Download Cellular Mechanisms of Learning and Memory

Cellular Mechanisms of Learning
and Memory
Memory
• Implicit (nondeclarative) memory is unconscious memory for
perceptual and motor skills
• Explicit (declarative) memory is a memory for people, places,
events and objects that requires conscious recall
2
Kandel et al. Principles of Neural Science, McGraw Hill, 2000
3
Bear et al. Neuroscience: Exploring the Brain, Lippincott Williams & Wilkins 2007
Gill-withdrawal reflex in Aplysia
The gill is the respiratory organ. A tactile
stimulus to the siphon elicits the gill-withdrawal
reflex.
4
Bear et al. Neuroscience: Exploring the Brain, Lippincott Williams & Wilkins 2007
5
Bear et al. Neuroscience: Exploring the Brain, Lippincott Williams & Wilkins 2007
Habituation of the Gill-Withdrawal Reflex
Repeated electrical stimulation of a sensory neuron leads to a
progressively smaller EPSP in the postsynaptic motor neuron.
6
Bear et al. Neuroscience: Exploring the Brain, Lippincott Williams & Wilkins 2007
Repeated stimulation of the siphon leads to a
depression of synaptic transmission between
the sensory and motor neurons as well as
between certain interneurons and the motor
cells.
There is no change in the sensitivity of
glutamate receptors with habituation.
Decrease in transmitter release; it is thought
to be due in part to a reduced mobilization
of transmitter vesicles to the active zone.
This reduction lasts many minutes.
7
Kandel et al. Principles of Neural Science, McGraw Hill, 2000
Sensitization of the Gill-Withdrawal Reflex
When an animal repeatedly encounters a
harmless stimulus it learns to habituate to it.
In contrast, with a harmful stimulus the animal
typically learns to respond more vigorously not
only to that stimulus but also to other stimuli,
even harmless ones.
A sensitizing stimulus to the head of Aplysia indirectly activates an
interneuron (L29) which makes an axoaxonic synapse on the terminal of
the sensory neuron.
8
Bear et al. Neuroscience: Exploring the Brain, Lippincott Williams & Wilkins 2007
Short-term sensitization of the gill-withdrawal reflex in Aplysia involves
presynaptic facilitation
Serotonin (5-HT) binds to two
receptors. G protein (Gs), activates the
cAMP-dependent protein kinase A
(PKA). PKA acts along three pathways:
1) PKA phosphorylates and close K+
channels. This increases the influx of
Ca2+, thus augments transmitter
release.
2) exocytotic release machinery is also
enhanced.
3 )Ca2+ channels are opened.
A second receptor, engages the G
protein (Go) that activates a
phospholipase C (PLC), which in turn
activate protein kinase C (PKC).
Pathways 2-2a and 3-3a involve the
joint action of PKA and PKC.
9
Kandel et al. Principles of Neural Science, McGraw Hill, 2000
Long-term sensitization of the gillwithdrawal reflex of Aplysia leads to
two major changes in the sensory
neurons of the reflex:
-persistent activity of protein kinase A
- structural changes in the form of the
growth of new synaptic connections.
10
Kandel et al. Principles of Neural Science, McGraw Hill, 2000
• Short-term facilitation (lasting minutes to hours), resulting from a single
tail shock or a single pulse of serotonin, leads to short-term modification
of preexisting proteins (like phosphorylation).
• Long-term facilitation (lasting one or more days) involves the synthesis of
new proteins.
PKA recruits the mitogen-activated kinase (MAPK) and together they
translocate to the nucleus (long-term pathway), where PKA
phosphorylates the cAMP-response element binding (CREB) protein. One
gene activated by CREB encodes a ubiquitin hydrolase, which in turn cause
persistent activity of PKA. The second gene activated by CREB encodes
another transcription factor C/EBP. This binds to the DNA response
element CAAT, which activates genes that encode proteins important for
the growth of new synaptic connections.
11
Long-term habituation leads to a loss of
synapses and long-term sensitization leads to
an increase in synapses
The number of presynaptic terminals is highest
in sensitized animals (about 2800) compared
with control (1300) and habituated animals
(800).
12
Kandel et al. Principles of Neural Science, McGraw Hill, 2000
Neural basis of memory learned from
invertebrate studies
• Learning and memory can result from modifications
of synaptic transmission
• Synaptic modifications can be triggered by
conversion of neural activity into intracellular second
messengers
• Memories can result from alterations in existing
synaptic proteins and synthesis of new proteins.
13
Explicit Memory in Mammals Involves LongTerm Potentiation in the Hippocampus
A brief high-frequency train of stimuli
to any of the three major synaptic
pathways increases the amplitude of
the excitatory postsynaptic potentials
in the target hippocampal neurons.
This facilitation is called long-term
potentiation (LTP).
LTP can be studied in the intact animal,
where it can last for days and even
weeks.
It can also be examined in slices of
hippocampus and in cell culture for
several hours.
14
Kandel et al. Principles of Neural Science, McGraw Hill, 2000
NMDA channels are activated  rise in Ca2+ triggers calcium-dependent kinases and
the tyrosine kinase that together induce LTP. The Ca2+/calmodulin kinase
phosphorylates channels and increases their sensitivity to glumate.
Once LTP is induced, the postsynaptic cell release a set of retrograde messengers, one
of which is thought to be nitric oxide, that act on protein kinases in the presynaptic
terminal to initiate an enhancement of transmitter release that contributes to LTP.
15
Kandel et al. Principles of Neural Science, McGraw Hill, 2000
Long-Term Potentiation Has a Transient
Early and a Consolidated Late Phase
Early phase of LTP lasts 1-3 hours; does not require
new protein synthesis.
Four or more trains induce a more persistent phase of
LTP (called late LTP) that lasts for at least 24 hours and
requires new protein and RNA synthesis.
The late phase of LTP involves the activation,
perhaps the growth, of additional presynaptic
machinery for transmitter release and the insertion
of new clusters of postsynaptic receptors.
16
Kandel et al. Principles of Neural Science, McGraw Hill, 2000
A model for the early and late
phase of LTP.
With repeated trains the Ca2+
influx also recruits an adenylyl
cyclase, which activates the
cAMP kinase leading to its
translocation to the nucleus,
where it phosphorylates the
CREB protein. CREB in turn
activates targets that are
thought to lead to structural
changes.
17
Kandel et al. Principles of Neural Science, McGraw Hill, 2000
Long term depression (LTD)
18
Bear et al. Neuroscience: Exploring the Brain, Lippincott Williams & Wilkins 2007
19
Bear et al. Neuroscience: Exploring the Brain, Lippincott Williams & Wilkins 2007
20
21