Genes to Remember

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Genes to Remember

• Christina Alberni
• Journal of Experimental Biology. 1999.

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• How does the brain form and recall memories?
• What are the biological changes that serve as the
  bases of memory?

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• Antibiotics that inhibit protein synthesis also
  inhibit long-term memory formation when given
  during learning.
• Many studies in species ranging from
  invertebrates to mammals show that a fundamental
  and conserved pre-requisite for long-term memory
  formation is the expression of genes and protein
  synthesis during and immediately after learning.

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• This critical period coincides with the
  consolidation phase of memory, the initial period
  necessary to transform incoming information into
  stable and storable modifications.
• If gene expression is blocked after this critical
  period is over, memory forms normally.

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Memory in invertebrates marine snail

• Aplysia calofornica is a marine snail with a
  relatively small number of large and readily
  identifiable neurons.
• It has been used in studies of memory for over 30
  years.

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• The form of learning best characterized in the
  snail is sensitization of the gill and siphon
  withdrawal reflex.
• When a touch stimulus to the animal is combined
  with a noxious treatment (chemical, electrical),
  the animal subsequently reacts more strongly (is
  sensitized to) the touch stimulus.

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• When a sensitizing (noxious) stimulus is applied,
  it produces an increase in neurotransmitter
  release, called facilitation, at the synapses
  that connect the sensory neuron (which senses the
  stimulus) to the motor neuron (which causes the
  gill and siphon withdrawal reflex).

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• Facilitation is mediated by the action of the
  neurotransmitter 5-HT, which is released by
  regulatory neurons and acts on the serotonin
  receptors of the sensory neurons.
• Sensory neurons respond to 5-HT with an increase
  in cAMP level and the activation of
  camp-dependent protein kinase A (PKA).

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• Long-term facilitation requires the activity of
  transcription factors belonging to the cAMP
  response-element binding protein (CREB) family.
• CREBs appear to be the genetic switch that turns
  on the expression of genes necessary for
  long-term memory.

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Memory in invertebrates fruit fly

• Drosophila melanogaster is the common fruit fly
• a favorite model organism for genetic studies for
  many years.

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• Benzer and colleagues used Pavlovian olfactory
  learning to train flies to avoid an odor paired
  with an electrical shock and identified dunce and
  rutabaga, two different single-gene mutations
  that impair associative learning.
• Biochemical and molecular analysis showed that
  the two genes encode cAMP-related proteins.

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• Tully and colleagues clone the Drosophila CREB
  gene, dCREB2.
• They showed that a dCREB2 knock-out completely
  blocked long-term memory, while increased
  expression of dCREB2 improved long-term memory
  formation.

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Memory in mammals mice and humans

• In mammals, CREB is a large family of
  transcription factors generated by alternative
  splicing.
• CREB is required for long-term memory formation
  in mammals, and mutations in CREB proteins impair
  memory formation.

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• Current research focuses on where and when in the
  brain CREB is activated during learning, what
  signals induce CREB response, and which
  CREB-regulated genes are required for memory
  formation.

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• The hippocampus is part of the brain that has
  long been known from clinical studies to be
  involved in memory formation.
• Lesions of the hippocampus in humans cause an
  inability to store new information into long-term
  memory.
• Recall of previously-stored information, however,
  is relatively unaffected.

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• Following training, in the hippocampus, cAMP
  concentration and PKA expression and activity are
  increased, CRE-dependent expression is activated
  and CREB phosphorylation is increased, suggesting
  that CREB response is modulated by the cAMP/PKA
  signaling pathway in mammals as in invertebrates.