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