Gill withdrawal reflex using Aplysia californica sea slug:
-A mantle-covered gill is used for breathing
-A siphon is used for expelling seawater and waste
-Gill withdrawal occurs when the siphon is touched
-Defensive mechanism used
by Aplysia
Habituation leads to decreased neurotransmitter release and
reduced gill withdrawal
Habituation vs. sensitization to repeated stimulus
Habituation:
mild stimulus
Sensitization:
noxious
stimulus
Repetitive shocks for 4 days induces shock memory for 2-3 weeks
= LTM
Short-term facilitation targets K+ channels, NT vesicles, & Ca2+
channels
Catalytic subunits of PKA translocate from the cytoplasm to the
nucleus
RNA polymerase needs direct contact w/ enhancer binding
proteins to activate transcription
CREB-2 represses transcription; CREB-1 displaces it to activate
*PKA kinase
Long-term sensitization (4-5 shocks) lasts for days and requires
lasting changes in synaptic connectivity
stimulating the tail then
the siphon increased
response in gill with
drawal
requires interneuron
release of 5HT 
increased cAMP 
increased PKA 
enhanced NT release
Long-term sensitization: MAPK, CREB; short-term sensitization:
5HT, cAMP activate PKA, closing K+ channels NT release
Learning to pair stimulus with reward: classical conditioning
Classical conditioning in Aplysia: pairing tail shock with water jet
on the siphon; output= gill withdrawal reflex
US
CS
US/CS: unconditional/conditional stimulus
Mechanism: activation of interneurons via CS increases Ca2+ to
enhance response to stimulus (activation of Ca2+-dep AdCyc)
Training and neuronal circuits in learning in Aplysia
siphon
5HT neuron (tail)
Conditioning vs. sensitization: preceding activity activates
calmodulin, AdCyc
Sensory
neuron
In classical conditioning, presynaptic depolarization increases
Glu release to amplify EPSP response
Classical conditioning employs coincidence detectors AdCyc (SN)
& NMDAR (MN)
Figure 21-53. Intracellular signaling pathways during
sensitization and classical conditioning in the Aplysia
gill-withdrawal reflex arc. Sensitization occurs when the
facilitator neuron is triggered by the unconditioned
stimulus (US) in the absence of the conditioned
stimulus (CS) to the siphon sensory neuron (see Figure
21-52). Classical conditioning occurs when the CS is
applied 1 – 2 seconds before the US, and involves
coincidence detectors in both the presynaptic siphon
sensory neuron and the motor neuron. In the sensory
neuron, the detector is an adenylate cyclase that is
activated by both Ca2+-calmodulin and by Gsα· GTP
(see Figure 21-42). In the motor neuron, the detectors
are NMDA glutamate receptors (see Figure 21-40).
Partial depolarization of the motor neuron induced by
an unconditioned stimulus (via an unknown transmitter)
from interneurons activated by the tail sensory neuron
enhances the response to glutamate released by the
siphon sensory neuron.
Conditioning in Drosophila to evaluate short-term memory
Genetic mutants in Drosophila that identified memory pathways
amnesiac: enhances AdCyc; dPACAP=
pituitary AdCyc activating peptide
Ddc: Dopamine
decarboxylase
rutabaga: defective
Ca2+-calmod dep.
AdCyc
dunce: PDE mutation
Declarative (explicit) memory: recall of facts or events
Nondeclarative (implicit) memory: unconscious memory for
procedural or motor skills (includes associative learned
tasks)
*Removal of either the ventromed prefrontal cortex (medial
temporal lobe) or the perirhinal cortex impairs DNMS
performance
**HM: epileptic patient who had bilateral medial temporal
lobotomy; developed profound anterograde amnesia
Declarative memory formation requires the prefrontal & perirhinal
cortexes
The delayed nonmatch-to-sample (DNMS) test:
-Measures declarative (explicit) learning and memory
-Requires subject to compare a presented object with a
previously-presented comparison object
-Selection of a novel object is encouraged by an edible
reward
-After novel object rule is learned, the delay period in
object presentation is increased from 10 to 120 sec
-Number of displayed objects requiring recollection
increases
-Model for human anterograde amnesia
Medial temporal lesions mimic human amnesia (declarative only)
Spatial learning & memory requires NMDARs in the hippocampus
(the Morris water maze test)
Explicit memory storage in vertebrate medial temporal system:
the hippocampus
DG to CA3: mossy fiber
pathway (nonassociative
LTP)
CA3 to CA1: Schaffer
collateral pathway
(associative LTP)
EC to DG: perforant pathway
(associative LTP)
Long-term potentiation: functional model for explicit memory
HFS:
100 Hz
(brief)
*increased EPSP amplitude maintained for >60 min
LFS:
<0.1 Hz
Long-term potentiation in CA1 is highly afferent-specific
LTP in the Schaffer collateral pathway requires:
Cooperativity: activation of
multiple afferents (NMDARdep)
Synapse selectivity: only the
active afferents will be
potentiated
Associative: requires
simultaneous pre/post activity
to depolarize postsynaptic cell
Spaced stimuli give larger sustained EPSP amplitude (LTP)
vs. one tetanic stimulation
Hippocampal neuron LTP requires simultaneous afferent
activity and postsynaptic depolarization
Postsynaptic depolarization activates CamKII & leads to
greater numbers of AMPARs in postsynaptic membrane
CamKII
CaMKII activity is regulated by Ca2+-calmodulin binding to
release regulatory “hinge”
LTP may not rely solely upon new AMPAR insertion, but also
enhanced NT release probability
The number of NT release events increases after LTP induction
Multiple spaced trains, or stimuli, leads to late-phase LTP; one
train evokes smaller increase in EPSP for less time
Genetic blockade of PKA eliminates late-phase LTP
Early-phase LTP does not require CREB activation, synapse
growth
Synaptic structural changes in L-LTP include new AZs, PSDs