Synaptic plasticity in simple systems

Question 1

What is learning and memory?

Answer 1

· Learning: ”the process of acquiring new information” – through experience, teaching or study
Memory: ”the persistence of learning in a state that can be revealed at a later time” – information that is learnt to be stored, encoded and retrieved at a later time

Question 2

What is nativism and empiricism?

Answer 2

· Nativism: Plato - ’All knowledge is innate’ – hardwired into our brains at the time of birth
- Empiricism: Aristotle - Learning is the process of drawing information into the mind. The mind is a ‘tabula rasa’ on which experience is subsequently recorded. The mind is moulded from the environment and sensory experience

Question 3

What is the physical basis of memory?

Answer 3

· Stephen Rose (1995): “Something, somewhere has to change”.
· Engrams are the physical manifestation of memory in the brain. Permanent physical change
· Plasticity is the physical process of experience-dependent change in the brain. Leads to memory formation.

Question 4

Are neurons static?

Answer 4

Neurons are not static; their dendrites are continuously active.

Question 5

How do we test memory?

Answer 5

· Simulated memory
· Memory in a petri dish – artificial networks from real neurons
Biological memory – most realistic, nervous system of whole organisms

Question 6

What theories are used for experimentation?

Answer 6

· William James (1890) – when two elementary brain processes
· Donald Hebb (1949) – when axon of site A is close to site B
· McClelland & Rumelhart (1986) – when unit a and unit b are simultaneously excited
· These views convey very similar ideas: memory can be encoded by experience-dependent changes in excitability.
Connectionism: networks of neurons – memory is not stored in single neurons, instead in dense networks of neurons

Question 7

What is synaptic plasticity and how can it be measured?

Answer 7

· Synaptic plasticity – how effectively neurons can communicate with each other
· Before learning: space between the neurons is important (called the synapse), neuron 1 is getting activity propagating across the synapse to the second neuron
· During learning (trial 1):
· Trial two: activity profile grows in the postsynaptic neuron
After learning: increase in activity in the postsynaptic neuron with less energy in the pre-synaptic neuron, can excite his neighbours so neurons can communicate more effectively

Question 8

What is LTP and LTD?

Answer 8

· Long-term potentiation (LTP) is the long-lasting enhancement in efficacy of the synapse between two neurons.
· Long-term depression (LTD) is an alternative form of plasticity in which there is a decrease in efficacy between two neurons. (opposite to LTP)
· Occurs in many areas in the central nervous system
· These forms of Hebbian learning might form the physiological basis of memory in the brain.
· Presynaptic neuron, synapse and postsynaptic neuron
· Slow stimulation of the presynaptic neuron, take a recording of the activity in the postsynaptic neuron
Tetanic stimulation, large stimulation fired within one or two seconds.

Question 9

What is associative LTP?

Answer 9

· A tetanus will elicit LTP if applied to a strong input.
· It will not do so if applied to a weak input alone.
However, when a tetanus is applied to both inputs simultaneously, LTP occurs in both. This is known as associative LTP.

Question 10

What are characteristics of LTP?

Answer 10

· Synapses in LTP behave according to Hebbian rules. These are:
1. The tetanus induces repeated contiguous pre- and post-synaptic activity.
2. This results in increased efficacy between pre- and post-synaptic neurons.
· These synapses have four properties:
1. Rapidity – LTP can be induced
2. Cooperativity
3. Associativity – weak stimulation of a single pathway is insufficient for LTP if one pathway is strongly activated the neighbouring neuron experience LTP
Input specificity

Question 11

What is connectionism?

Answer 11

· Memory is distributed in networks of neurons.
· Parallel distributed processing (PDP) McLelland & Rumelhart (1986) – inspired the parallel nature of brain networks
· Input and output with a dense network in-between, activity is propagated across the layers
Architecture consists of a neural network made up of idealised neurons connected with Hebb-like synapses. – artificial synapses

Question 12

What is backprogation?

Answer 12

· Backpropogation: The networks are presented with training sets. Containing several examples of inputs with corresponding outputs
· Actual output – desired output = error. Connections have values reflecting their strengths.
· errors
The error signal is propagated backwards and the initially random weightings are adjusted with learning until errors are minimal.

Question 13

What are the advantages of connectionism?

Answer 13

· Biological realism. – don’t need to be biologically realistic, easy to learn and test
· Networks learn through experience. – trial and error, how we operate in the real world, using mistakes to adjust behaviour
· Graceful degradation. – lesions to the units degrades memory but doesn’t abolish, distributed across the networks
Analytical solutions not required. – parallel networks meaning errors can be resolved easily

Question 14

What are the disadvantages of connectionism?

Answer 14

• Notion that they can learn anything given enough training. – unlike our real brains, we cannot be good at everything
• Information is sub-symbolic. – abstract connection views
• Training is time consuming. – have to go through the process of input and output
• Networks forget learned material fast. – when they’re trained on other data sets, unlike our real brain

Question 15

Learning in simple networks?

Answer 15

· Is there any evidence that networks of real neurons use Hebbian principles?
· It is possible to manipulate and observe the activity of real networks.
· LTP and LTD can be shown:
· In artificially grown neurons – in lab conditions
· In slices of brain tissue – taken from animals
In the nervous system

Question 16

How are Real neurons used in artificial networks?

Answer 16

· Networks of real neurons can be grown in vitro (in cell culture in the lab) and studied. Plasticity can be studied in these networks.
· Tao et al (2000): Neurons taken from embryonic rats spontaneously branch out and form synaptic connections with each other. LTP can spread to other synapses, wanted to investigate how it happened
Found the spread of LTP were highly selected

Question 17

Can LTP be measured in real neural networks?

Answer 17

· LTP can also be studied in real neuronal networks in the brain. Brain slices can be maintained in culture and investigated.
· The hippocampus has an important role in memory formation. LTP has been demonstrated in several areas within its circuitry.
· Bliss & Lomo (1974): Stimulated perforant pathway in hippocampus of rabbits.
Recorded from dentate gyrus.

Question 18

What are the mechanisms of LTP?

Answer 18

· LTP relies on a cascade of molecular events that are becoming well-understood.
· LTP increases the efficacy of synapses in three ways:
1. More neurotransmitter is released from the pre- synaptic terminal.
2. More receptors available for binding at the post- synaptic terminal.
Retrograde messengers – pass backwards from the post synaptic neuron to the presynaptic neuron, stimulating the pre to post more neurotransmitters into the cleft

Question 19

What does LTP depend on?

Answer 19

· LTP depends on NMDA receptors.
· NMDA receptors contain ion channels that can admit calcium Ca2+ (Ca2+) or sodium (Na+) ions.
The channel is normally blocked by the magnesium (Mg2+) ion. – preventing any neurotransmitters from going into the receptor

Question 20

What to presynaptic neurons trigger?

Answer 20

· Presynaptic action potentials trigger glutamate release.
· Glutamate binds to the receptor. – not activated by glutamate as it’s blocked
· No Ca2+ can enter.
· Mg2+ ion dislodged when post- synaptic terminal is depolarized.
The pre- and post-synaptic terminal must be active for LTP to work.

Question 21

Is LTP the basis of learning?

Answer 21

· Martin & Morris (2002): there are 4 criteria for testing this hypothesis:
1. Detectability. Changes should be detectable in the nervous system.
2. Mimicry. Artificially induced synaptic weight changes. – planting artificial memory in animals
3. Anterograde alteration. Preventing induction of synaptic weight changes during a learning experience.
Retrograde alteration. Altering synaptic weight changes induced by a prior learning experience.

Question 22

What is Detectability?

Answer 22

· Do neurons shows changes in synaptic strength after behavioural learning? Can this be measured after learning has occurred?
· Aplysia are commonly used as an experimental model.
· Few neurons arranges in simple networks
· Behaviour and neural activity easy to measure
· Reflex: touch results in the withdrawal of the siphon, mantle or gill.
Light touch causes the gill and siphon to withdraw, a strong stimulus causes the aplysia to squirt ink through the siphon.

Question 23

Classical conditioning in aplysia

Answer 23

· Electrical stimulation of tail (US) = gill withdrawal (UR)
· Electrical stimulation of tail (US) + Mild stimulus to mantle (CS+) = gill withdrawal (UR)
· Mild stimulus to mantle (CS+) = gill withdrawal (CR).
· Mild stimulus to siphon (CS-) = never paired with electrical stimulation of tail (US).

Question 24

Classical conditioning in aplysia - how does it happen?

Answer 24

· Murphy + Glanzmann (1999):
· Assessed the strength of a specific sensory-to-motor synapse before, during, and after classical conditioning. – received stimulation through an electrode
· Learning-related changes in synaptic efficacy.
· Changes were NMDA-dependent.
Conclusion: this form of learning causes excitability changes and these are dependent on the NMDA receptor. – supports the hypothesis that it plays a role in classical conditioning

Question 25

What is mimicry?

Answer 25

· Programming real networks with artificial memories by changing synaptic weights. Artificially inseminate real networks with false memories

Question 26

· Does the blocking of synaptic changes prevent learning?

Answer 26

· Several different types of learning are susceptible to disruption: · Spatial learning (hippocampal dependent) · Classical eyeblink conditioning (cerebellar dependent). Lesions of the hippocampus severely impair spatial learning. Lesions of the cerebellum abolish motor learning.

Question 27

· Does blocking NMDA function impair spatial learning?

Answer 27

· The Morris Water Maze. · Rats spontaneously search for a surface. – surface to get out of the water, the more they go on the surface the easier t is to find After they find it once, they take less time to find it on successive occasions.

Question 28

· Does blocking the NMDA function impair spatial learning?

Answer 28

AP-5 in an NMDA antagonist. · It binds the NMDA receptor without activating it. · This prevents glutamate from binding to it. · Morris (1989): · Small amounts of AP-5 (group 1) or saline (group 2 – control group) were infused into the hippocampus of rats. – AP-5 meant to block out MNDA function · Group 1 were severely impaired at spatial learning compared with group 2. Can cause anterograde spatial amnesia

Question 29

Classical eyeblink conditioning

Answer 29

· This is a very simple form of learning. · Universal – shown in all mammalian species · Psychophysically well characterised. · How does it work? · Unconditioned stimulus: airpuff to the eye Unconditioned response: eyeblink reflex · Unconditioned stimulus: airpuff to the eye · Unconditioned response: eyeblink reflex Conditioned stimulus: auditory tone · Every 10th trial the CS is presented alone. The full CR can be recorded because it is not interrupted by the US and UR. · Anticipation becomes earlier throughout trials Overtime the auditory tone by itself creates a response of an eye-blink over time

Question 30

Leison studies?

Answer 30

· Using classical conditioning to search for the engram. · Removal of: The entire cerebral cortex · Removal of: the hippocampus · Removal of: the entire forebrain · Fails to abolish learning The essential circuitry must be in the remaining structures. = cerebellum and brain stem

Question 31

What are engrams?

Answer 31

Engrams are the physical manifestation of memory in the brain.

Question 32

Engram in the cerebellum?

Answer 32

- Reversible lesions: an alternative way of testing structure-function relationships. - Local infusions of drugs can ‘switch off’ normal function in small areas of the brain. - What happens if we switch these areas off during learning? - Need multiple pairings to create a conditioned response, extinction is another form of learning. Absence of an unconditioned stimulus - Activate the cerebellum for a period of time, CRs cannot be expressed, cerebellum returns to normal after drugs ware off

Question 33

Hebbian synapses in purkinje cells?

Answer 33

- Hebbian synapses between parallel fibres and purkinje cells may form the basis of learning during eyeblink conditioning. - Critical for learning during eye blink responses - CS acquires eyeblink (CR). - The same mechanism is likely to underpin other forms of cerebellar motor learning.

Question 34

Cerebella long-term depression (LTD)?

Answer 34

``` · Opposite to LTP · An alternative form of plasticity. · Cerebellar LTD · Decrease in the efficacy between Purkinje cells and parallel fibres. · May underlie motor learning. ```

Question 35

AMPA receptors and learning

Answer 35

· Some areas of the cerebellar cortex are important for eyeblink conditioning. · CNQX is a substance that blocks the AMPA receptor, preventing glutamate from acting on it. · If cerebellar LTD and classical eyeblink conditioning share common mechanisms, inactivating AMPA receptor should block learning. · Do CNQX infusions in lobule HVI of cerebellar cortex prevent learning? Atwell et al (2001): 3 groups. · Group 1: infused of CNQX · Group 2: infused CTX-CNQX · Group 3: No CNQX Tested during the drug and when it was waring off , investigated whether HP1 inhibits learning or whether other areas are responsible · Findings · Controls acquired CRs normally. · HVI animals acquired no CRs in phase 1. Started to to acquire CRs. · Blocking AMPA receptors prevents learning as well as LTD. · CTX animals acquired CRs, but more slowly than the control group. Blocking the receptors prevents LTD from happening

Question 36

What is the most important component in LTD?

Answer 36

· AMPA glutamate receptor is one of the most important components of LTD. · Ionotropic receptor that gates ions including CA2+ and Na+. Responsible for most of the rapid glutamate signalling in the nervous system.

Question 37

What is Retrograde alteration?

Answer 37

· If the synaptic weights acquired during learning are later disrupted, does this cause forgetting? · Attwell et al. (1999): Infused CNQX into lobule HVI of the cerebellar cortex after acquisition of conditioned responses. AMPA receptors are essential for CR acquisition and CR retention.