Download Small System of Neurons

Small Systems of Neurons
Studies of the snail
Aplysia show that small
systems of neurons are
capable of forms of
memory and learning
Eric Kandel
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Howard Hugh Medical
Institute
Columbia University
Undergradute BA in
history and literature
from Harvard College
MD at the New York
University School of
Medicine
Motivation
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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?
Definitions
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Learning is the ability to modify behavior in
response to experiences.
Memory is the ability to store that modification
over a period of time.
Commonality
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1.
2.
Aren’t humans unique in their abilities? Aren’t 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).
Approach
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In the 1950’s, 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.
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
Steps in Study of Memory
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Define a simple behavior that can be modified by
learning and that gives rise to memory storage.
Identify the cells that compose the neural circuit of the
behavior.
Locate critical neurons and interconnections that had
been modified by the behavior.
Analyze the cellular and molecular changes occurring
at those neurons and interconnections.
The Simple Behavior:
Aplysia’s Defense Reflex
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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
Habituation
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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.
Habituation & Memory
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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.
Sensitization
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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 animal’s
preexisting response to a stimulus as a result
of the presentation of a second noxious
stimulus.
Sensitization Experiment
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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
Distinct Memory Phases
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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.
Identifying the Cellular Circuit:
Aplysia’s Abdominal Ganglion
The Cellular Circuit
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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.
Neuronal Modifications
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In 1894, Santiago Ramon y Cajal suggested that
memory is stored in the growth of new connections.
Kandel’s 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.
Cellular & Molecular Changes:
Short Term Memory (Modular Circuits)
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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.
Short Term Memory Overview
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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.
Cellular & Molecular Changes:
Long Term Memory
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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 Cajal’s
hypothesis.
One gene produces Ubiquitin Hydrolase which causes
the persistent activation of PKA.
Long Term Memory Overview
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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/lec14361/0
01.htm
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