Small Systems of Neurons

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Small Systems of Neurons

• Studies of the snail Aplysia show that small
  systems of neurons are capable of forms of memory
  and learning

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Eric Kandel

• Howard Hugh Medical Institute
• Columbia University
• Undergradute BA in history and literature from
  Harvard College
• MD at the New York University School of Medicine

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Motivation

• Humans in a large part are what we have learned
  and remembered.
• We are unique in our abilities to acquire new
  ideas from experience and to retain those ideas
  in memory.
• What changes occur in the brain when we learn and
  how is this information retained in the brain?

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Definitions

• Learning is the ability to modify behavior in
  response to experiences.
• Memory is the ability to store that modification
  over a period of time.

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Commonality

• Arent humans unique in their abilities? Arent
  our abilities to learn, etc qualitatively
  different from other organisms?
• Ethologists (Lorenz, Tinbergen, and Frisch)
  demonstrated that there are commonalities in
  animal behavior.
• Thus, such commonality suggests that their may be
  some underlying common neuronal mechanisms
  (example cellular and molecular similarities
  between our neurons and synapses).

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Approach

• In the 1950s, Eric Kandel became interested in
  opening up what psychoanalysts had been treating
  as a black box. He wanted to study the
  behaviors of memory and learning using the modern
  empirical approaches of biology.
• Knowing it was unlikely to make progress studying
  the complex pattern of interconnections in the
  human or vertebrate brain, he thought that he
  could apply a reductionist methodology to the
  problem of memory and learning.
• He chose to work with the marine snail, Aplysia,
  in the vein of working with model organisms like
  Drosophila, yeast, bacteria, and bacteriophages.

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The Marine Sea Slug Aplysia

• Aplysia made a good candidate for study for a
  number of reasons.
• Small Numbers of Neurons (20,000)
• 10 Ganglia collections (2000 cells each)
• Large, Visible Uniquely Pigmented Neurons

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Steps in Study of Memory

1. Define a simple behavior that can be modified by
   learning and that gives rise to memory storage.
2. Identify the cells that compose the neural
   circuit of the behavior.
3. Locate critical neurons and interconnections that
   had been modified by the behavior.
4. Analyze the cellular and molecular changes
   occurring at those neurons and interconnections.

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The Simple BehaviorAplysias Defense Reflex

• When a weak or moderate stimulus is applied to
  the siphon, the gill contracts and withdraws into
  the mantle cavity.
• There are two forms of learning associated with
  this reflex habituation and sensitization

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Habituation

• Habituation is a decrease in the strength of a
  behavioral response that occurs when an initially
  novel stimulus is presented repeatedly.
• This is probably the most wide-spread of all
  forms of learning.
• It allows animals to ignore meaningless stimuli
  so that they are more likely to attend to
  meaningful stimuli.

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Habituation Memory

• Studies of habituation have provided
  opportunities for understanding short and
  long-term memory.
• After 1 training session of 10 to 15 stimuli,
  snails habituate the stimuli but the normal
  reflex begins to return within an hour and fully
  returns within a day.
• After 4 training session of 10 stimuli each,
  snails habituate the stimuli and this state lasts
  for weeks.

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Sensitization

• Sensitization is more complex than habituation in
  that the animal has to learn to respond strongly
  to an otherwise neutral stimulus.
• It is the prolonged enhancement of an animals
  preexisting response to a stimulus as a result of
  the presentation of a second noxious stimulus.

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Sensitization Experiment

• In this case, Aplysia is given a shock to the
  tail, and then the gill reflex is induced.
• Aplysia respond to the previously innocuous
  habituated stimuli with a strong gill withdrawal
  reflex

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Distinct Memory Phases

• A single shock gives rise to a memory lasting
  only minutes no protein synthesis required.
• Four or five spaced shocks gives rise to a memory
  lasting many days requiring protein synthesis.

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Identifying the Cellular CircuitAplysias
Abdominal Ganglion
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The Cellular Circuit

• The circuit contains 24 mechanoreceptor sensory
  neurons that innervate the siphon skin.
• These sensory neurons make direct monosynaptic
  connections with 6 gill motor cells.
• The sensory neurons also made indirect connection
  to the gill motor cells through interneurons
  (excitatory and inhibitory).
• This circuit was found to be invariant among
  individuals studied.

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Neuronal Modifications

• In 1894, Santiago Ramon y Cajal suggested that
  memory is stored in the growth of new
  connections.
• Kandels research showed that although the
  connections are invariant, their specific
  strength is not.
• Homosynaptic changes occur in a synapse because
  of activity in that synapse, while heterosynaptic
  changes occur in a synapse due to activity in an
  adjacent modulatory interneuron.

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Cellular Molecular ChangesShort Term Memory
(Modular Circuits)

• Modulatory interneurons transmit serotonin which
  acts on the sensory neuron.
• Serotonergic receptors cause increases in cyclic
  AMP (cAMP) and the activation of the
  cAMP-dependent protein kinase (PKA).
• PKA phosphorylates K and Ca channel proteins,
  causing a reduction and influx of their
  associated ions, respectively.
• Ionic concentrations cause vesicles containing
  neurotransmitters to fuse with the pre-synaptic
  membrane and release their contents.
• Thus, the short term sensitization is caused by
  increases in the amount of neurotransmitter.

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Short Term Memory Overview

• Short-term memory is a modulation of the strength
  of an existing synapse, through temporary
  changes in the amount of neurotransmitter
  released. This does not require new protein
  synthesis.

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Cellular Molecular ChangesLong Term Memory

• Increased levels of serotonin activates PKA and
  mitogen-activated protein kinase (MAPK), both of
  which enter the nucleus.
• These kinases activate the transcription factor
  CREB-1 (cAMP Response Element Binding protein-1)
  which promotes expression of genes leading to the
  growth of new synaptic connections. Thus,
  supporting Cajals hypothesis.
• One gene produces Ubiquitin Hydrolase which
  causes the persistent activation of PKA.

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Long Term Memory Overview

• Long-term memory is a modulation of the strength
  of an existing synapse, through growth in the
  number of synapses. This requires new protein
  synthesis.

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• http//www.pitt.edu/super1/lecture/lec14361/001.h
  tm
• Eric Kandel, Nobel Lecture, The Molecular Biology
  of Memory Storage A Dialog Between Genes and
  Synapses, December 8, 2000.
• Eric Kandel (1979) Small Systems of Neurons,
  Scientific American