prof. stephan anagnostaras lecture 5: memory consolidation

Prof. Stephan Anagnostaras

Lecture 5: Memory Consolidation

Neurobiology of Learning and Memory

Multiple memory trace theory

McGaugh, 2000

Duncan, 1949

Squire: retention of TV shows after ECS

At least 2 kinds of consolidation

• Moleculartimescale of minutes to hours

• Systems timescale of weeks to years

Protein synthesis inhibition

Pavlovian fear conditioning protocol

• Bright White Lighting• Grumbling Noise• Ammonia Odor• Flat Shock Grids

Training Context

Shock US

Tone CS

Context CS

TRAINING

Pavlovian fear conditioning protocol

• Bright White Lighting• Grumbling Noise• Ammonia Odor• Flat Shock Grids

Testing Context

Context CS

TRAINING CONTEXT TEST

CR = Freezing

Freezing response assessed by blind time-sampling

Pavlovian fear conditioning protocol

• Baseline Period• Dark Red Lighting• Triangular Insert• White Noise• Vinegar Odor• Staggered Shock Grids

Alternate Context

TRAINING CONTEXT TEST

Tone CS

TONE TEST

CR = Freezing

Bourtchuladze et al., 1998

Anisomycin(protein synthesis)

Protein kinase Ainhibitor

Transgenic mice With reduced PKA

Josselyn et al., 2002 - CREB inhibition

CREB inducible repressor Anisomycin

Systems Consolidation

Amnesic humans display a time-limited retrograde amnesia of declarative memory

Temporally-graded retrograde amnesia

From Squire, Haist, & Shimamura (1989)

Zola-Morgan & Squire, 1991

Stuart Zola

Consolidation models

Rabbit (rat & mouse) Trace eyeblink depends on the hippocampus (Kim et al., 1995)

Within-subjects design (Anagnostaras et al., 1999)

REMOTE TRAINING

10 Tone-Shock Pairings

Within-subjects design

50 days later

REMOTE TRAINING

RECENT TRAINING

10 Tone-Shock Pairings(different tone)

Which contexts and tonesUsed were counterbalanced

Within-subjects design

50 days later next day

REMOTE TRAINING

RECENT TRAINING

LesionSHAMDH0–2–3–6AP

Electrolytic Dorsal Hippocampus Lesion

Within-subjects design

50 days later next day

10 dayrecovery

next day

REMOTE TRAINING

RECENT TRAINING

Sham or Hippocampus

Lesion

RECENT CONTEXT

REMOTECONTEXT

Test OrderCounterbalanced

DH lesions spare remote context memory

Remote Contextual Fear

DH lesions disrupt recent context memory

B12345678Minutes0255075100Remote Contextual Fear Recent Contextual Fear

DH lesions produce a time-limited retrograde amnesia of contextual fear

B12345678Minutes0255075100 C0RecentRemote(first six min)255075100Remote Contextual Fear Recent Contextual Fear Context Summary

Within-subjects design

50 days later next day

10 dayrecovery

next day

REMOTE TRAINING

RECENT TRAINING

Sham or Hippocampus

Lesion

RECENT CONTEXT

REMOTECONTEXT

Within-subjects design

50 days later next day

10 dayrecovery

next day

next day

next day

REMOTE TRAINING

RECENT TRAINING

Sham or Hippocampus

Lesion

RECENT CONTEXT

REMOTECONTEXT

REMOTE TONE

RECENT TONE

• Baseline Period• Dark Red Lighting• Quiet• Pine Shavings Odor• No Grids• Like Home Cage

Third Context for Tone Testing Only

Within-subjects design

50 days later next day

10 dayrecovery

next day

next day

next day

REMOTE TRAINING

RECENT TRAINING

Sham or Hippocampus

Lesion

RECENT CONTEXT

REMOTECONTEXT

REMOTE TONE

RECENT TONE

DH lesions spare remote tone fear memory

Remote Tone Fear

DH lesions spare recent tone fear memory

B0255075100MinutesBLBL134562Remote Tone Fear Recent Tone Fear

DH lesions spare tone fear memory

B0255075100MinutesBLBL134562Remote Tone Fear Recent Tone Fear

Remote(six min)C0255075100RecentTone Summary

DH lesions produce a highly selective deficit in recent contextual fear memory

DHSham

Context Summary0RecentRemote(first six min)255075100 Tone SummaryRemote(six min)0255075100Recent

Content could be:• Context-shock association• Just memory of the context

Systems gradientsin monkeys, rats,rabbits, and mice

Bontempi et al., 1999

Bontempi et al., 1999

Bontempi et al., 1999

Figure 4 Factor analysis showing clustering of response accuracy and metabolic activity in mouse brain regions during retention testing. a, Retrieval performance of recent information (5 days retention) appears in the hippocampal cluster. b, Retrieval performance of remote memories (25 days retention) now appears in the cortical cluster. c, Correlation matrix table. Correlation coefficients for the 5- and 25-day retention groups are presented above and below the solid black line, respectively. Shaded boxes show significant correlations (P < 0.05). HPC, hippocampus; EC-SUB, entorhinal cortex/subiculum; aCC and pCC, anterior and posterior cingulate cortices; FC ant. and FC post., anterior and posterior parts of the frontal cortex; ACC nuc., accumbens nucleus.

Semantic amnesia Hodges et al.focal temporal cortex damage

Frankland et al., 2001, NatureCortical disruption of CamKIIa: fear conditioning

Frankland et al., 2001, NatureCortical disruption of CamKIIa: water maze

Frankland et al., 2001, Nature

Cortical disruption of CamKIIa: water maze

hpc

cortex

Squire & Alvarez, 1995

McClelland,McNaughton,& O’Reilly, 1995