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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_(psychology).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
DeclarativeRelational/SpatialExplicit
Non-DeclarativeProceduralImplicit
Non-associative learning e.g.Sensitization/Habituation
Skill & Habit e.g. Tower of Hanoi
Priming e.g. picture/word fragments
Conditioning – Associative Motor reflex learning e.g. eyeblink
Emotional responses e.g. fear conditioning
Episodic e.g. events
Semantic e.g. facts
•Larry Squire•Howard Eichenbaum
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 – pg 761
movie
DNMS – pg 757 T-maze Bar pressing Eye blink
Taxonomy of Long-term Memory
Memory
DeclarativeRelational/SpatialExplicit
Non-DeclarativeProceduralImplicit
Non-associative learning e.g.Sensitization/Habituation
Skills & Habits e.g. Tower of Hanoi
Priming e.g. picture/word fragments
Conditioning - AssociativeMotor reflex learning e.g. eyeblink, classical
Emotional responses e.g. fear conditioning
Episodic e.g. events
Semantic e.g. facts
Temporal lobe Medial diencephalic
Neocortex
Cerebellum
Neocortex
Amygdala
Spinal Cord/cranial nerves&nuclei
Striatum
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 EditionCh 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?
Isolate relevant synapses The technique:
Stimulate - Record Electrophysiology
Extracellular Intracellular
Imaging Membrane potential Calcium
Combine with Pharmacology or Genetic manipulation
Investigating synaptic plasticity
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 slicesize 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. Stim/Record, Get LTP/LTD, Look at relationship
The results suggest a model for increasing and decreasing synaptic strength that involves:
1. Increases in [Ca]I
2. Activation of second messengers – cAMP, cGMP3. Modulation of protein kinase/phosphotase activity.4. Phosphorylation/Dephosphorylation of other proteins
1. 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 2004http://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 2004http://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 true1. 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.
