Prof. Stephan Anagnostaras

Lecture 4: Amnesia in humans and animals

Neurobiology of Learning and Memory

Neurobiology of Learning and Memory

Memory structuresMemory structures

RB

Animal models of memoryAnimal models of memory

•HM inspired investigation of MTL animal models of memory

•no verbal abilities in animals, so can’t use terms “explicit” or “declarative” memory

•CAN look at what happens with hpc damage… (area affected in many human amnesics)

Object recognition memory task: Non-recurring items Delayed Non-Match-to-Sample (DNMS)Object recognition memory task: Non-recurring items Delayed Non-Match-to-Sample (DNMS)

•usually w/monkeys (but babies, too), can also do w/rats (Mumby box)

•give sample object w/reward underneath

•take away objects & wait delay period

•present 2 objects (1 from before (sample)): need to pick NEW object (the non-match w/food under)

•can increase delay b/w sample & pair to test memory more finely

DNMS task in monkeysDNMS task in monkeys

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Effects of lesions on Delayed Non-Match-to-Sample (DNMS)Effects of lesions on Delayed Non-Match-to-Sample (DNMS)

•MTL-lesioned monkeys won’t pick new object (can’t remember sample object from before)

Which part of MTL is important?

•monkeys w/hpc lesions do poorly•rhinal ctx lesions have even BIGGER effect (problem w/ shorter delay)

Which area is typically more affected in humans w/ brain damage?•Remember that hpc is particularly susceptible to damage from ischemia (stroke, heart attack)

Rhinal cortex overlays the hippocampus (hpc)Rhinal cortex overlays the hippocampus (hpc)

Summary of monkey studiesSummary of monkey studies

• Hippocampus critical

• Surrounding cortex exacerbates deficit

• Amygdala not critical for these tasks

Memory in rats ( and mice): what is it that they must remember?Memory in rats ( and mice): what is it that they must remember?

Several views on hippocampus

• Explicit memory is an example of the kind of memory the hippocampus processes

• The hippocampus is only involved in explicit memory

• The hippocampus is specialized for spatial memory and was co-opted for explicit memory when language developed

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Several paradigmsSeveral paradigms

• Will talk about fear conditioning later

• Spatial memory paradigms- Olton Radial arm maze- Morris Watermaze

• Nonspatial paradigms- object recognition- spatial recognition- social recognition- social transmission- relational learning

Win-Shift spatial working memory on the Olton radial arm maze: UnshiftedWin-Shift spatial working memory on the Olton radial arm maze: Unshifted

A. Unshifted Phase

4 Random Arms Baited-Open4 Arms Closed 5 Minute Maximum(Trial over when 4 correct)Errors = Revisits

–Food deprived mice aresearching for food pellets

–Isolated noise-buffered room–Maze itself is isotropic–Lots of distal extramaze cues

Spatial delayed non-matching to sample

Win-Shift spatial working memory on the Olton radial arm maze: UnshiftedWin-Shift spatial working memory on the Olton radial arm maze: Unshifted

A. Unshifted Phase

4 Random Arms Baited-Open4 Arms Closed 5 Minute Maximum(Trial over when 4 correct)Errors = Revisits

Win-Shift spatial working memory on the Olton radial arm maze: ShiftedWin-Shift spatial working memory on the Olton radial arm maze: Shifted

Delay

2-60 min

B. Shifted PhaseA. Unshifted Phase

4 Random Arms Baited-Open4 Arms Closed 5 Minute Maximum(Trial over when 4 correct)Errors = Revisits

4 Shifted Arms BaitedAll Arms Open5 Minute MaximumErrors = Revisits between or within phase

Win-Shift spatial working memory on the Olton radial arm maze: ShiftedWin-Shift spatial working memory on the Olton radial arm maze: Shifted

Delay

2-60 min

B. Shifted PhaseA. Unshifted Phase

4 Random Arms Baited-Open4 Arms Closed 5 Minute Maximum(Trial over when 4 correct)Errors = Revisits

4 Shifted Arms BaitedAll Arms Open5 Minute MaximumErrors = Revisits between or within phase

???

Win-Shift A phase: 4 random arms baited and open

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Win-Shift B phase: opposite 4 baited; all open

1. Mouse placed in home cage

2. Maze cleaned with ethanol

--Delay period--

3. Mouse placed into enclosed center

Win-Shift B phase: opposite 4 baited; all open

poor memory

Achreceptorknock-out(subtype=M1)

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•Measure latency to mount plaform & swim path (distance traveled to platform)

•Use spatial cues in room (posters, etc) to locate submerged platform (same place ea. time)

Water Maze HiddenPlatform Task

Watermaze day 1Watermaze day 1

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Watermaze day 3Watermaze day 3

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Watermaze day 5Watermaze day 5

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Hpc lesions disrupt hidden platformwater maze learning (spatial learning)

Normal NeocorticalControl lesion

Hippocampallesion

WatermazeWatermaze

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Watermaze visibleWatermaze visible

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Eichenbaum, 2000

Hippocampal (hpc) place cells: encode memory for spatial location?Hippocampal (hpc) place cells: encode memory for spatial location?

Left-turn trials: individual hpc cells fired as rat passed through each of a series of locations (red circled areas and arrows) running up the stem of the T-maze and turning onto the left choice arm where it received a reward (black well). Right-turn trials: a diff set of cells fired as the animal passed through the same set of locations on the stem as well as when it turned onto the right choice arm (green circles and arrows). These findings indicate that the hpc represents each type of trial separately.

T-maze:Run to particulararm to receivereward

Nature Reviews Neuroscience 1; 41-50 (2000)

Social Transmission of Food Preferences

Eichenbaum, 2000

Mumby Box

(Clark, West, Zola, & Squire, 2001)

Object Recognition

Rampon et al. (2000) - CA1 NMDA KO

Social recognitionSocial recognition

Social recognitionSocial recognition

Delay

Kogan, Frankland, & Silva, 2000

HippocampalLesion

Anisomycin

CREB -/-

Social discrimination: non-match to sampleSocial discrimination: non-match to sample

4 min baseline + 4 min test

Social discrimination: non-match to sampleSocial discrimination: non-match to sample

Delay

4 min baseline + 4 min test 4 min baseline + 4 min test

xSocial discriminationxSocial discrimination

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Different types of learning & memory rely on different brain structuresDifferent types of learning & memory rely on different brain structures

Explicit memoryImplicit memory

Facts(semantic)

Events(episodic)

Medial temporal lobe; diencephalon

Procedural memory:skills & habits(basal ganglia) Skeletal musculature

(cerebellum)

Classical conditioning

Emotional Responses(amygdala)

Priming(neocortex)

Eyeblink conditioning in rabbit

Classical (Pavlovian) conditioning and memoryClassical (Pavlovian) conditioning and memory

There are many different forms of classical conditioningand the responsible brain structure depends on the form

Examples: a) Pavlovian fear conditioning:

Tone --> Shock Then: Tone --> freeze(CS) (US) (CS) (CR)

• Depends on the amygdala • + the hippocampus with trace procedure• + the hippocampus if the CS is a context

b) Eyeblink conditioningTone --> puff of air to eye Then: Tone --> eyeblink(CS) (US) (CS) (CR)

•Depends on cerebellum• + hippocampus with trace procedure

• Declarative knowledge of task always depends on hippocampus

Eyeblink conditioning (depends on cerebellum)Eyeblink conditioning (depends on cerebellum)

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ToneCS

Air PuffUS

ON

ON

OFF

OFFTime

Speaker

Speaker

Air Nozzle

Air Nozzle

Thread to3rd eyelid

Thread toeyelid

Eyelid Mvmtmeasuring device

Eyelid Mvmtmeasuring device

Cerebellar eyeblink circuitCerebellar eyeblink circuit

Kim & Thompson, 1997

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

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

Clark & Squire, 1998

Trace eyeblink In humans

Role of awareness

Clark & Squire, 1998

Trace eyeblink In humans

Role of awareness

SummarySummary

Ongoing debate over the role of the hippocampus

• Unitary role in explicit, conscious declarative memory

• Independent roles in spatial navigation versus declarative memory

SummarySummary

• Can definitely study role of MTL structures in memory

• Many experiments in animals not possible in humans

• Still ‘correspondance’ problem exists between human and animal studies