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Predicting not to predict too much: How the cellular machinery of the brain may anticipate the uncertain future. Yadin Dudai Department of Neurobiology The Weizmann Institute of Science. The textbook account of the biography of a memory:

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slide1

Predicting not to predict too much:

How the cellular machinery of the brain

may anticipate the uncertain future

Yadin Dudai

Department of Neurobiology

The Weizmann Institute of Science

slide2

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.

Storage

LTM

Consolidation

(The dual-trace hypothesis)

(The consolidation hypothesis)

STM

Time

(Combining Ribot 1882, Muller & Pilzecker 1900, Hebb 1949, McGaugh 2000, Dudai 2004)

slide3

An alternative account:

  • Active Memory

Inactive Memory

(After Lewis 1973, Dudai 2004, Nader 2005)

(The recurrent phases hypothesis)

(The reconsolidation hypothesis)

What do the data indicate?

slide4

100

LiCl ip

Hrs

Hrs - Yrs

80

Toxicosis US

Aversion CR

Taste CS

60

Aversion Index

NaCl ip

40

20

0

Central gustatory area,

insular cortex

An Experimental System: Conditioned Taste Aversion (CTA)

(Same magnitude of memory

even if first test performed

after several months)

slide5

The algorithm for the formation of long-term memory

in cortex and its molecular implementation

consolidation

Triggering memory encoding

consolidation

(Berman, Lamprecht, Rosenblum, Naor, Bahar, Kobilo, Shema & Dudai, 1996-2009)

Prima facie, this model fits the classic, unidirectional, account of LTM

But do the data support such ‘deterministic’ interpretation?

I will now demonstrate 4 ways to alter long-term CTA memory in cortex

slide6

A. Molecular changes in cortex following encoding

ERK1/2

PSD95

Elk-1

0.5

LTM

STM

Memory

Consolidation

180

240

(Fits, but does not prove,

the dual-trace hypothesis)

Magnitude of observed effect

B. Blockade of long-term memory in cortex

Time

0.5

Scopolamine

Anisomycin

96h

30

60

90

120

Time after training (min)

Method No. 1: Disruption of consolidation

Taste memory consolidates in the insular cortex

(Note time windows of consolidation)

(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& Dudai 1996, Berman et al. 1998, Kobilo-Moav & Dudai unpublished, Elkobi et al. 2008)

slide7

Method No. 2: Experimental ‘extinction’

Retrieval

Training

Non-reinforced retrieval

LTM

STM

1

4

5

6

Days

Days

Memory

Consolidation

Time

(untested control

doesn’t decline

in 4 months)

(Agnostic to the

dual-trace hypothesis)

(Eisenberg et al. 2003, Stehberg & Dudai unpublished)

Long-term taste memory extinguishes with use in the insular cortex

slide8

Retrieval

Retrieval

LTM

Training

Anisomycin into cortex

STM

1

2

5

6

7

8

Days

Memory

Consolidation

Reconsolidation

Vehicle

Time

(Does not fit the original

dual-trace- and consolidation

hypotheses)

Anisomycin

Post-retrieval test days

(Eisenberg et al. 2003)

Method No. 3: Disruption of ‘Reconsolidation’

Long-term taste memory reconsolidates in the insular cortex

Boundary conditions on reconsolidation:

Extinction – No, New encoding - Yes

(Background: Misanin 1968, Sara 2000, Nader et al. 2000)

slide9

consolidation

Method No. 4: Disruption of persistence

It now appears that there might be

potential plastic opportunities even in the absence of retrieval

(Berman, Lamprecht, Rosenblum, Naor, Bahar, Kobilo, Shema & Dudai, 1996-2009)

slide10

PKMz can be inhibited by the pseudosubstrate peptide, ZIP

Protein kinase M zeta (PKMz) is an autonomous form of the

atypical PKC, PKCz, synthesized from PKMz mRNA

z

(after Hernandez et al. 2003)

slide11

ZIP

ZIP

Memory

Memory

LTM

Training

Training

STM

Time

Memory

Consolidation

100

(Demonstrates that very-LTM

requires persistent enzyme activity

and is capable of rapid alterations)

Time

Aversion index

60

20

Ctrl

1 Month

Ctrl

3 Months

Time from ZIP

to test

Time from training

to ZIP

(Data compiled from Shema, Sacktor & Dudai. 2007, Shema, Sacktor, Hazvi & Dudai 2009)

Back to Method No. 4: Disruption of persistence

Long-term taste memory is quickly erased by an inhibitor of PKMz

(Background: Pastalkova et al. 2006)

effect of zip on cta memory in cortex
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?
slide13

The weakest link?

A cellular model: PKMz increases insertion of AMPA receptors

into the membrane via phosphorylation of scaffold/trafficking proteins

(Drawing modified from Hernandez et al. 2003)

slide14

Take home message

  • 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 for
  • the unpredictable demands of the future.
slide15

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)

Item accessibility

The extended cyclic model: multiple windows of plasticity,

trace modifiable in the presence and in the absence of reactivation

slide16

WIS

Reut Shema

Shoshi Hazvi

Efrat Furst

Orit Furman

Kelly Ludmer

Daniel Levy

Avi Mendelsohn

Uri Nili

Dana Bezalel

Aya Ben-Yakov

Micah Edelson

Yossi Chalamish

Yaara Yeshurun

Shiri Ron

NYU

Joe LeDoux

Lila Davachi

Nava Rubin

SUNY

Todd Sacktor

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