Transcript Eyeblink Conditioning: From Reflex to Consciousness

Eyeblink Conditioning: From
Reflex to Consciousness
PSY391S
April 3, 2006
John Yeomans
Pavlov and Search for Engram
• Visceral reflexes: Salivation and gastric
acid.
• Laws of conditioning: pairing, extinction,
recovery, generalization, etc.
• Conditioning in Cortex?
• Search for Engram: Lesions of cortex don’t
block learning of mazes or conditioning
(Lashley).
• Correlates of learning: whole cortex active
initially.
Eyeblink Conditioning
• Easier to measure in rodents and humans.
• Slow acquisition and extinction.
• Disynaptic reflex circuit for unconditioned
reflex (US-shock and UR) in brain stem.
• Activity in hippocampus and cerebellum
correlates with acquisition of delay
conditioning.
• Hippocampus not critical; ipsilateral
cerebellum is!
Recording from Cerebellum
• Activity in Interpositus or Red N. precedes and
predicts conditioned response (CR).
• Microlesions or inhibition of Interpositus or Red
N. blocks learning (Thompson).
• Circuits for CS (tone), US (shock) found in CBel.
• Purkinje cells inhibited by pairing climbing fiber
and parallel fiber stimulation: Long-term
depression.
• Similar for leg flexion and vestibular-ocular reflex
(Ito)
Interpositus activity
Greater Eyeblink
CS and US Pathways
To Cerebellum
Trace Conditioning
• Gap between CS and US. Harder to
learn.
• Hippocampus needed for trace
conditioning, but not delay conditioning.
• Blocked by MAM, a poison that prevents
neurogenesis in dentate gyrus.
• MAM does not block fear conditioning, but
that is easier task.
Awareness
• Eye-blink conditioning in humans.
• Hippocampus damage blocks trace conditioning,
but not delay conditioning.
• When asked later, normal subjects can say
whether CS and US were paired for trace task,
but not for delay task (Clarke and Squire).
• Awareness related to success of trace
conditioning, but not delay conditioning.
• Hippocampus stimulation.
• Search for Consciousness—Imaging correlates
and testing awareness?
Plasticity and Learning
PSY391
April 5, 2006
John Yeomans
Neurons and Learning
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Simple circuit approach—Aplysia
Monosynaptic reflex.
7 giant Motoneurons identifiable.
30 sensory neurons identified.
Habituation, sensitization, conditioning.
Short term and long-term changes.
Synaptic changes, proteins and genes.
Kandel.
Sensitization:
3 facilitating interneurons
5HT increases release in presynatic
terminals
Larger EPSP in Motoneuron L7
Mechanisms of Plasticity
• Habituation leads to smaller EPSP;
Sensitization leads to larger EPSP.
• Changes in presynaptic terminal lead to
more or less transmitter release (Ca++).
• Sensitization involves more cAMP, protein
Kinase A, and K+ channel changes.
• Long term changes require gene
transcription protein synthesis and CREB.
• Is this the same as mammals?
Hippocampus
• Slices allow intracellular study of neurons
and synapses.
• Hippocampus is needed for new long-term
declarative memories in humans.
• LTP plasticity has many properties of
memory.
• Problem: Circuits into and out of
hippocampus aren’t known, so the
functions of neurons aren’t known.
Long-Term Potentiation
• Three glutamate synapses in series,
dentate gyrus, CA3, CA1.
• All show LTP with high-frequency
stimulation (100 Hz “tetanus”).
• LTP lasts for hours (early phase), days or
weeks (late phase).
• Input specific, and associative.
• Like learning and memory?
LTP Mechanisms in CA1
• AMPA depolarizes postsynaptic neuron to
remove Mg++.
• Glutamate can open NMDA receptors.
• Hi Ca++ entry activates CaMKII and PKC.
• More AMPA receptors are added to
postsynaptic membrane  early LTP
(hours).
• In addition, NO can increase presynaptic
release in some synapses (“retrograde
transmission”). cGMPCa++ channels
Nucleus
NO made in
Synapse not nucleus
LTD Mechanisms in CA1
• Low frequency stimulation (1-5 Hz).
• Low Ca++ activates phosphatases.
• Internalization of AMPA receptors
Long-Term Depression.
Early and Late-phase LTP
• Early phase LTP (hours) does not require new
protein synthesis (gene transcription).
• Gene transcription is needed for long-term LTP
(days).
• Several kinases activate CREB, which activates
gene transcription. Many signals (e.g. Ach, DA,
NE, opiates) influence many kinases.
• Many proteins are needed for growth of dendritic
spines and synapses for long-term changes.
Long-term Memories
PSY391S
April 10, 2006
John Yeomans
Short and Long-term Memory
• Retrograde amnesia after concussion.
Memories return in order toward time of
injury.
• Electroconvulsive shock induces RA
similarly in humans and animals.
• Consolidation Hypothesis.
• Protein synthesis inhibitors block longterm storage of memories, but not STM, in
animals.
Hippocampal Damage
• H.M. can’t form new, stable verbal
(declarative) memories.
• He can form immediate memories (for
seconds), but they are lost when
distracted.
• He can learn new motor tasks (procedural
learning). (Cerebellum and striatum, e.g.)
• He has high IQ and remembers events
before surgery well.
Long-term Storage of Memories
• Hippocampus needed for laying down new
LTMs, but not for long-term storage after
weeks.
• Permanent memories and abilities are
believed to be stored in cortical areas for
each function, e.g. speech, personal
history, complex skills, feelings.
Hippocampus in Rodents
• Needed for spatial memories: 8-arm-maze,
water maze, Barnes maze.
• Needed for contextual fear conditioning, but not
simple fear conditioning.
• Needed for trace conditioning but not delay
conditioning.
• Needed for social communication between rats.
• Long and short term memories different: Protein
synthesis needed for LTM and LTP.
Spatial Memory in Rats
How are memories converted to
long-term, then to short-term forms?
• Theory: Synaptic changes are the basis of
all memories.
• Number of synapses depends on
dendrites and spines.
• Many proteins are needed to make
synapses grow and retract.
• Dendrites and spines grow and retract.
Dendrite Growth
Spine Growth
Neurogenesis
• New neurons are formed in dentate gyrus
and olfactory bulb (BRDU, 3H-thymidine
markers).
• Needed for new olfactory memories, and
for trace conditioning.
• Can be stimulated by serotonin, estrogen,
seizures or genes.
• Can be inhibited by stress/depression and
hormones, or by toxins (MAM, radiation).
Reconsolidation
• If memories are recalled again (new tests in rodents),
they become more vulnerable to ECS or to protein
synthesis inhibition.
• Are memories then reconsolidated in hippocampus?
• Suggests transfer back and forth between more
permanent (cortex) and less permanent (hippocampus)
forms.
• Limbic frontal cortex connected and active in these
exchanges.
• How are memories recalled and brought back into
temporary storage?
Long-term Storage
• How does hippocampus receive new information
for memories? (via entorhinal cortex)?
• How does hippocampus convert memories into
long-term stores? (frontal cortex, e.g. anterior
cingulate)?
• How are long-term memories stored in cortex
synapses?
• Are long-term stores lost in reconsolidation, and
if so, how?
• How are memories exchanged between HPC,
frontal cortex?
Genes and Memory
PSY391S
April 12, 2006
John Yeomans
Gene Control
• Knockdown of RNA: Antisense oligos (DNA) to
inhibit mRNA in vivo.
• Knockout of Gene: Remove gene permanently
from genome.
• Transgenic: Add extra copies of gene
permenently.
• Inducible: Add promoter so that you canturn the
gene on or off at will (tetracycline—Tet).
• Gene transfection by virus, electroporation, or
inhibition by repressors.
Long-term Memories and CREB
• Long term memories improved by spaced
trials vs. massed trials.
• Aplysia: CREB knockdown blocks longterm, but not short-term, sensitization.
• Block of Long-Term Memory (several
tasks) and long-phase LTP in CREB
knockout mice. STM and short-phase LTP
unaffected.
Genes and Fruit Flies
• Olfactory memory can be tested in test
tubes full of flies.
• Flies go toward smell, but shocked at one
end of tube.
• Smart flies avoid, but dumb flies return, to
end where shock given.
• Rutabaga, dunce, turnip all mutants that
indicate that cAMP important for learning.
CREB
• CREB repressor before training blocks
olfactory memory in flies, on second day,
but not first day.
• Increasing CREB (by activator) leads to
much improved long-term memory. One
trial only needed for olfactory memory on
next day.
• “Genius fruit flies”?
Improved Memories with NMDA
and CREB
• Viral CREB in basolateral amygdala
improves long-term, but not short-term
fear-memories
• Viral CREB in VTA or N. Acc improves
drug sensitivity.
• Memory improvement with stimulants, or
added AMPA or NMDA receptors.
• Doogie: NR2B improves LTP and LTM
Viral-CREB in Amygdala
3 days
14 days
Alzheimer’s Disease
• Poor memory (senile dementia) + neural
changes post mortem (plaques and
tangles).
• B-amyloid and tau proteins.
• Early onset due to APP and presenilins.
• Down’s, APP and Ch21.
• Late onset due to environment and to
ApoE eta4 copies.
• Prediction of susceptibility by age and
genes.
Amyloid Plaques and
Neurofibrillary Tangles
Dying of cholinergic axon terminalstauamyloid?
Genes and Alzheimer’s Disease
Amyloid Precursor Protein Ch21
Presenilins Ch1
Apolipotropin e4 Ch19
Can amyloid production be slowed, stopped or reversed?
Can Alzheimer’s be stopped or
reversed?
• Environment—Active lives, active brains.
• Cholinergic agonists. Slight slowing of
loss.
• NGF? Anti-amyloid? Anti-tau?
• How long can we live productively and
independently?
• Can we enhance memory?
• Should we enhance humans?