Transcript 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
Long-term (older)
Short-term (recent)
memory
memory
Consolidation process
(resistant)
(vulnerable)
Experimental Evidence for
Consolidation Theory
Pinel (1969)
Water
bottle
niche
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, 2nd 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-toSample 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
OR
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
similar deficits
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:
1. How many different colors did you see?
2. Tell me the names of the colors?
3. How many different colors were followed
by the horn?
4. Tell me the name(s) of the colors that were
followed by the horn?
Bechara et al - cont.
• Results:
• Normal group
• Amygdala lesion
• Hippo. lesion
• MTL lesion
conditioned SCR
good declarative memory
no conditioned SCR
normal declarative memory
normal conditioned SCR
no declarative memory
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 1 hr. Sham lesion
2. Ischemia 1 hr. Hippo. lesion
3. Ischemia 1 wk. Hippo. Lesion
Mumby box
Mumby box
Mumby box
Result??
- Group 2 demonstrated normal memory
- Group 3 demonstrated severe memory deficit
Cort.
Mumby
Ischemia
Hypothesis
Cortical glutamate neuron
Perforant path
Excess glutamate release
CA1
Hippocampal CA1 neuron
(becomes hyperactive
and dies)
Excess glutamic acid
Cort.
Cortical neurons
(become dysfunctional)
memory impairment
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
• Medial temporal
lobe amnesia
Similar Memory
Dysfunctions
• 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
Dentate Gyrus
Neuron
1 –Transmitter Release
Perforant path
Stimulate
here
2 - Depolarization of
Sufficient Magnitude
Entorhinal
Cortex Neuron
1. 1 and 2 must occur concurrently.
2. Both occur with high frequency stimulation
(tetanus) of the entorhinal cortex
LTP from concurrent activation of
two different inputs
2. Depolarization
1. Transmitter release
Perforant path
Unconditioned
Stimulus
LTP occurs
here
Conditioned
Stimulus
1. 1 and 2 must occur concurrently.
Conditioned Response
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
Structural changes
(post-synaptic cell)
nitric oxide synthesis
(retrograde transmitter)
Structural changes
(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
Will excess CAMKII produce
LTP?
• Petitt et al. (1994)
- inject the hippocampal slice (CA1) with a virus
- virus causes CA1 cells to manufacture
LTP Develops During learning
• Mitsuno et al. (1994)
- Radial arm maze
- Experiment 1.
Two groups of rats:
1. Experimental group - maze learning
2. Control group – handled
Measured LTP in the hippocampus after 7 days of
maze training or handling
Result: Enhanced population spike in trained rats
Mitsuno et al.- cont.
• Experiment 2
- determine the amplitude of population spike each
day after maze training
Result:
- Population spike gradually increases over training
days in maze-trained, but not in handled group
Question: Does the increase in the population spike
really reflect memory or simply some
performance variable??
Does Learning Affect Neurogenesis
in the Hippocampus?
• Gould et al. (1999)
Morris water maze training in rat
enhances survival of new neurons
in hippocampal dentate gyrus
net increase in number of new neurons
Question: Implications for Memory???
What other brain structures
contribute to memory?
• The Dorsolateral Prefrontal Lobes
• Working memory = memory in the active state
- the memory that the organism needs and uses for
the performance of acts in the short term
- often called Short Term Memory
The Prefrontal Lobes and
Working Memory
Fuster et al. (1995)
- monkeys
- cryoprobe to cool the dorsolateral prefrontal cortex
- delayed matching to sample task
- Result:
deficits at short delay intervals (e.g., 8 seconds)
Recall: Lesions of medial temporal lobe structures do
not produce delays at such short delay intervals
The Dorsolateral Prefrontal
Lobes and Working Memory
• Fuster et al.
- delayed response task
- recorded from cells – dorsolateral prefrontal cortex
• Result:
- a type of neuron that only becomes active during
the delay period
- activity is specific to the memory task
- working memory cells???
The Dorsolateral Prefrontal
Cortex and Working Memory
• Humans - frontal lobe damage
- damage produces deficits in delay tasks
- deficits similar to that observed in monkeys
• Humans – PET scan during working memory task
- Petrides et al. (1993ff)
- verbal working memory task
Petrides et al. (1993) – cont.
3. Externally ordered condition
- experimenter reads numbers from 1-10, omitting
one number
- subjects asked to monitor the numbers carefully
in order to determine which number was omitted
• Pet scans performed under all conditions
• Results:
Increased activity in dorsolateral prefrontal cortex
during the self- and externally-ordered conditions
Petrides et al. (1993)
• Verbal Working Memory Task
- three conditions
1. Control condition
- Count aloud from 1 to 10 repeatedly for 60
seconds
2. Self-ordered condition
- Say aloud the numbers 1-10 in random order
without repeating a number
- Start a new trial with the number 1
ALZHEIMER’S DISEASE
• The most common form of dementia.
3 Pathological Changes in the Brain:
– Extensive Neural Degeneration
– Neurofibrillary Tangles
• threadlike tangles in the neural cytoplasm
– Amyloid Plaques
• Spherical clumps of scar tissue composed of
degenerating neurons interspersed with an abnormal
protein called amyloid
ALZHEIMER’S DISEASE
ALZHEIMER’S DISEASE
• Pathological changes are prevalent in the
structures of the medial temporal lobe and
the basal forebrain.
• In addition to retrograde and anterograde
amnesia, AD patients show some short-term
memory loss and some implicit memory
loss.
ALZHEIMER’S DISEASE
Patients with AD show a reduction in
cholinergic (ACh) activity:
• Less acetylcholine
• Less choline acetyltransferase (synthesis)
• Less acetylcholinesterase (breakdown)
– Also lower levels of NE & 5-HT
ALZHEIMER’S DISEASE
TREATMENT
• Acetylcholine agonists tried as nootropics
(memory-improving drugs), but have failed.
• Now developing acetylcholinesterase
inhibitors that seem to be working (e.g.,
Rivastigmine; a.k.a. Exelon)
– Shown to improve CNS function and daily
living over 6 month period.