Download Long term sensitization

Exam
Written exam will take place on Monday June 20, 2016, at 9 – 10.30 AM, in the room 1.40
After written exam one should sign up for an oral exam, which will take place on June 21-22,
2016, in the room 4.69
Learning and memory
Route recall, by licensed London
taxi driver, from Hyde Park to
Primrose Hill, results in PET
activation of the right hippocampus.
Maguire et al. Learning to find your way: a role
for the human hippocampal formation. Proc R
Soc London B, 1996.
Learning and memory
The central problem of the mind, if you will, or the nervous system, is this: when an
animal learns something, it can do something different than it could before, and its
brain cell must have changed too, if it is made out of atoms. In what way is it different?
We do not know where to look, or what to look for, when something is memorized. We
do not know what it means, or what change there is in the nervous system, when a fact
is learned. This is a very important problem which has not been solved at all.
The Feynman Lectures on Physics, Volume I,
California Institute of Technology (Caltech), 1963.
Definition of learning:
Learning is an adaptive change in behavior caused by experience
Definition of memory:
Memory is the storage and recall of previous experiences
In Search of the Engram
Jerzy Konorski (1903 – 1973)
Donald Hebb (1904 – 1985)
Coined the term neural
plasticity and developed
theoretical ideas
regarding it. They were
similar to those
proposed soon after by
Donald Hebb.
Lashley was trying to find a
specific location that stored a
memory. He started to doubt that
memory center exists.
„When an axon of cell A excites a
cell B and repeatedly or
persistently takes part in firing it,
some growth process or metabolic
change takes place in one or both
cells such that A's efficiency, as
one of the cells firing B, is
increased".
"Neurons that fire together
wire together."
Types of learning and memory
There are two types of long term memory:
Implicit memory (or nondeclarative memory) - how to perform something
Explicit memory (or declarative memory) - factual knowledge of people, places, and things, and what
these facts mean.
Explicit memory can be further classified as episodic (a memory for events and personal experience)
or semantic (a memory for facts).
Habituation
A bottom view of Aplysia illustrates the
respiratory organ (gill), which is normally covered
by the mantle shelf. The mantle shelf ends in the
siphon, a fleshy pipe used to expel seawater and
waste. A tactile stimulus to the siphon elicits the
gill-withdrawal reflex. Repeated stimuli lead to
habituation. Weak stimuli give rise to short term
habituation, lasting from minutes to hours. A more
powerful and long lasting stimulus will result in a
long term habituation that can remain for weeks.
A. The observed behavior. B. Experimental setup and recordings showing shortening of sensory action potential and decrement of
motoneuron EPSP with repeated stimulation. C. (Left) Simplified model of the synapse to account for habituation by depression of
calcium current. (Right) Changes in structure of synaptic terminal during long-term habituation leading to functional disconnection.
Sensitization
Sensitization of the gill withdrawal reflex
of Aplysia. Noxious stimulation in a form
of strong electrical shock delivered to the
head or tail, leads to an enhacement of the
relfex response.
A. Experimental setup and the observed behavior. B. (Left) Recordings of gill response amplitude showing habituation to sensory input and
sensitization by stimulation of nociceptors from the head. (Right) Broadening of sensory action potential and facilitation of the motoneuron
EPSP during sensitization of the gill reflex. C. (Left) Simplified model of the synapse to account for sensitization (reduced K currents
during the impulse and increased Ca entry). (Right) Structural changes i.e., increase of size and number of active zones, underlying longterm sensitization.
Short and long term sensitization
Short term sensitization
The mechanism for short term sensitization is that particular
ion channels are affected in such a manner that more calcium
ions will enter the nerve terminal. This leads to an increased
amount of transmitter release at the synapse, and thereby to
an amplification of the reflex.
Long term sensitization
The stronger stimulus will give rise to increased levels of the
messenger molecule cAMP and thereby protein kinase A.
These signals will reach the cell nucleus and cause a change in
a number of proteins in the synapse. The formation of certain
proteins will increase, while others will decrease. The final
result is that the shape of the synapse can increase and thereby
create a long lasting increase of synaptic function. In contrast
to short term memory, long term memory requires that new
proteins are formed.
Associative learning (classical conditioning)
Associative learning is the process by which an association between two stimuli or a
behavior and a stimulus is learned
The siphon withdrawal reflex also exhibits classical
conditioning when a weak stimulus to the siphon or
mantle shelf (the conditioned stimulus or CS) is
paired with a shock to the tail (the unconditioned
stimulus or US). The mechanism is similar to
sensitization.
Tail shock (the US) produces greater facilitation of
the monosynaptic EPSP from a sensory to a motor
neuron if the shock is immediately preceded by
spike activity in the sensory neuron than if it occurs
without spike activity.
When the tail shock and mantle stimulus (CS+) are
paired, the response to mantle stimulus is increased.
Conditioning and reactions
Conditioning
Reaction
Classical conditioning of Aplysia
US: shock to the tail
CS: weak stimulus to the mantle
Full gill withdrawal by the weak CS
Classical conditioning (Pavlovian, type I)
US: taste of food
CS: ringing a bell
Salivation to bell alone
Operant conditioning (instrumental, type II, discovered by Konorski) – change of behavior depending
on consequences
Behavior (intentional action e.g. response in a class) -> Consequences (reinforcement given afer
desired action, e.g., good mark) -> Increased likelihood to respond again
Conditioning in economics
Many modern day advertisers use classical conditioning in some way. The ads show products as CS,
pairing them with images that are designed to elicit positive emotional, or other cognitive, reactions.
As a result the viewers of the ad will buy more of this product.
Operant conditioning of a single neuron
Operant conditioning of a single neuron in the motor cortex of an awake, behaving
monkey. A Meter registering rate of impulse firing; when firing rate exceeded a preset
level, dial become illuminated and few drops of fruit juice was given. B. Records of
impulse activity. C. Graph of average firing rate during successive experimental periods.
D. Relation to muscle activity.
Aversion learning
Aversion learning takes place when a subject associates taste of certain food with symptoms
caused by a toxic, spoiled, or poisonous substance. We become averse to the taste of something
that causes nausea, sickness, or vomiting.
Neural pathways mediating taste aversion learning in the mammal. Aversion learning requires
a site at which the taste and aversive pathways meet, and the nucleus of the solitary tract is a
likely candidate.
Complex learning
Imprinting
Konrad Lorentz with ‘his’ goslings. The goslings
imprinted on Lorenz as he was the first moving
stimuls they saw after hatching.
Latent learning
Observational learning
Latent learning is not immediately
expressed in a response. Rats who
previously could explore the maze
learned to find food faster than another
group of rats that had not previously
explored the maze.
Observational learning is learning that occurs through observing the behavior of others. In 40-ies
one tit (sikorka) had learned to steal the cream from the top of milk bottle delivered to the doors
in London. Over a 12 years period cream stealing was common in whole Great Britain.
Hippocampus
Evolution of the hippocampus, as exemplified
in lower vertebrate (shark), a mammal (rat)
and the human. Hippocampus is an ancient
part of the brain.
Sea horse (Hippocampus)
Hippocampal circuits are organized in a highly distinctive manner. It contains
stereotyped micro- and local circuits. The main parts are: entorhinal cortex (EC),
dentate gyrus (DG), hippocampus (CA3, CA1), subiculum (Sub).
Long term potentiation (LTP)
First experimental demonstration of long term potentiation in the anastethized rabbit (1973). High frequency
tetanic, 20 Hz stimulation was applied to the perforant fibers for 15 seconds and was repeated at times marked
by arrows in the graph. The test was a single shock at various intervals after that. The amplitude of the
synaptic response (EPSP spike) of the dentate cell grew to a much greater amplitude. The time course of the
increase over a period of 6 hours is plotted. In dentate cells LTP lasts for several hours and could be
demonstrated over periods of days or weeks.
LTP properties
In general, properties of LTP fit closely into Hebb’s and Konorski’s original concepts. In the
experiments on hippocampus, some additional properties were found.
A. Weak repetitive stimulation of one pathway may be not sufficient to elicit LTP.
B. For weak inputs to be potentiated they must be paired with strong inputs.
C. Strong repetitive stimulation of one pathway can be sufficient to elicit LTP in that pathway, but not in
unstimulated pathway.
From Hebbian rule to spike-timing-dependent plasticity
A Hebbian rule “those who fire together, wire together” might incorrectly suggest that if two
neurons fire exactly at the same time, their connection gets stronger. Experiments that
stimulated two connected neurons with varying interstimulus asynchrony showed that the
presynaptic neuron has to fire just before the postsynaptic neuron for the synapse to be
potentiated. If an input spike tends, on average, to occur immediately after an output spike,
then that particular input gets weaker. This phenomenon is called spike-timing-dependent
plasticity (STDP).
In typical STDP, causal activity results in
long-term potentiation (LTP), while
acausal activity elicits long-term
depression (LTD). At some cortical
synapses, the temporal window for LTD
(dashed gray line) is extended
LTP: postsynaptic or presynaptic locus?
LTP was elicited neither by postsynptic depolarizing current alone nor in response to synaptic input under voltage
clamp (no depolarization). Only stimulation paired with postsynaptic depolarization resulted in LTP. It suggests that
LTP is based on changes in postsynaptic structure.
Postsynaptic LTP mechanism
Mechanisms underlying LTP are depenedent on NMDA receptors.
(NMDAR). These receptors are blocked by Mg2+ ions at resting membrane
potentials. Depolarization removes the block and allows Ca 2+ to pass
through the channel and enter the cell.
Evidence for a presynaptic locus
C. Analysis of quantal mechanism at synapse in the hippocampus. The histogram of numbers of quantal events
(excitatory postsynaptic currents) is different before and during LTP. There is shift towards higher values
signifying enhanced presynaptic vesicle release. It suggests that both presynaptic and postsynaptic factors
contribute to LFP.
LTP mechanism – early phase
Long-term potentiation has a transient early phase (lasting1-3 hours) and a consolidated late
phase(lasting 24 hours or more).
When the postsynaptic membrane is depolarized by the actions of the AMPA receptor-channels, the
depolarization relieves the Mg2+ blockage of the NMDA channel. This allows Ca2+ to flow through the
NMDA channel. The resulting rise in Ca2+ in the dendritic spine triggers calcium-dependent kinases
which phosphorylate non-NMDA receptor-channels and increases their sensitivity to glutamate.
Retrograde messengers act on presynaptic terminal to initiate an enhancement of transmitter release.
Late-phase LTP
With repeated trains the Ca2+ influx recruits the cAMP-PKA-MAPK-CREB signaling pathway and leads
to synthesis of new mRNA , which causes structural changes and forming of new synapses.
Change in synaptic strength can store complex memory
Three aspects of the circuit
give it the ability to store
and retrieve patterns.
1. Each of the input cell (a
to f) makes a sufficiently
strong connection to
activate postsynaptic cell.
2. Each output cell (z to u)
sends an axon collateral that
makes an excitatory
connection with itself and
the other five output cells.
3. Each of the 36
connections are modifiable
through an LTP-like
mechanism.
Repeated presentations of the pattern will lead to output which is amplified version of the input. The
“memory” for the pattern is not stored in any one synapse or one cell. Rather, it is distributed throughout
the network at multiple sites. If a partial input pattern is presented, e.g.,{101000}, the network can
complete the pattern and produce an output that is approximately full input pattern {303022}. This
property arises from the distributed representation of the memory within the circuit.