
(Eisenberg et al. 2003)
1 2 65 7 8Days
Retr
ieval
Anisomycin into cortex
Anisomycin
Vehicle
Post-retrieval test days
Training
Long-term taste memory reconsolidates in the insular cortex
Time
Mem
ory
STM
LTM
Consolidation
(Does not fit the original dual-trace- and consolidation hypotheses)
Reconsolidation
Retrieval
Method No. 3: Disruption of ‘Reconsolidation’
Boundary conditions on reconsolidation:Extinction – No, New encoding - Yes
(Background: Misanin 1968, Sara 2000, Nader et al. 2000)
(Berman, Lamprecht, Rosenblum, Naor, Bahar, Kobilo, Shema & Dudai, 1996-2009)
It now appears that there might bepotential plastic opportunities even in the absence of retrieval
consolidation
Method No. 4: Disruption of persistence
Protein kinase M zeta (PKM) is an autonomous form of the atypical PKC, PKC, synthesized from PKMmRNA
(after Hernandez et al. 2003)
PKM can be inhibited by the pseudosubstrate peptide, ZIP
Long-term taste memory is quickly erased by an inhibitor of PKM
Time
Mem
ory
STM
LTM
Consolidation
(Demonstrates that very-LTM requires persistent enzyme activity and is capable of rapid alterations)
100
20
60
Avers
ion index
Time from training to ZIP
Time
Tra
inin
g
Mem
ory
(Data compiled from Shema, Sacktor & Dudai. 2007, Shema, Sacktor, Hazvi & Dudai 2009)
3 MonthsCtrl1 MonthCtrl
Time from ZIP to test
ZIP
Tra
inin
g
Mem
ory
ZIP
Back to Method No. 4: Disruption of persistence
(Background: Pastalkova et al. 2006)
Effect of ZIP on CTA memory in cortex:
• Once erased, memory can be reacquired – and re-erased• Not prevented by very intensive training• Not rescued by spontaneous recovery and US-reinstatement• Applies to multiple past taste-associations• Does not apply to taste recognition• Undetected before the taste association is established• Undetected within the first hour after training (i.e.,
consolidates)• Not replicated by a general serine/threonine kinase inhibtior
(H7)• Not replicated by microinfusions into the hippocampus• A manifestation of a physiological regulatory process?
A cellular model: PKM increases insertion of AMPA receptorsinto the membrane via phosphorylation of scaffold/trafficking proteins
(Drawing modified from Hernandez et al. 2003)The weakest link?
•There are multiple opportunities for a long-term memory trace to change in cortex :in consolidation ,
in extinction (where it is mostly the expression that changes) ,in post-retrieval reconsolidation ,and possibly also in the absence of retrieval .
•This modifiability of the cellular substrate of memory seems a basic attribute of memory. It is tempting to propose that it reflects the need to update and integrate new information into old, i.e., the need of memory systems to prepare forthe unpredictable demands of the future .
Take home message
Memory models: which is closer to reality?
The dual-trace model: Consolidation just once per item, deterministic
The cyclic model: multiple windows of plasticity,trace modifiable in reactivation (reconsolidation)
The extended cyclic model: multiple windows of plasticity,trace modifiable in the presence and in the absence of reactivation
Ite
m a
cce
ssib
ility