Biopsychology of Memory

Biopsychology of Memory

What is Memory?

The storage of information about our experiences

Major Research Questions

What is the biological substrate(s) of memory?

Where are memories stored in the brain?

How are memories accessed during recall?

What is the mechanism of forgetting?

Early Hypotheses about the Brain Substrates of Memory

Two prominent psychologists

- Karl Lashley

- Donald Hebb

Karl Lashley

Studied memory of complex maze learning in rats

Design:

-train lesions of the cortex test their memory

Results:

- only large lesions of the cortex produced deficits

- similar deficits were obtained no matter where the

cortical lesion was located

Lashley’s Two Principles

1. Principle of Mass Action ~ Memories for complex tasks are stored diffusely throughout the neocortex.

2. Principle of Equipotentiality ~ All parts of the neocortex play an equal role in the storage of memories for complex tasks.

IMPORTANT POINT:

Lashley’s research discouraged thinking about localized regions important for memory

Donald Hebb - 1949ff

Two memory systems

- short-term storage system

- long-term storage system

Short-term storage = reverberatory activity
Long term storage = structural change
Different substrates for short- vs. long-term storage
Transfer from short- to long-term storage =

CONSOLIDATION OF MEMORY

The Evidence for Hebb’s Consolidation Theory

RETROGRADE AMNESIA

Russell and Nathan - 1949

- World War II concussions

- Short-term or recent memory was vulnerable

- Long-term or older memory was resistant

CONSOLIDATION MODEL OF MEMORY

Experimental Evidence for Consolidation Theory

Pinel (1969)

Design:

Days 1-5 Exploration of Box, no water present

Day 6 1. Water present, rats drink

2. Electroconvulsive shock (ECS) given

at various times after drinking

Day 7 Retention Test - count niche explorations

Squire et al. 1975

ECS treatments in depressed humans

Two memory tests - one before, one after ECS treatments

- pick from a list of T.V. shows those that played for only

one season

- some shows were from 1-3 years before ECS, some from

4-5, 6-7, 8-9, and 10-17 years previously.

RESULTS:

- Retrograde amnesia for events that occurred from 1-3 years

prior to ECS

- consolidation of memory can continue for a long time

period

The Case of H.M.

Epileptic seizures

William Scoville, 1953 – Neurosurgeon

Bilateral medial temporal lobectomy

Brenda Milner – Neuropsychologist

H.M.’s Memory Deficit

Retrograde Amnesia - Loss of some memories for information learned before (3 years) the surgery

Anterograde Amnesia – Inability to form enduring memories for events occurring after the surgery

Intact short-term memory

H.M. - Formal Testing for LTM

Long-term Memory Tests – Deficient

Digit Span + 1 test
Matching to Sample
Maze Learning

Perceptual Tests - Normal

Gollin Incomplete Pictures Test
Mooney Face Perception Test

Long-term Memory Tests – Normal

Mirror drawing
Rotary pursuit
Pavlovian trace eyeblink conditioning
Gollin incomplete pictures
Tower of Hanoi Puzzle

Digit Span + 1 Test

1,3,2,7,9

1,3,2,7,9,6,

1,3,2,7,9,6,4

etc.

Explicit Memory(Declarative)

Memory that is directly accessible to conscious recollection

Memory of facts, events

- "knowing that" something happened

Memory with record

Impaired with medial temporal lobe damage

Implicit Memory(Procedural)

Memory not accessible as specific facts or data

Memory that is contained within learned skills or cognitive operations

-"knowing how"

Expressed only in performance

- motor skill learning

- cognitive skill learning

Not impaired with medial temporal lobe damage

What has H.M. taught us about the neural substrates of memory?

The importance of the medial temporal lobes

There is localization of function for memory

Different brain structures for short- and long-term memory

Medial temporal lobes contribute to memory consolidation

Memories are not permanently stored in the medial temporal lobes

Different brain structures for "explicit" vs. "implicit" memory

H.M.’s MRI Scans

The Contribution of the Hippocampus

Corsi – 1970

Case R.B. - 1986

Zola-Morgan et al. (1986)

Case R. B.

Severe ischemic episode hypoxia

Extensive memory tests

- Story recall

- Paired associates recall ~ 10 pairs of words

Dog – Umbrella

Car – Face

Mask - Pencil

- Diagram recall

Zola-Morgan et al. - cont

R.B. died in 1983

Obtained brain 4 hours after death

Brain Pathology

- Hippocampus

1. CA1 subfield gone

2. 4.6 million neurons missing

Little, if any, damage to other brain areas

HIPPOCAMPAL ANATOMY

Rempel-Clower et al. (1996)

Three additional cases

GD, LM, WH

All suffered from cardiovascular problems

- hypotension

- ischemia during surgery

- seizures with respiratory distress

Patient GD

Bilateral cell loss in hippocampal CA1 subfield

Other hippocampal subfields intact

Extra-hippocampal cell loss

- small region of the left amygdala

- small region of the left fornix

- region in the right globus pallidus

Patient LM

Bilateral cell loss in hippocampal CA1, CA2, CA3 subfields and dentate gyrus

Extra-hippocampal cell loss

- Entorhinal cortex (layers II and III) – major source

of input to hippocampus

- minor cell loss in areas of cortex and cerebellum

Patient WH

Bilateral cell loss in hippocampal CA1, CA2, CA3 subfields, dentate gyrus

Extra-hippocampal cell loss

- entorhinal cortex

- subiculum

- fornix, striatum, pons

Important implications for the effects of cardiac arrest and cardiovascular disease on brain integrity

Two Questions

How does ischemia/hypoxia damage the hippocampus?

Why the selective damage (e.g., CA1 damage) in some cases?

Animal Models of Ischemia

Davis – 1986

- Radial arm maze to assess spatial memory in rats

- Design:

1. 30 min. ischemic period (carotid artery clamp)

2. 30 day recovery period

3. Maze training

- Results:

1. ischemic rats demonstrate memory impairments

2. cell loss in hippocampal CA1 subfield

How Does Ischemia/Hypoxia Cause Hippocampal Damage?

Microdialysis:

- ischemia elevates glutamate in the hippocampus

How?

ischemia/hypoxia

anoxic depolarization of glutamate bouton

1. Excessive glutamate release

2. Reversal of the glutamate reuptake system

additional glutamate release

Two Effects of Excess Glutamate on the Postsynaptic Hippocampal Neuron

Early, immediate effect

Delayed effect over a 24 hour period

Early, Immediate Effect of Glutamate

Excess glutamate release

Extended period of depolarization in postsynaptic cell

Excessive Na+ influx

Water pulled osmotically into neuron

Neurons swell and burst

Delayed Effect of Glutamate

Neurons demonstrate morphological and biochemical signs of disintegration over 24 hour period

Dependent on the presence of CA++ in the extracellular fluid

Glutamate receptors:

Kainate receptor

AMPA "

NMDA "

mGlu " class

The Glutamate NMDA Receptor
(N-methyl-D-aspartate)

Associated with Ca++ ion channel

At rest, Ca++ channel blocked by magnesium ion

Sufficient depolarization from Na+ influx thru’ kainate and

AMPA receptor Na+ channels

ejects magnesium ion

permits Ca++ flow into soma

activation of numerous enzymes, 2^nd messengers

The NMDA Receptor – cont.

Abnormally excessive glutamate release

Prolonged period of Ca++ influx

Excessive activation of enzymes

Delayed cellular disintegration

What Evidence Points to the NMDA Receptor in Ischemia?

Gill et al. (1987)

1. ischemia elevates glutamate in hippocampus

2. lesion of perforant pathway

(major glutamate input pathway to hippocampus)

prevents ischemia cell death in CA1 region

3. MK – 801, a glutamate receptor antagonist

Protects against ischemic cell death in CA1 region

HIPPOCAMPAL ANATOMY

Why the selective damage to the CA1 region in some humans?

Probable Answer(?)

The CA1 region has the highest concentration of glutamate receptors in the brain.

Animal Models of Medial Temporal Lobe Amnesia

Tests of Memory

Monkey:

- Nonrecurring-Items Delayed Nonmatching-to-

Sample Test (DNMS) - Explicit memory

- Delayed Response Task - Explicit memory

- Barrier Motor-Skill Task - Implicit memory

- Lifesaver Motor-Skill Task – Implicit memory

Rats:

- Mumby Box - Explicit memory

Characteristics of Human Amnesia Produced by MTL lesions in Monkeys

Memory impaired on several tasks including ones identical to those failed by human patients.

Memory impairment exacerbated by increasing the retention delay.

Memory impairment is not limited to one sensory modality.

Memory impairment is enduring.

Skill-based memory is spared.

Immediate memory is spared.

What Areas in the Temporal Lobe Contribute to Memory Consolidation?

Hippocampus

Neocortex

Amygdala

Zola-Morgan et al. (1980s-1990s)

Is the hippocampus the only medial temporal lobe structure important for memory consolidation?

Compared DNMS scores across experiments:

-Hippocampal plus surrounding cortex lesions (H+)

-Hippocampal plus amygdala plus all surrounding

cortex lesions (H+A+)

1. The medial temporal lobectomy monkey

Result:

The H+A+ lesion produces the greatest deficit.

Why does H+A+ lesion produce more memory impairment than the H+ lesion?

Possibilities:

1. The amygdala contributes to explicit memory

2. The cortex surrounding the amygdala contributes

to explicit memory

Zola-Morgan et al.

Five groups of monkeys

1. Group A amygdala lesion, spared the cortex

2. Group H+ hippo. lesion plus surrounding cortex

3. Group H+A hippo. lesion plus surrounding

cortex plus amygdala lesion

4. Group H+A+ Hippo. plus surrounding cortex

plus amygdala plus surrounding

cortex lesion

5. Group N Unoperated Control

Zola-Morgan et al.

Results:

Group A no deficit

Group H+A

Group H+

Group H+A+ worse than all other groups

Conclude:

1. Amygdala doesn’t contribute to explicit memory

2. Cortex surrounding the amygdala may contribute

A Dissociation of Hippocampal vs. Amygdala Memory Function in Humans

Declarative (Explicit Memory)

(Hippocampal Function)

versus

Emotional Memory

(Amygdala Function)

Bechara et al. (1995)

Three patients:

- one with bilateral hippocampal damage (H+)

- one with bilateral amygdala damage due to

Urbach-Wiethe Disease (A)

- one with bilateral medial temporal lobe

damage (H+A+)

Normal control group: no brain damage (n=4)

Bechara et al. - cont.

Pavlovian Conditioning Task

Procedure:

- present green, blue, yellow and red slides

Blue slide 100 decibel boat horn

(Conditioned Stimulus) (Unconditioned Stimulus)

Skin Conductance Response

(Unconditioned Response)

(Sympath. Nerv. System

Activation)

Bechara et al. – cont.

Pavlovian Conditioning:

- Over repeated slide presentations (trials):

Subject learns that blue slide predicts aversive US

Blue slide elicits learned anticipatory anxiety

indicated by the SCR

Conditioned Response

Five minutes following conditioning trials:

- subjects asked four questions to assess declarative

memory (memory for facts)

Bechara et al. - cont.

Four Questions:

How many different colors did you see?
Tell me the names of the colors?
How many different colors were followed by the horn?
Tell me the name(s) of the colors that were followed by the horn?

Bechara et al - cont.

Results:

Normal group conditioned SCR

good declarative memory

Amygdala lesion no conditioned SCR

normal declarative memory

Hippo. lesion normal conditioned SCR

no declarative memory

MTL lesion no conditioned SCR

no declarative memory

Bechara et al. - cont.

Conclusion:

A Double Dissociation

Amygdala contributes to the formation of emotional memories (fear, anxiety)
Hippocampus contributes to the formation of explicit (declarative) memories

Amygdala vs. Hippocampal Damage in Monkeys

A double dissociation similar to humans

Why does the H+A+ lesion produce a more severe impairment than the H+A or H+ lesion?

Is it do to damage to cortex which surrounds the amygdala?

What is the cortex?

Perirhinal and Parahippocampal Cortex

Entorhinal Cortex

Hippocampus

Zola-Morgan et al.

DNMS Task

Three groups:

1. Group N

2. Group H+A+

3. Group PRPH perirhinal/parahippocampal

lesion

Result: PRPH Group severe deficits comparable to

H+A+ Group

Conclude: The critical area may reside in PRPH cortex

What about the hippocampus by itself?

Murray and Mishkin (1998)

Compared AH vs. perirhinal (Rh) cortical lesions in monkeys

DNMS Test

Result:

- Absolutely no effect of the AH lesion

- Severe deficit with Rh lesion

Important point:

- Rh lesions do not produce retrograde amnesia

Mumby and Pinel (1994)

Compared AH lesions vs. perirhinal cortex lesions in rats

Mumby Box Test

Results:

- Little effect of AH lesion

- Significant effect of perirhinal cortex lesion

But…..What about R.B.and G.D.???

Rather selective damage to hippocampal CA1 subfield produced substantial anterograde memory impairments

The Problem:

Why does limited damage to the hippocampal subfields produce significant memory deficits whereas only minimal or no deficits occur with total removal of the hippocampus???

Mumby et al. (1996)

Three groups of rats:

1. Ischemia Sham lesion Mumby box

2. Ischemia Hippo. lesion Mumby box

3. Ischemia Hippo. Lesion Mumby box

Result??

- Group 2 demonstrated normal memory

- Group 3 demonstrated severe memory deficit

Mumby

Ischemia

Hypothesis

Is There a Function for the Hippocampus in Memory?

The Evidence for a Function:

Selective hippocampal lesions in rats

Deficits:

1. Morris Water Maze

2. Radial Arm Maze

A Contribution for the hippocampus in spatial memory

A Hippocampal Function in Memory? – cont.

Additional evidence for a role in spatial memory:

Hippocampal size in different species of birds

- Homing pigeons have a larger hippocampus

- Birds that store seeds in wide-spread caches have a

larger hippocampus than non-seed storing species

- Black-capped chicadee:

hippocampal size increases in the fall

A Hippocampal Function in Memory?

London Taxi Drivers

- posterior hippocampal region enlarged compared

to comparison group

- anterior hippocampal region reduced in size

- drivers with more experience have a larger

posterior, but smaller anterior, hippocampus than

less experienced drivers

Suggests:

- the experience of navigating may have led to the

enlargement

Can the Adult Brain Generate New Neurons?

Gage and colleagues (1997ff.)

Stem cells - adult mouse hippocampal dentate gyrus

- versatile cells

- resemble stem cells in the developing embryo

- continuously divide

- many die soon after division

- some mature into dentate gyrus granule cells

- the process of neurogenesis

QUESTION: How can neurogenesis be enhanced?

Gage et al. (1997)

Adult mice – two genetically identical groups

Two living conditions for 40 days

- standard laboratory cages

- enriched living condition - complex environment

Results:

- enriched mice 1. larger dentate gyrus

(young adult) 2. 15% more dentate gyrus

granule cells

3. significantly faster learning in

Morris water maze

Gage et al. (1999)

Adult mice

Two living conditions:

- standard cage

- standard cage plus running wheel (4.78 km/day)

Result: Runners

- enhanced neurogenesis

- enhanced performance in Morris Water maze when

tested 30 days into housing condition

POSSIBILITY: New neurons may contribute to

improved memory???

What About Neurogenesis in the
Primate Brain?

Gould et al. (1998)

Adult Monkeys

- neurogenesis in the adult dentate gyrus

Stress and neurogenesis:

adult males placed in unfamilar colony

1. subjected to aggression/stress by dominant males

2. reduced number of developing dentate granule cells

3. Glucocorticoids inhibit hippocampal neurogenesis

Does Neurogenesis Occur in the Human Brain?

Erickson et al. (1998)

- made use of DNA marker (BrdU) used in mice

- only labels DNA in cells (i.e., stem cells) preparing

to divide

- marker inherited by daughter cells and future

descendants of original dividing cell

- BrdU will be observed in mature neurons

- given to certain cancer patients to monitor tumor

growth rate

Erickson et al. - cont.

- examined hippocampus of five deceased patients

- each displayed new dentate gyrus granule cells

A Hippocampal Function in Memory??

Hippocampal place cells

- respond when the rat is in a particular place its

environment

- their place response takes several minutes to

develop while the rat explores a new environment

CONCLUSIONS:

One specific function of the hippocampus is the storage of memories for spatial location

MEDIAL TEMPORAL LOBE VS. DIENCEPHALIC AMNESIA

Korsakoff’s Syndrome

- chronic alchoholism

- anterograde Amnesia

- severe retrograde amnesia

- damage to the diencephalon

- thiamin (vitamin B1) deficiency

1. mammillary bodies (hypothalamus)

2. thalamic mediodorsal nucleus

- Case N.A.

MEDIAL TEMPORAL LOBE VS. DIENCEPHALIC AMNESIA

Diencephalic

Amnesia Similar Memory

Medial temporal Dysfunctions

lobe amnesia

The mammilary bodies, mediodorsal thalamus and temporal lobe structures which contribute to memory may be components of the same circuit

What are the physiological/structural changes that form the substrate for memory?

A focus on the hippocampus

Long-term Potentiation (LTP)

The enduring facilitation of transmission across a synapse as a function of repeated activation

First observed in the hippocampus – 1973

Occurs at several different hippocampal synapses

Occurs in numerous brain areas

Can be induced in a matter of seconds

Can last for months

Can be studied in the hippocampal slice preparation

LTP: TWO CONDITIONS REQUIRED

LTP from concurrent activation of two different inputs

2. Depolarization 1. Transmitter release

LTP:
MECHANISM

EXPERIMENT 1:

Hippocampal slice
Apply NMDA receptor antagonist
Apply high frequency stimulation to induce LTP in dentate gyrus neurons

RESULT: LTP IS BLOCKED

CONCLUSION:

1. Glutamate is necessary for LTP to occur

2. NMDA receptor activation is also necessary

LTP:
MECHANISM

EXPERIMENT 2.:

Hippocampal slice
Apply high frequency stimulation to induce LTP

in dentate gyrus neurons

Reduce Ca⁺⁺ activity in the post-synaptic neuron

RESULT:

1. LTP is blocked

CONCLUSION:

2. Ca++ is necessary for LTP

LTP:
MECHANISM

CONCLUSIONS:

1. NMDA receptors are necessary for LTP

2. Ca⁺⁺ is necessary for LTP

What is the Role of Calcium?

CA++ enters via NMDA Receptors

activates CA++ dependent enzymes

protein synthesis nitric oxide synthesis

(retrograde transmitter)

Structural changes Structural changes

(post-synaptic cell) (pre-synaptic cell)

What are the structural changes produced by LTP that lead to enhanced synaptic transmission?

1. Increased Receptors or Receptor Sensitivity

2. Increased Transmitter Release

3. Increased Number of Synapses

4. Structural Change of Dendritic Spine

LTP: Mechanism – cont.

LTP blocked by inhibition of protein synthesis

LTP blocked by blocking nitric oxide synthesis

Is There a Relationship Between LTP and Memory?

Several lines of evidence point to one

1. NMDA receptor antagonists injected into the hippocampus or amygdala produce learning/memory deficits in different tasks

Some controversy in the results

2. LTP develops in the hippocampus or amygdala

during different forms of learning

3. Genetic alterations of LTP mechanisms

The Relationship Between LTP and Memory during Fear Conditioning?

Rogan et al. (1997)

- Pavlovian fear conditioning in rats

- Tone (CS) footshock(US) (paired trials)

- Tone comes to elicit fear reflected in freezing (CR)

over trials

- Lesions of the lateral amygdala block freezing CR

Rogan et al. – cont.

Design:

- two groups of rats:

1. Group 1 Paired trials

2. Group 2. Unpaired trials

- recorded population response to tone from lateral amygdala

- three phases of the conditioning procedure

1. Pre-training– recorded response to tone alone

2. Training – recorded response during paired and

unpaired trials

3. Test phase (1 day later) – recorded

response to tone alone

Rogan et al. - cont

Results:

- Population response became larger in rats receiving paired trials than in rats receiving unpaired trials

- Larger population response was present in rats receiving paired trials during the test phase 24 hrs. after training

Conclude:

- Response of lateral amygdala neurons to tone is

enhanced as a function of learning

- Suggests that an LTP mechanism may be the

substrate for the enhancement

Genetic Alterations of LTP Mechanisms and Effects on Learning

The "Knock-out" mouse model

- mice deficient in the genes necessary for the

production of NMDA receptors, CA++ - dependent enzymes, etc.

Recall:

1. CA++ enters the NMDA receptor channel

2. CA++ activates enzymes Structural changes

LTP

Tsien et al. (1996)

Created a "knockout mouse"

- deficient in gene responsible for an essential

subunit of hippocampal CA1 NMDA receptors

- renders the CA1 NMDA receptors non-functional

Results:

- deficient in LTP at CA1 synapses

- deficient in learning in Morris water maze

What happens if you increase the function of NMDA receptors? Will you facilitate LTP and learning?

Tang et al. (1999)

Created a mouse with a type of NMDA receptor that stays open longer More CA++ influx

- the Doogie mouse

- new receptor is located in various brain regions

Result: Compared to control mice Doogie mice demonstrate

- enhanced hippocampal LTP

- enhanced fear memory

- enhanced learning in the Morris water maze

- enhanced visual object recognition memory

What are the Ca++ dependent enzymes?

There are several called protein kinases

- Protein kinase C

- Type II Ca++/Calmodulin-dependent protein

kinase or CAM-KII

- Tyrosine kinase

What if we create a knockout mouse for CAMKII?

Silva et al. (1992)

- CAMKII abundant in hippocampus

- Developed a mouse deficient in CAMKII mRNA

1. examined hippocampal LTP

2. examined spatial learning in Morris water maze

- Result:

1. deficient LTP

2. retarded Morris water maze learning