Learning and Memory
NSCI 201
Nov 29, 2005
Albert Borroni
King 125 / x58345
albert.borroni@oberlin.edu
Session divided into 2 Parts
 Part I: Categorizing Learning/Memory –
Ch 23
 Part II: Cellular/Molecular aspects – Ch
24
PowerPoint will NOT be made available – take
notes
Part I: Categorizing Memory
 Readings
Ch 23 Bear et al (2001) Exploring the Brain
2nd Edition
 MSN article w/ hyperlinks
"Memory (psychology)," Microsoft®
Encarta® Online Encyclopedia 2004

http://encarta.msn.com © 1997-2004 Microsoft Corporation. All
Rights Reserved.
http://encarta.msn.com/encyclopedia_761578303_1/Memory_(psyc
hology).html
Is there a time dependent aspect?
 Sensory memory – very short term memory
 Short Term: Ebbinghaus - Serial position
curve
 Working memory
 Long-term

retrograde amnesia
 Consolidation – impaired for declarative/relational
memory in amnesics - anterograde
Support for categorizing Long-term
memory into “Systems” – human studies
 Observing humans with amnesia
 Phenomenology
 Functional/Organic
 Retrograde/Anterograde
 Preserved learning - What is being measured is the key to determining if
person can learn/form memories.


Amnesic seems to learn who you are
Tower of Hanoi
 Observing humans with difficulties in other domains
Taxonomy of Long-term Memory
Memory
Declarative
Relational/Spatial
Explicit
Non-Declarative
Procedural
Implicit
•Larry Squire
•Howard
Eichenbaum
Non-associative learning e.g.Sensitization/Habituation
Episodic e.g. events
Skill & Habit e.g. Tower of Hanoi
Semantic e.g. facts
Priming e.g. picture/word fragments
Conditioning – Associative
Motor reflex learning e.g. eyeblink
Emotional responses e.g. fear conditioning
What brain regions are involved?
 Look at humans who have deficits or are
engaged in the activity – PET, fMRI etc.
 The animal equivalent of human amnesic

Lesions – knock out certain regions or
chemical processes





Surgical removal of tissue
Aspirating tissue
Electrolytic
Pharmacological
Molecular/Genetic – pg 802
If we are to use animals, what is the
appropriate test?
 Radial arm maze –
 movie
 DNMS – pg 757
 T-maze
 Bar pressing
 Eye blink
pg 761
Taxonomy of Long-term Memory
Memory
Temporal lobe
Medial diencephalic
Declarative
Relational/Spatial
Explicit
Non-Declarative
Procedural
Implicit
Spinal Cord/cranial nerves&nuclei
Non-associative learning e.g.Sensitization/Habituation
Episodic e.g. events
Neocortex
Skills & Habits e.g. Tower of Hanoi Striatum
Semantic e.g. facts
Priming e.g. picture/word fragments Neocortex
Cerebellum
Conditioning - Associative
Motor reflex learning e.g. eyeblink, classical
Emotional responses e.g. fear conditioning
Amygdala
Summary: What regions are involved in
the formation of long-term memories?
 Different areas


Declarative – Hippocampus and Neocortex
Procedural – Cerebellar nuclei/cortex, striatum
 Distributed - Neural Networks
Your turn.
 Can you put together evidence from other
experiments or experiences that support of
refute the proposed taxonomy?
 Does involvement of a region in the formation
of long-term memories necessarily mean that
the memory is stored in that region?
Part II. Cellular / Molecular Aspects
 Bear et al (2001) Exploring the Brain 2nd
Edition
Ch 24 pgs 776-778, 786-end
A different approach
 At the turn of the century, Ramon y Cajal
suggested that nervous tissue was composed
of cells and that the point at which the cells
communicated with each other (synapse) was
the critical point where learning occurs.
Your turn
 How would you experimentally address the
question of how memories are stored – not
where but how. What are the relevant
questions?
 How do we investigate what occurs at the
level of the synapse? What is the question?




Is it plastic?
What conditions are required for plasticity to occur?
Can plasticity be modulated?
Is it the same in all regions?
Investigating synaptic plasticity
 Isolate relevant synapses
 The technique:
Stimulate - Record



Electrophysiology
 Extracellular
 Intracellular
Imaging
 Membrane potential
 Calcium
Combine with
 Pharmacology or Genetic manipulation
The ideal model system
 Animal must have
 Small nervous system
 Large, identifiable neurons and inputs
 Identifiable circuits
 Simple genetics
 Start with a behavior and move to monitoring the
critical synapse.
 Next, look at the cellular/molecular components
involved through pharmacological and/or genetic
manipulations
Simple systems
 Aplysia – Eric Kandel
 Examples
 Movie
 Hermissenda
 Examples
 Next: An example of a reduced preparation
from a complex system from which we can
investigate the induction, expression and
consolidation of synaptic plasticity
A complex system: the preparation
 Coronal Neocortical/hippocampal slice
size of thumbnail
 Record in layer II/III
 Transcallosal stimulation
The Experiment
 Stimulate every 30 seconds
 Record responses across all electrodes
 After 20 minutes of stable recordings, activate axons
with pattern of activity that induces plasticity
(conditioning pattern).
 Start stimulating/recording again at a 30 second
interval.
 Compare amplitude of an average of 5-10 responses
immediately before the conditioning pattern with an
average calculated 30 minutes after conditioning
pattern ends.
The Results
LTP – Long-term
potentiation
LTD – Long-term
depression
What’s next??
 With the preparation described in the
previous slides we would then




confirm that this is a physiologically relevant
synaptic modification.
Try to prevent the change with various
manipulations
See if we could determine what conditions
cause LTD
Determine the relationship between conditions
causing LTD & LTP
examples
Results

All of these manipulations, and more, have been
done in simple systems and in mammalian tissue.


The results suggest a model for increasing and
decreasing synaptic strength that involves:
1.
2.
3.
4.
1.
Stim/Record, Get LTP/LTD, Look at relationship
Increases in [Ca]I
Activation of second messengers – cAMP, cGMP
Modulation of protein kinase/phosphotase activity.
Phosphorylation/Dephosphorylation of other proteins
Changes in the phosphorylation state of proteins
involved in the release and/or reception of NT leads
to changes in synaptic efficacy i.e produces
synaptic plasticity.
One possible hypothesis: John Lisman
Built to explain 2 basic observations
1) Phosphorylation of AMPA receptors increases their
ability to conduct Na ions. Dephosphorylation decreases
their ability to conduct. These two processes are always
in competition.
1) Depolarization through activation of AMPA
receptors triggers calcium influx through NMDA
receptors and VDCCs
2) High levels of intracellular calcium lead to LTP, low
levels lead to LTD - BCM
How/when does intracellular calcium
change?
 Synaptic activity – Excitatory activity
 Depolarization as a result of activation of AMPA
receptors by glutamate.
 Depolarization activates VDCCs and/or NMDA
channels
 Level of depolarization can affect the level of
intracellular calcium
 Level of depolarization can be changed by pattern of
activity and presence/absence of modulators.
Take Neurophysiology course.
Long-term changes seem to require more then
a simple change in state of phosphorylation.
 Probably associated with reorganization
(development) or a subtle change in contacts that is
more then changes in the phosphorylation state of
existing proteins.
 Changes in the number and size of synapses have
been seen in Aplysia, hermissenda and even rat
hippocampus as a result of activity that induces
LTP/LTD.
 Blocking transcription can prevent long-term changes
in synaptic efficacy
 These changes are probably the result of activating
early immediate genes, the “softening up” of the
current synaptic arrangement and the incorporation
of new proteins which form new contacts. Pg 735
Engaging the genome pg 804
 Aplysia (since supported by gene knockout experiments in mice and other manipulation
in various LTP/LTD preparations)







Ca activates second messengers and kinases
2nd messengers (cAMP) migrate along tubules to the soma
and into the nucleus
Kinases in the nucleus (cAMP kinase, MAP kinase)
phosphorylate CREB 1
CREB 1 displaces CREB 2, binds to CRE promotes
transcription of downstream RNA
Proteins are created, moved to the synapse and
incorporated into the synapse.
NCAM is downregulated temporarily.
The key to all this (phosphorylation and gene activation
related changes) is that these systems are continually being
updated. They are not static.
Putting it all together
 Different areas of the brain receive and process different
aspects of our world. Different areas may be responsible for
different memory “systems/types.” Different areas probably work
together – distributed storage (network).
 Neurons in those regions contact neurons within the same
region and other regions.
 The connections within and between these regions are, for the
most part, plastic in that their connections can change strength
under the correct circumstances – Increases in calcium
activation of a cascade of intracellular events .
 Changes in strength correspond to learning and can be
assessed through changes in how animals behave in a
particular situation.
Are memories veridical?
 Daniel Schacter & Elizabeth Loftus
 MSN media Group memories "Memory
(psychology)," Microsoft® Encarta® Online
Encyclopedia 2004
http://encarta.msn.com © 1997-2004 Microsoft Corporation. All Rights
Reserved. http://encarta.msn.com/media_461550851_761578303_1_1/McMartin_Preschool_Case.html
 MSN media Misinformation Memory (psychology),"
Microsoft® Encarta® Online Encyclopedia 2004
http://encarta.msn.com © 1997-2004 Microsoft Corporation. All Rights
http://encarta.msn.com/media_461576439_761578303_1_1/Misinformation_Effect.html
 Reconsolidation
Helping your memory
 Encoding process




Imagery
Extra: Short-term memory: Chunking
Depth of processing
Sleep
Questions????
Question 1
 Which of the following are true
1. The amygdala is involved in creating
memories in a fear conditioning paradigm.
2. The hippocampus plays no role in the
storage of memory.
3. The observation of sensory memory is
important for the understanding of
declarative memory formation.
4. Ebbinghaus suggested that synapses were
the location where memories are stored.
 1 is the only correct answer.
Question 2
 In the Lisman model the responsibility for the
determination of whether a syanpse will
demonstrate LTP or LTD rests in the hands of
this particular ion.
 Answer: Calcium.
Question 3
 True or False
 There is only one type of memory and the
hippocampal region is critical for the
formation of those memories.
 Answer : There are many types of memories.
They can be separated temporally as well as
by which area of the brain is involved in the
formation and/or storage of those memories.
Question 4
 True/ False
 The formation of short-term memories is
postulated from various studies which include
those done by Ebbinghaus (serial position)
and Lisman (human EEG studies).
 Answer False – First off Lisman didn’t do
EEG studies. Second, Lisman’s didn’t really
do any experiments. He postulated the
biochemical mechanism for LTP/LTD.