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Integrative Functions of the Nervous System. Topic 5a. Lecture Overview. Learning and Memory Introduction Sensitization and Habituation in Aplysia Long-term Potentiation and Depression. Learning. 50+ years ago Donald Hebb proposed that learning is mediated by changes in synaptic strength

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lecture overview
Lecture Overview
  • Learning and Memory Introduction
  • Sensitization and Habituation in Aplysia
  • Long-term Potentiation and Depression
  • 50+ years ago
    • Donald Hebb proposed that learning is mediated by changes in synaptic strength
      • As an animal learned a response, some synapses became stronger
why are learning and memory important
Why are learning and memory important?
  • To be able to adapt to changes in the environment
    • Learning
      • Acquire and process information from the environment
        • Changes the nervous system
    • Memory
      • Ability to retain this information
learning vs memory
Learning vs Memory
  • Learning: process that will modify a subsequent behaviour
  • Memory: ability to remember past experiences
  • Memory essential to learning—storage and retrieval of records left by learning
  • Learning depends on memory
hypothesized memory processes



Incoming information

Working memory

Long-term storage



Short-term storage

Sensory buffers





Loss of information

Hypothesized Memory Processes

Adapted from Rozenzeig, 2002

sensory memory
Sensory memory
  • Large capacity, but rapid decay
  • Sensory association areas involved
  • Example: Your mother is lecturing you and you aren’t paying attention, however, if asked, you can repeat the last sentence she said.




short term memory working memory
Short-term memory(Working memory)
  • Lasts for seconds to minutes
  • Severely limited capacity
    • magical 7 ± 2 – hold for digits, letters, etc.
  • Available to conscious awareness
  • Prefrontal cortex involved
  • Example: remember a phone number between looking it up and dialing




intermediate term memory
Intermediate-term Memory
  • Lasts for hours and days
  • May be transferred to LTM through rehearsal
  • Example: remembering where you parked your car




declarative memory
Declarative Memory
  • Involves hippocampus and medial temporal lobes
  • Neurons in hippocampus register information about the space surrounding an animal (rat studies)
    • Hippocampus contains a cognitive map of the external environment
hm the man with no memory
HM, the man with no memory
  • Henry Molaison
  • Epileptic patient
  • Hippocampus removed in 1957 (age 27)
  • Global amnesia
  • Could not “learn” anything after the surgery
  • Some retrograde memory loss
    • Likely not due to loss of hippocampus
  • Mentioned in 12,000 research articles
  • First studied by Brenda Milner at the Montreal Neurological Institute
  • Participated in research studies for 55 years
synaptic plasticity
Synaptic Plasticity
  • Change in synaptic function in response to patterns of use
  • Synaptic facilitation/sensitization
    • Repeated APs result in increased Ca2+ in terminal
    • Increased neurotransmitter release
  • Synaptic depression/habituation
    • Repeated APs deplete neurotransmitter in terminal
    • Decreased neurotransmitter release
a reductionist model
A reductionist model
  • Eric Kandel (Nobel Prize 2000)
    • Use a simple model to delineate the basic mechanisms of memory and learning
    • Use those findings to address memory & learning in vertebrates
    • Model of choice: Aplysia californica

aplysia californica
Aplysia californica

why aplysia
Why Aplysia?
  • Aplysia have:
    • A relatively small number of neurons (~20,000)
    • Relatively large neurons (up to 1 mm in diameter)
    • Culturable neurons that form circuits in vitro
    • Responses are visible and measurable
    • Response triggered by several electrical synapses firing simultaneously
nervous system
Nervous system
  • No brain
  • Number of ganglia
    • Control sensory and motor behaviour in nearby region
    • Also contain interneurons
      • Allow connections between ganglia
abdominal ganglion
Abdominal ganglion

gill withdrawal reflex
Gill withdrawal reflex
  • On dorsal surface
    • Gill and siphon located under mantle
    • Normally gill and siphon extend out from mantle
  • Touch or threat
    • Gill and siphon pulled back under mantle
  • Discrete number of cells involved
    • All have been identified
gill withdrawal reflex1
Gill withdrawal reflex
  • Depends on ~100 neurons
    • ~50 are sensory
    • ~40 are motor
    • ~10 are interneuron
  • Stimulation excites sensory neuron to fire an AP
    • Directly activates motor neuron
    • Indirectly activates motor neuron via polysynaptic connections via the interneurons
kandel aplysia
Kandel & Aplysia
habituation sensitization
Habituation & Sensitization
  • Habituation
    • Repeated stimulus leads to “ignore”
    • “negative” memory (i.e., not stored)
  • Sensitization
    • Noxious shock results in response
    • Results in consolidated memory
      • “kept” memory
short long term synaptic plasticity
Short & Long Term Synaptic Plasticity
  • Gill withdrawal reflex
    • One training trial
      • Short-term memory lasting minutes
    • Repeated, spaced training
      • Long-term memory lasting days to weeks
  • Simplest formation of implicit learning
  • Novel stimulus
    • Pay attention first time
    • Repeated exposure
      • If neither beneficial or harmful--ignore
  • Size of EPSP by sensory neuron on motor neuron decreases in amplitude
  • Inactivation of calcium channels
  • Less Ca2+ entering nerve terminal of pre-synaptic membrane
    • Less neurotransmitter released
  • Large increase in amplitude of EPSP
  • Increase in amount of NT released
  • Amplification due to interneurons

signalling by the interneurons
Signalling by the Interneurons
  • Excitatory interneurons release serotonin (5-HT)
  • 2 serotonin receptors
    • 5-HT2-like receptor
      • PLC pathway
    • 5-Ht4/6/7-like receptor
      • Adenylate cyclase pathway
short term sensitization
Short-term Sensitization

structural changes
Structural Changes
  • Storage of long-term memory results in physical changes in the pre-synaptic termini
    • Habituation
      • Retraction of pre-synaptic termini
      • In Aplysia, 35 fewer connections with motor neurons and interneurons
    • Sensitization
      • Increase in number of connections
      • In Aplysia, 2fold increase
long term changes in habituation and sensitization
Normal Aplysia showed 1300 axon terminals on sensory neurons.

Aplysia experiencing sensitization had 2800 terminals.

Aplysia experiencing habituation had 800 terminals.

Long-term Changes in Habituation and Sensitization

Long-term sensitization

long term memory
Long-term Memory
  • cAMP binds to and activates CREB
    • cAMP response element binding protein
  • MAPK may also be involved
  • CREB translocates to nucleus and increases gene expression of specific gene
  • Changes protein profile of synapse—changes in size etc
feedback loop
Feedback loop
  • One gene synthesized in response to CREB is ubiquitin hydroxylase
    • Degrades regulatory domain of PKA
    • Results in continuous activity of PKA
    • Ks is continuously phosphorylated
    • AP prolonged
    • Ca influx almost permanent
    • Continued release of NT
  • Brain-derived neutrophic factor
  • Activated by NMDA receptor
  • In Aplysia, blocking BDNF—no long-term memory
  • Corticosteroids decrease BDNF
  • Role?
    • Activates growth of dendritic spines
    • Role in generation/localization of new receptors
learning pathways in vertebrates
Learning Pathways in Vertebrates
  • Uses glutamate receptors
  • Requires an influx of Ca2+ into the post-synaptic cleft
  • Ca2+ activates (directly or indirectly) three protein kinases
    • Calcium/calmodulin kinase II
    • Protein kinase C
    • Tryosine kinase fyn
long term potentiation
Stimulation of pre-synaptic neuron leads to a long-term increase in the magnitude of EPSPs in post-synaptic neurons
  • First measured in hippocampal tissue
Long-term potentiation
synaptic plasticity1
LTP strengthens existing synapses and creates new ones
  • Important for recovery of function post stroke
Synaptic plasticity

Presynaptic density

Synaptic structure

Before LTP

After LTP

Before LTP

After LTP

ltp and firing rate
For LTP to occur, rapid rate of stimulation is needed
  • EPSP’s are summated as successive EPSP’s occur and before past EPSP’s have dissipated
LTP and Firing Rate
ltp and glutamate receptors
LTP and Glutamate Receptors
  • AMPA (α-amino-3-hydroxy-5-methylisoxale-4-proprionic acid)
    • Activated first
    • Ionotropic
    • Local depolarization events
  • NMDA (N-methyl-D-aspartate)
    • Ionotropic--Ca2+ channel
    • Normally blocked by Mg2+
    • Requires depolarization event and Glu binding to activate

AMPA receptor (blue):

    • Ionotropic Na+ channel
  • NMDA receptor (pink):
    • Ionotropic Ca2+ channel

calmodulin dependent kinase ii
Calmodulin-dependent kinase II
  • CaMKII
    • Node in LTP
      • Autophosphorylation
      • Binds to NMDA
      • Stabilizes AMPA

  • At least 2 phases:
    • Establishment
      • Induced experimentally by single high-frequency stimulus
      • Involves kinases but not protein synthesis
    • Maintenance
      • Experimentally requires a series of high-frequency stimuli
      • Requires protein synthesis
late ltp
Late LTP

ERK is a member of the MAPK family

involved in signalling cascades

pre synaptic changes
Pre-synaptic changes
  • LTP results in changes in pre-synaptic termini
    • Increased synaptotagmin
    • Increased number of synaptic vesicles
  • Mediated by nitric oxide??
    • Maybe cell-cell adhesion??

protein synthesis
Protein synthesis
  • Likely occurs in dendrites
  • mRNA transcribed in nucleus
  • Delivery to dendrites
synaptic tagging
Synaptic tagging
  • Protein tags present in active synapses
  • Direct localization of mRNA bundles

long term depression
Long term depression
  • “Reverse” of potentiation
  • Decrease in dendrite/spines
  • Due to low frequency stimulation
  • May be necessary for eliminating memory traces
  • Important in motor learning
  • NT is glutamate
  • Receptors involved are AMPA, NMDA and mGlu
  • Involves MAPK and phosphorylation of AMPA receptors
    • AMPA receptors are endocytosed
still many questions
Still many questions
  • Beginning to understand how signals lead to changes in synapses
  • How do synaptic pathways provide details?
  • Retrieval of memory?
  • Requires skills of biologists, neurologists, psychologists
what you should know
What you should know:
  • Mechanisms of sensitization and habituation
  • Role of NMDA and AMPA in long-term potentiation