Transcript Alberni Genes to Remember

Genes to Remember
Christina Alberni
Journal of Experimental Biology.
1999.
• How does the brain form and recall
memories?
• What are the biological changes that serve
as the bases of memory?
• 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.
• 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.
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.
• 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.
• 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).
• 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).
• Long-term facilitation requires the activity
of transcription factors belonging to the
cAMP response-element binding protein
(CREB) family.
• CREB’s appear to be the genetic switch
that turns on the expression of genes
necessary for long-term memory.
Memory in invertebrates: fruit fly
• Drosophila melanogaster is the common
fruit fly
• a favorite model organism for genetic
studies for many years.
• 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 cAMPrelated proteins.
• 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.
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.
• 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.
• 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.
• Following training, in the hippocampus,
cAMP concentration and PKA expression
and activity are increased, CREdependent 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.