Learning and Memory NSCI 201 Nov 29, 2005

Albert Borroni King 125 / x58345 [email protected]

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

2 nd 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 curve Serial position  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 person can learn/form memories.

What is being measured is the key to determining if  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 –

pg 761

 movie     DNMS –

pg 757

T-maze Bar pressing Eye blink

Taxonomy of Long-term Memory

Memory

Temporal lobe

Relational/Spatial Explicit Episodic e.g. events

Neocortex

Semantic e.g. facts Non-Declarative Procedural Implicit

Spinal Cord/cranial nerves&nuclei

Non-associative learning e.g.Sensitization/Habituation Skills & Habits e.g. Tower of Hanoi

Striatum

Priming e.g. picture/word fragments

Neocortex

Conditioning - Associative

Cerebellum

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

Edition Ch 24 pgs 776-778, 786-end 2 nd

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

  1.

 All of these manipulations, and more, have been done in simple systems and in mammalian tissue.

Stim/Record, Get LTP/LTD, Look at relationship 1.

2.

3.

4.

The results suggest a model for increasing and decreasing synaptic strength that involves: 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 2 nd 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 1_1/Misinformation_Effect.html

Memory (psychology)," Microsoft® Encarta® Online Encyclopedia 2004 http://encarta.msn.com © 1997-2004 Microsoft Corporation. All Rights http://encarta.msn.com/media_461576439_761578303_ 

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.

2.

The amygdala is involved in creating memories in a fear conditioning paradigm.

The hippocampus plays no role in the storage of memory. 3.

4.

The observation of sensory memory is important for the understanding of declarative memory formation.

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.