Learning

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Learning Memory

• Vedran Lovic

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Lecture Outline

• Introduction to Basic Concepts
• Karl Lashleys Search For Memory
• Patient H.M.
• Different Types of Learning and Memory
• Non-human Animal Approaches
• Cellular Basis of Learning and Memory
• Genetic Manipulations

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1. Learning Memory

• Speaking, bicycling, multiplication by 7s,
  urinary control, taste of oranges, balancing when
  standing, anxiety associated with public
  speaking, smell of bananas, the appearance of
  your face, your mothers name, first day of
  school
• Alzheimers Disease, Traumatic Brain Injury,
  Schizophrenia, Epilepsy, Dementia, Strokes,
  Tumors etc.
• Life without memory is very unlike life as the
  rest of us know it indeed, it is almost no life
  at all
• Luis Bunuel

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1. What is Learning and Memory?

• Learning relatively permanent change in an
  organisms behavior as a result of experience
• Memory the ability to recall or recognize
  previous experience
• One cannot logically be a determinist in
  physics and chemistry and biology, and a mystic
  in psychology. (D. Hebb)

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1. Memory Formation Stages

• 1. Encoding processing of incoming information
• Acquisition registers inputs in sensory
  buffers Consolidation creation of strong
  representation over time
• 2. Storage the result of acquisition and
  consolidation
• 3. Retrieval utilizes stored information to
  crate a conscious representation or to execute a
  learned behavior

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1. Temporal (Time) Memory Subtypes

• Sensory memory (milliseconds to seconds)
• Short-term/working/on-line (seconds to minutes)
• Long-term memory (minutes to years)

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1. Theoretical Questions About Memory

• Is all learning (and memories) the same?
• If not, are there different neural circuits
  mediating different types of learning?

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2. Karl Lashleys Search for the Engram

• Memory new or strengthened connections between
  two brain areas???
• Engram the physical representation of what has
  been learned
• Cutting this connection will destroy memory

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2. Karl Lashleys Search for the Engram

• Lashley trained the rats to solve a maze then he
  cut different parts of the cortex
• No knife cut significantly impaired rats
  performances
• Removing parts of the cortex did impair
  performance, but the amount of retardation
  depended more on the amount of brain damage than
  on its location

Page 499
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2. Karl Lashleys Search for the Engram

• it is not possible to demonstrate the isolated
  localization of a memory trace anywhere in the
  nervous system. Limited regions may be essential
  for learning or retention of a particular
  activity, but the engram is represented
  throughout the region (1950)
• EQUIPOTENTIALITY all parts of the cortex
  contribute equally to complex behaviors such as
  learning any part of the cortex can substitute
  for any other
• MASS ACTION the cortex works as a whole, and
  the more cortex the better

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3. Patient H.M.

• Epileptic seizures since the age 16
• Had to stop work at 27 because his seizures could
  not be controlled
• Seizures originated in medial temporal lobes
  (much of hippocampus and amygdala removed)
• 1953 William Scoville neurosurgeon removed
  medial temporal lobe bilaterally
• H.M. showed behavioral problems and Scoville
  sought help from young neuropsychologist, Brenda
  Milner

Page 500
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3. Patient H.M.

• No language or perceptual deficits or motor
  deficits
• IQ unchanged (118)
• Intact digit span short-term memory
• No language or perceptual deficits
• IQ unchanged
• Severe memory impairment - amnesia

Page 500
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3. What is Amnesia?

• Partial or total impairment of memory
• Infantile amnesia inability to remember events
  from early infancy or early childhood
• Fugue state transient disturbance of
  consciousness in which a person performs
  purposeful acts but has no conscious recollection
  of those actions
• Transient Global Amnesia short-lived neurologic
  disturbance characterized by memory loss (usually
  loss of old memories and an inability to form new
  memories) most often caused by ischemia
  (interruption of blood flow to the brain usually
  due to constriction or obstruction in blood
  vessels)

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3. What is Amnesia?

• Amnesia can be specific
• Amnesia for the meaning of nouns but not verbs
  and vice versa
• Amnesia for recognizing animals but not people or
  who become amnesic for human faces but not for
  other objects

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3. Patient H.M.

• Global anterograde amnesia inability to form
  new memories
• every day is alone in itself, whatever enjoyment
  Ive had, and what ever sorrow Ive had
• Retrograde amnesia loss of memories that took
  place prior to brain damage
• H.M.s retrograde amnesia is not global he
  knows who he is, where he lived, where he went to
  school etc.

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3. Can Patients Like H.M. Learn Any New
Information?

• Psychologist Edouard Claparède put a pin between
  his fingers before shaking hands with a woman
  with Korsakoffs syndrome (discussed later on),
  characterized by memory problems
• Several days later, the patient could not
  remember the event but refused to shake
  Claparèdes hand saying sometimes people hide
  pins in their hands

OUCH!!
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Different Types of MemoryImplicit Learning

• H.M. could learn new motor tasks
• Could not remember doing the task before
• Hence he implicitly learned but could not
  explicitly remember doing the task

Page 495
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• Pursuit-rotor task
• The Gollin Test

Page 495
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4. There Are at Least Two Kinds of Long-Term
Memory

• Explicit conscious, intentional recollection of
  previous experience
• Declarative
• Fact
• Memory
• Knowing what
• Examples knowing what the capital of Germany is.
  Remembering your first day at the university

• Implicit unconscious, non-intentional form of
  memory
• Non-declarative
• Skill
• Habit
• Knowing how
• Examples knowing how to ride a bicycle. Knowing
  how to play hockey.

Pages 495-8
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Different Types of Explicit MemoryInterview of
G.O. by Dr. Levine

• Do you have a memory of when you had to speak in
  public?
• Well yes, Im a call centre trainer with Modern
  Phone Systems, so I did a lot of speaking because
  I did a lot, a lot of training all across Canada.
  I also went to parts of the States.
• Do you remember one time that you were speaking?
  Can you tell us about one incident?
• Oh yes! Well I trained thousands and thousands
  of clients on a wide variety of topics including
  customer service, inbound and outbound
  telemarketing. Handling difficult customers.

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• Do you remember one training session that you
  gave? Something that may have happened, a
  specific incident?
• Well for example I always recommended that people
  take customer service first. And I always had
  people come up with four things about themselves,
  three that were true and one that was false. Not
  necessarily in that order.
• But this was something ongoing, so every training
  session you would tell people this, right?
• Yes

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• So what were looking for is one incident or one
  time that you gave a training session or any
  other speech that you want to tell us about. A
  specific incident.
• Oh well I customized a lot of material for many,
  many companies. And I also did lots of training
  at the home office
• OK, so what were asking is do you remember one
  time you gave a talk?
• Oh! Yes I do.
• One specific time not over a series of times, one
  time, can you tell us about that?
• Oh sure yes, it was at the home office and yes,
  many many people were there

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• One occasion. When did it take place?
• When? Well I left Modern voluntarily in 1990.
• But this one occasion when did it take place?
• Ummm, well I started in the Modern home office.
• Im getting the impression that you have a really
  good memory for all the training that youve done
  but you dont seem to be able to come up with a
  specific talk that maybe stands out in your mind
  for any reason? Would you agree with that?
• Oh yes well I always trained customer service.
• So there was no talk that maybe something went
  wrong or something strange happened?
• No, no I was a very good trainer.

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4. Patient K.C. Loss of All Episodic Memories,
Preservation of Semantic Memories

• Patient K.C.
• Motorcycle accident
• Subdural hematoma (a pool of blood under the dura
  mater) was surgically removed
• Short-term memory OK
• Retrograde and anterograde amnesia
• All episodic memories have been lost

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4. Two Kinds of Explicit Memory

• Episodic Memory (personal experiences)
• Conscious awareness of past events
• Autobiographical memory
• Example Recalling your last birthday (who is
  there, what are you wearing, etc).

• Semantic Memory (facts about the world)
• Examples Capital of Italy, your mothers name,
  distinction between rocks and animals etc.
• No episodic recollection of the specific
  circumstances surrounding this learning

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4. Korsakoffs Syndrome

• Damage to diencephalon (dorsomedial thalamus and
  mammillary bodies) causes amnesia
• Strokes, tumors, trauma, and metabolic problems
  (associated with alcoholism) (vitamin B1
  deficiency)
• Korsakoffs syndrome 1) retrograde amnesia, 2)
  anterograde amnesia, 3) lack of insight, 4)
  apathy, 5) meager content in conversation, 6)
  confabulations.
• Confabulations the recitation of imaginary
  experiences to fill gaps in memory

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4. The Neural Basis of Explicit Memory

• H.M. case led neuropsychologist to focus on the
  hippocampus
• Remember that H.M. brain resection included
  several structures making conclusions difficult
• Hippocampus as a storage site for memory?
• Hippocampus consolidates new memories?
• Hippocampus plays the role of librarian for
  memories?
• Hippocampus is responsible for tagging memories
  with respect to context the location and time
  of their occurrence?

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4. Evidence for Consolidation Theory

• Electroconvulsive shock therapy (ECT)
• Originally used in attempts of treating
  schizophrenia
• Treatment of major depression
• Hypothesis Memories are solidified in long-term
  stores over days, weeks, months and years
• Hippocampal patients have retrograde amnesia
  (6-24 months) and inability to form new memories

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4. Evidence for Consolidation Theory

• Patient R.B. memory loss after ischemic episode
  (reduction of blood to the brain) during heart
  bypass surgery
• Dense anterograde amnesia
• 1 to 2 years retrograde amnesia
• Autopsy overall hippocampus looked intact
• Histological analysis indicated a loss in CA1
  region of the hippocampus

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4. Where Are Memories Located?

• If memories are distributed throughout the cortex
  than damage to the cortex will lead amnesia
• Lesions of the lateral cortex of the anterior
  temporal lobes (entorhinal and parahippocampal
  cortex also) produce retrograde amnesia
• Patients can form new memories
• Alzheimers disease and herpes simplex
  encephalitis
• Is this where the memory is stored? Possibly
  they are probably distributed throughout the
  brain

Alzheimers Disease Page 504
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4. The Neural Basis of Explicit Memory
Page 508
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4. Episodic Memory
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4. What About The Neural Basis of Implicit
Memories?

• Insight from Parkinsons Disease patients
• Basal ganglia - dopamine
• Patient J.K. PD (DA cells in basal ganglia die)
• On one occasion, he stood at the door of his
  bedroom frustrated by his inability to recall how
  to turn on the lights. He remarked I must be
  crazy. Ive done this in my life, and now I cant
  remember how to do it!
• Huntingtons Chorea mirror drawing task

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4. The Neural Basis of Implicit Memory

• Motor-based implicit memory is thought to be
  mediated by a circuit separate from limbic
  structures (explicit memories)
• Basal ganglia (caudate nucleus and putamen
  dopamine) and cerebellum (classical conditioning
  slide 38)
• Huntingtons Chorea (degeneration of cells in
  basal ganglia) fail to improve in mirror
  tracing task.

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Brief Summary For This Section

• Anterograde amnesia (episodic memory) damage to
  the limbic system (medial temporal lobe) and
  diencephalon (dorsomedial thalamus)
• These structures are not a location of memories
  they are important for consolidation
• Damage to temporal lobe associated with
  retrograde amnesia
• Patients can form new implicit memories
• Motor based implicit memories are mediated by
  basal ganglia

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5. Modern Search for the EngramNon-human Animal
Models

• Classical Conditioning Models
• Eye Blink Conditioning
• Fear Conditioning
• Operant Conditioning
• Morris Water Maze

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5. Localized Representation of Memory

• Ivan Pavlov classical conditioning
• CSUCS UCR
• CS CR

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5. Classical Conditioning - Eye-Blink
Conditioning

• Studied in humans and rabbits
• Puff of air is paired with tone
• Consequently tone alone elicits an eye-blink
  response
• Cerebellum mediates eye-blink conditioning

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5. Classical Conditioning - Fear Conditioning
Fear Responses
Threatening Stimuli
Defensive behavior Autonomic arousal
Hypoalgesia Reflex potentiation Stress hormones
Natural Threat Conditioned Stimulus
This has been demonstrated in flies, worms,
snails, pigeons, fish, rabbits, cats, rats, dogs,
monkeys and humans.
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5. Fear Conditioning in the Laboratory

• Mild shock (UCS) produces startle/freeze response
  (UCR)
• Shock (UCS) is paired with tone (CS)
• CS produces CR (freezing)
• Dependent measure is freezing/urination/defecation

Page 492
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5. Fear Conditioning Where is it in the Brain?

• Techniques lesions, electrical recording, neural
  tracing
• Information about the CS and US is transmitted to
  amygdala (12 regions lateral amygdala)
• Information is transmitted from amygdala to the
  behavioral, autonomic, and endocrine response
  control systems located in the brainstem.

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5. Fear Conditioning Where is it in the Brain?
MGv- ventral medial geniculate nucleus
Auditory Cortex
MGm- medial medial geniculate nucleus
MGv
MGm
Thalamus
Amygdala
Behavior ANS HPS
CS (10 kHz tone)
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5. Fear Conditioning What Happens if Amygdala
is Lesioned?
Auditory Cortex
MGv
MGm
Thalamus
Amygdala
CS (10 kHz tone)
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5. Fear Conditioning What Happens if MG of
Thalamus is Lesioned?
Auditory Cortex
MGv
MGm
Thalamus
Amygdala
CS (10 kHz tone)
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5. Fear Conditioning What Happens if Auditory
Cortex is Lesioned?
Auditory Cortex
MGv
MGm
Thalamus
Amygdala
CS (10 kHz tone)
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5. What About Context of Conditioning?

• Rats sometimes exhibit fear responses when they
  are returned to the chamber in which the tone and
  shock were paired, or a chamber in which shocks
  occur alone
• This is an example of contextual fear
  conditioning

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5. What Structure Mediates Contextual Fear
Conditioning?
Fear Reaction
Amygdala
Hippocampus
Contextual Stimulus (the look of the room,
location, etc.)
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5. Is Hippocampus Important for Spatial Learning
and Memory? Operant Conditioning Approach
Internalized cognitive map Dependent
measure Latency to find platform
Page 494
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5. Hippocampus Spatial Learning and Memory
Lesions of the hippocampus cause deficits in
spatial learning Animals fail to show improvement
over time no memory of location in space
Intact rats show rapid improvement over trials
Page 494
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5. Hippocampus Spatial Learning and Memory
birds that store food in different locations have
relatively larger hippocampi
Page 506
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6. Cellular Basis of Learning and Memory

• Donald Hebb
• Hebbian synapse and cell assemblies
• Learning and memory are based on modification of
  synaptic strength among neurons that are
  simultaneously active
• Axon A excites cell B slightly, and axon C
  excites B more strongly. If A and C fire
  together, their combined effect on B may produce
  an action potential
• neurons that fire together wire together

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6. Cellular Basis of Learning and Memory
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6. Cellular Basis of Learning and Memory Hebbian
Synapse Long Term Potentiation (LTP)

• LTP is an experimental model of Hebbian synapse
• Long Term Potentiation or Enhacement (LTE) a
  change in the amplitude of an excitatory
  postsynaptic potential that lasts for hours to
  days in response to stimulation of a synapse
• Most often studied in hippocampus
• Neurons that have previously been activated
  simultaneously, are more easily activated
• Why are they more easily activated?
• Changes in synapse? Changes inside neurons?

Pages 181-182
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6. Cellular Basis of Learning and Memory LTP
Changes in The Synapse

• Protein synthesis is important Cycloxemide
  (protein synthesis inhibitor) blocks memory
  formation
• Glutamate plays an important role in LTP
• Two glutamate receptors NMDA and AMPA
• Postsynaptic neuron more sensitive

Pages 181-182
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If NMDA receptors are important, could organisms
learn faster and have better memory if they have
more NMDA receptors?How can we increase the
number of NMDA receptors?
6. Cellular Basis of Learning and Memory
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7. Genes and Learning and Memory Genes for NMDA
Receptors

• Neurotransmitter receptors are proteins
• These proteins are encoded in DNA
• Can we alter DNA so that more NMDA receptors are
  produced? YES
• TRANSGENIC animals refers to animals in which new
  or altered genes have been deliberately
  introduced into the genome
• Transgenic mice can be made to produce more NMDA
  receptors
• KNOCKOUT animals refers to animals in which
  particular gene has been disabled by the
  experimenter

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7. Genes and Learning and Memory Genes for NMDA
Receptors

• Transgenics rate of learning in the water-maze
  is faster

WT wild type (control)
Tang et al., 1999
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7. Genes and Learning and Memory Genes for NMDA
Receptors

• Are NMDA Transgenic Mice Smarter?
• YES
• Transgenic mice learn fear conditioning faster
  and remember it longer

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7. Genes and Learning and Memory Genes for NMDA
Receptors

• Is Transgenic Mice Intelligence Unadaptive?
• Rain Man effect?
• NO
• Transgenic mice have a faster extinction of fear
• Transgenic mice unlearn faster
• It is adaptive to unlearn irrelevant things
  faster

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7. Genes and Learning and Memory Genes for NMDA
Receptors

• NMDA knockout mice
• Unable to induce LTP
• Learning deficits
• Can these deficits be reversed?
• Enriched environment significantly improved the
  performance of knockouts

Rampon et al, 2000
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7. Genes and Learning and Memory Genetic Models
of Alzheimers Disease

• AD is characterized by memory deficits
• Memory deficits are believed to be due to brain
  atrophy associated with beta-amyloid plaques
  (they lead to reduced number of dendrites and
  cell death)
• Transgenic mice (PDAPP) contain genes that lead
  to increased number of beta-amyloid plaques
• PDAPP show memory deficits in the water-maze

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7. Genes and Learning and Memory Drosophila
Models

• Conditioning choice between two tubes with two
  different odors
• One tube associated with shock, the other no
  shock most learned rapidly to avoid the shock
  side
• Dunce (genetic mutant) could not learn this
• Amnesiac (genetic mutant) could learn this but
  would forget it rapidly

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7. Genes and Learning and Memory Are there any
problems with the use of transgenics and
knockouts?

• broken animals
• Grow up, from conception, with missing genes
• Other genes might have different function in the
  absence of knocked-out genes

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7. Genes and Learning and Memory The Role of
CREB (protein) in Memory

• Is CREB important for LTM?
• IF yes, would increased CREB produced better
  memory?

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DNA changed - CREB inserted herpes virus
becomes a viral vector
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Increased CREB in the Amygdala Produced Enhanced
Fear Conditioning and Memory
Rats injected with Herpes vector carrying CREB
show much better memory
Josselyn et al., 2001
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