Learning and Memory

A/Prof Lyndsey Collins-Praino

lyndsey.collins-praino@adelaide.edu.au
Suggested Reading
• Chapter 24, `Memory Systems’, pp 823-863. In Bear,
Connors and Paradiso (2016) Neuroscience: Exploring
the Brain. Wolters Kluwer.

University of Adelaide
Lecture Objectives
• By the end of this lecture, you should be able to:
– Describe the types of memory systems, including short-term,
long-term and working memory.
– Compare and contrast different types of long-term memory.
– Discuss the search for the engram, including the work of Lashley,
Hebb and the localisation of memory in the neocortex.
– Explain, in brief, the mechanisms of LTP and LTD.
– Describe the types of memory impairment that can result from
lesion of the medial temporal lobe.

University of Adelaide
Learning and Memory
• Learning: acquisition of new knowledge or skills

• Memory: retention of learned information so that it will

available when needed

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Three Stage Model of Memory
• 3 memory stores where information is held and worked
on
– Sensory memory, Working memory and Long-term memory
– Differences in function capacity and duration

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Sensory memory: Large capacity, very short
duration
• Separate store for each of the five
senses
– All sensory input that enters the
system
– Most studied are visual (iconic
memory) and auditory (echoic
memory)

• Trace of sensory input stays in

memory for a very brief time
– < 1 second for sights or up to a few
seconds for sounds

• Function: hold sensory info long

enough for it to be analyzed by
unconscious processes and either
moved to the next store (working
memory) or forgotten

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 How does information move from sensory
memory to working memory?
• Through attention, which
acts as a gate keeper
– We are good at screening
out irrelevant stimuli and
focusing on the relevant:
selective attention

• Even when not actively

paying attention to
something, we can be
triggered by a stimulus that
has special meaning to us
– What word do you think
can cause people to switch
the voice they attend to at a
party?

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 Working memory: Small capacity, short
duration
• Active manipulation of
information you’re holding in
mind right now
% Recall
– Like the CPU of a computer
• Lasts approximately 20 seconds
• Can hold 7 +/- 2 pieces of
information
• Rehearsal can extend length of
time that info can be remembered
– Example: repeating a phone
number over and over
• If info isn’t encoded into long-
term memory, it’s lost
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Working memory and the brain
• Working memory is dependent
on the prefrontal cortex
• Evidence from delayed response
task
– Monkey is shown food placed into
well under two identical covers;
delay period; monkey is given food
if original well chosen
– Lesions of the prefrontal cortex
significantly impair this task
• PET scans demonstrate 6 areas in
the frontal lobe that are active
during delay period in humans
• People with prefrontal lesions
have trouble problem-solving and
planning behaviour
– Do not learn from recent
experience and errors made (e.g.
maze task)

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Working memory and ageing
• Working memory shows
marked decline in older
adults
– May be source of age-
related deficits on a variety
of cognitive tasks

• Prefrontal cortex shows

significant cell loss and
shrinkage with age

Young adult Older adult

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 How does information move from working
memory to long-term memory?
• Process by which we transform
what we perceive, think or feel into
an enduring memory.
• Automatic encoding:
automatically remember
something with NO effort
– Example: what did you have for
breakfast today?
– Usually is of personal relevance and
has built-in retrieval cues
• Effortful encoding: when you
have to work to memorize
something
– Example: studying for this exam
– Usually involves rehearsal

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 Encoding Caveats
• Encoding is better when we: (1) space out rehearsal over
time; (2) organise info as we learn it; (3) link new info to
info already in memory and elaborate on it
• Serial position effect: we remember the first and last
items in a series better than the middle items

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Effectiveness of Encoding: Craik and Tulving
• Elaborative encoding is more effective than other types of
encoding
– Increased activity in the lower left frontal lobe and medial
left temporal lobe
• The more activity in these regions, the more likely to remember info

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 Long Term Memory: Limitless Capacity,
Long-duration
• Like the hard drive of a computer

Declarative Non-declarative

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 Long Term Memory: Limitless Capacity,
Long-duration
• Like the hard drive of a computer
We’ll focus
on this

Declarative Non-declarative

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 Why do we remember little from before we
were 2-3 Years Old?
• Slower development of explicit
memory (than implicit)

• Explains why you remember

how to walk (implicit, learned at
about 12 months), but not taking
your first step or learning your
colors (explicit)

• Slower development of episodic

than semantic memory

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 The Search for an engram: Lashley
• Engram: physical location of a
memory; memory trace
• 1920s: Karl Lashley:
– Examined the effects of brain lesions
on maze learning in rats
– Larger lesions were associated with
more errors on maze task
– Location of lesions didn’t affect
performance
• Proposed 2 principles:
– 1. Equipotentiality: all parts of the
cortex contribute equally to learning
and memory
– 2. Mass action: the cortex works as a
whole, and more cortex is better
• Engram is spread throughout the
cortex, not localized to one area
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The problem with Lashley’s conclusion
• 1. Lesions were very large and damaged several cortical
areas involved in learning and memory
• 2. Rats could relay on many senses to solve the maze in
addition to memory: smell, feel, sight

Lashley was wrong…not all cortical areas contribute equally

to all memories

BUT…all of the cortex does contribute to memory storage

and an engram can be widely distributed in the brain

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 Consolidation and Storage of Declarative
Memory: Medial Temporal Lobes
• Hippocampus
• Entorhinal cortex
• Perirhinal cortex
• Parahippocampal
cortex

Path of information flow:

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 What happens on the cellular level?

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 Distributed memory storage
• With repeated exposure,
due to changes in synaptic
strength, there is a unique
pattern of activity for each
face
• Since no single neuron
represents an object,
damage to a specific
neuron isn’t catastrophic
for memory
– More neurons in network =
more unique memories can
be stored and more resistant
to damage memories are

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 Hebb and the Cell Assembly
• Representation of an object is
made up of all cortical cells
activated by that object
– Cell assembly: reciprocally
inter-connected

• As long as cell assembly is

active, object is held in
working memory

• If activation lasts long enough,

consolidation of memory
would occur by strengthening
connections

• Destruction of only some cells

in assembly can’t eliminate
engram

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 In other words…
• “Neurons that fire together, wire together”

Central to learning and memory formation

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Long Term Potentiation: The Light
Side
Hippocampal trisynaptic
circuit:
• Perforant pathway:
– Entorhinal cortex à
dentate gyrus
• Mossy fibers:
– Dentate gyrus à CA3
• Schaffer collaterals:
– CA3 à CA1

• Hippocampal slices can be

kept alive in vitro for up Don’t worry about specific pathways. Just
to 40 hours know that these fibre bundles connect
– Can stimulate and record regions of the hippocampus to each
synaptic responses other and to the cortex.
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 Discovery of LTP
• Lømo (1966): high frequency
electrical stimulation of perforant
pathway fibres causes increase in
magnitude of excitatory post-
synaptic potentials (EPSP) in post-
synaptic neurons
– Need many bursts of stimulation (50-
100)over a short period of time Record here
(100/sec) (tetanus)à input can last (Dentate gyrus) Stimulate
under a second here
– Known as long-term potentiation or
LTP

• Post-synaptic neuron response is still

increased on subsequent stimulations

• Not unique to the perforant pathway

à stimulation of any connection in
hippocampus can lead to LTP

• Can last for several months (possibly

forever)
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Molecular Basis of LTP
• LTP relies on glutamate
release pre-synaptically
– Binds to NMDA and AMPA
receptors post-synaptically

• Also dependent on
simultaenous depolarization
of post-synaptic membrane:
leads to unblocking of
NMDA receptor by Mg2+
and in-rush of Ca2+

• Ca2+ influx leads to:

– 1. Increased efficiency of
existing AMPA receptors
– 2. Insertion of more AMPA
receptors into post-
synaptic membrane

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 Long Term Potentiation: Lasting Changes
• Ca2+ influx activates kinases, which act on substrates to induce local changes at the
synapse, such as alterations in morphology and transcription of RNA
– Dendritic spines grow and sprout to accommodate new synapses

• Transcribed mRNA is translated into proteins that stabilize synaptic changes

Source:
Lamprecht
and
LeDoux,
Nat Rev
Neurosci
5, 45-54.

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 Long-Term Depression: The Dark
Side
• Neural circuits that contain
memories are made by weakening
some circuits and strengthening
others

• BCM theory: LTD occurs when

the pre-synaptic inputs are
activated when the post-synaptic
membrane is only weakly
depolarized or is hyperpolarized
– Results in a prolonged decrease in
response at the synapse

• Low frequency (1-5 Hz) tetanic

stimulation of fibres results in LTD
– As opposed to bursts of high
frequency stimulation = LTP

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 Mechanisms of LTD
• Due to low frequency of stimulation, there is a slow rise in
[Ca2+] in the post-synaptic neuron
• Leads to dephosphorylation of AMPA receptors
• Cause AMPA receptors to be internalized, decreasing
sensitivity of synapse

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A Memory Eraser? PKM(zeta)
• Protein kinase M zeta
(PKMζ) appears to be
critical for the maintenance
of LTP and certain types of
memory
– Maintains changes in synaptic
strength by continuing to
phosphorylate targets
• Inhibition of PKMζ with
injection of a small peptide
called ZIP can erase LTP Injections of ZIP into the amygdala reduces
and memories from days fear-potentiated startle response (Parsons
and Davis, Nature Neuroscience, 2011
before the injection

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What can lesions of the medial temporal
lobe teach us?

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 First let’s briefly talk about amnesia…
• Concussion, chronic alcoholism, brain tumor, stroke, etc. can all
lead to amnesia
• Retrograde amnesia: Forget things in the past
• Anterograde amnesia: Inability to form new memories

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The Case of H.M.: Temporal Lobectomy
• In 1953, at age 27, H.M. had a large portion of his medial
temporal lobe removed bilaterally to treat epilpepsy

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Following surgery:
Unaltered Altered
• Could still read, converse and • Unable to make new
solve problems; personality and declarative memories
intelligence were unchanged (severe anterograde
• Working memory was amnesia)
unchanged – Despite working with Milner
– Could remember information if and Corkin for 50 years, they
concentrating on it, but had to introduce themselves to
information was lost once him each time
distracted – Affected both episodic and
• Non-declarative memory was semantic memory
unchanged • Some degree of retrograde
– Could learn mirror drawing amnesia
task, even if didn’t remember – Could remember some of
learning childhood, but had no memory
for events in years before
surgery

While memory consolidation relies on medial temporal lobe, implicit

memory and distant memory storage/retrieval rely on other brain areas
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 Support for the movement of long-term
memories out of the hippocampus
• Smith and Squire (2009):
asked people questions
about news events over the
previous 30 years
• Retrieval of newer memories
caused more activation of
the hippocampus, while
retrieval of older memories
caused more activation of
the frontal cortex
• Hippocampus was still
active even with old
memories
– Engram may never totally
leave hippocampus

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 Memory Disorder: Korsakoff’s Syndrome
• Brain damage caused by prolonged
thiamine (vitamin B1) deficiency
– Impairs the ability of the brain to
metabolize glucose
– Leads to a loss of or shrinkage of neurons in
the brain
– Often due to chronic alcoholism
– Symptoms include severe memory
impairment, apathy, confusion, forgetting,
and confabulation (taking guesses to fill in
gaps in memory)
• Can involve many brain regions, but
usually associated with damage to
dorsomedial thalamus and mammillary
bodies (part of the Papez circuit)

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 Memory Disorder: Alzheimer’s Disease
• Gradually progressive loss of
declarative (particularly episodic
memory) , usually beginning in old
age
– 99% of cases are late onset and ~50%
of late onset patents have no known
relative with the disease

• Associated with accumulation of

abnormal protein aggregations:
– Extracellular plaques made of
amyloid beta
– Intracellular neurofibrillary tangles
(NFTs) made of tau

• No disease-modifying treatment
– Current symptomatic treatments try
to raise brain levels of acetylcholine
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Lecture Objectives
• By the end of this lecture, you should be able to:
✔ Describe the types of memory systems, including short-term,
long-term and working memory.
✔ Compare and contrast different types of long-term memory.
✔ Discuss the search for the engram, including the work of Lashley,
Hebb and the localisation of memory in the neocortex.
✔ Explain, in brief, the mechanisms of LTP and LTD.
✔ Describe the types of memory impairment that can result from
lesion of the medial temporal lobe.

University of Adelaide