Sites of Plasticity in Eyeblink Conditioning

Question 1

What are two implications from the finding that the cerebellar is very uniform?

Answer 1

1. Apply general cerebellar theories to explain classical conditioning
2. Use data from classical conditioning to test general predictions

Question 2

What do models predictis the key synapse for plasticity?

Answer 2

Synapses between parallel fibres and purkinje cells

Question 3

The evidence on sites of plasticity can be split into two areas, what are they?

Answer 3

1. Cerebellum vs brainstem
2. Cerebellar cortex vs deep cerebellar nuclei

Question 4

What does it mean that evidence shows conditioning occurs in decerebrate preparation?

Answer 4

Site of plasticity must be in either the cerebellum or brainstem- it has to be one or another

Question 5

What is the pro-brainstem argument?

Answer 5

Both sides agree that lesions of the anterior interpositus nucleus stop CRs

Disagree on the mechanism of this effect:
-One side claims this is evidence for plasticity in the cerebellum
-The other claims that the lesions work because they affect the brainstem, causing a ‘performance deficit’

Question 6

What do we know about the interpositus nucleus?

Answer 6

That it tonically excites the red nucleus so there is always a background excitation on brainstem pathways

Question 7

How could this tonic activation affect learning?

Answer 7

Learning in brainstem area X produces a command for the CR but that can only affect motor neurons if there is sufficient background excitation from interpositus via the red nucleus

Question 8

How can we test this involvement of the tonic activation?

Answer 8

Lesion the interpositus nucleus to remove tonic excitation from the motor neurons

Thid could lead to much smaller or undetectable CRs

E.g. if the CR= 30 spikes/second and the tonic activation = 50 spikes/second, the motorneuron threshold = 50 spikes/second
SO removing the 50 spikes/second from the tonic activation coming down means the CR command won’t make it through the motorneuron

Question 9

What are the anti-brainstem arguments? Removing tonic excitation

Answer 9

Evidence FOR this view is weak

Removal of tonic excitation should affect UCRs but effects on UCRs are weak and unreliable: UCRs still present, even when CRs NOT present

Question 10

What are the anti-brainstem arguments? Sites

Answer 10

2. There’s never been a clear brainstem site proposed for this plastic site so we don’t know where to look

Question 11

What are the anti-brainstem arguments? Cortical lesions

Answer 11

Evidence AGAINST this view is strong

It is known that the cerebellar cortex inhibits tonically all the time the interpositus nucleus which excites the red nucleus

Unilateral cortical lesions decrease CR amplitude
BUT
Unilateral cortical lesions increase UCR amplitude (slightly)

This cannot be explained by simple tonic effect on motorneurons- must be SPECIFIC effect on CRs

Question 12

What are the anti-brainstem arguments? Reversible inactivation studies

Answer 12

Evidence AGAINST this view is strong

Inject Muscimol, a GABA antagonist (acts as an inhibitory agent stopping neurons from firing in the target) into the red nucleus

Carry out CC

At the end of training when we test the next day after the muscimol has worn off, there are CRs
- this means performance has been affected by this treatment but NOT LEARNING

However, if the same thing is done in the interpositius nucleus (cerebellum), there are no CR responses after muscimol wears off
- so both performance and LEARNING are affected

We can conclude that the major site of plasticity for rabbit NMR and eyeblink conditioning is within the cerebellum

Question 13

What is the issue with localising the site of plasticity in the cerebellum?

Answer 13

There are TWO CANDIDATE SITES of plasticity in the cerebellum where both CS and UCS information are available
- cerebellar cortex OR deep cerebellar nuclei (second does not come from a model prediction but from anatomy which is also controversial)

Question 14

What happens if we lesion the cortical cerebellar cortex?

Answer 14

Unilateral cortical lesions (in right place) impair conditioned responses
bilateral lesions abolish them
cortical lesions block conditioning

Necessary evidence, but not sufficient.

Question 15

What can we do to inactivate the cerebellar cortex?

Answer 15

We know the parallel fibre-purkinje cell synapses use glutamate as a transmitter
Simple spikes are generated from the activation of AMPA receptors, a subtype of glutamate receptor

We can use the reversible blocking agent CNQX to block AMPA receptors

Question 16

What did Attwell, Rahman & Yeo (2001) do and what did they find when using CNQX to block AMPA receptors?

Answer 16

Used radioactive labelling to show where the drugs went in the brain

Leave the animal for 6 weeks then section it to show where radioactivity was

Can show the injection here affected the cortex but not the deep nuclei

There were no CRs when the drug was active so no learning of CRs
There was also no CRs the next day after the drug had worn off

Question 17

What is a caveat in Attwell, Rahman & Yeo’s (2001) study?

Answer 17

CNQX may not be acting just on the synapses between parallel fibres and Purkinje cell

The synapses between mossy fibres and granule cells could also have been affected

However, either of these sites indicates the importance of cerebellar cortex

Question 18

What did Jirenhead et al. (2007) do and find with cortical electrophysiology?

Answer 18

Done in a decerebrate ferret

Recorded from the cortical eyeblink area in HVI and recorded what happened during conditioning

The first trial had effectively no effect on the CS

But once learning is complete, he showed for the first time that the relevant cortical purkinje cells ceased firing, as predicted

This was reflected in the electrophysiology responses as an absence of firing of relevant purkinje cell nuerons during the acquisition of CRs

Question 19

What is a caveat of Jirenhead et al.’s (2007) study?

Answer 19

These results were obtained in the decerebrate preparation (ferret) and while preliminary data suggest Purkinje cells behave similarly in intact rabbits and mice, there is still some problems with identification of relevant region of cortex

Question 20

What is a caution regarding the cerebellar cortex in learning?

Answer 20

Current evidence supports key role for cerebellar cortex in initial learning

It is possible that the changes in Purkinje cell firing subsequently produce learning in the deep nuclei

Evidence currently very confusing, e.g. Boele et al (2013)

Question 21

If it’s the cerebellar cortex that control initial learning, why is deep nuclear inactivation also effective at blocking learning?

Answer 21

The suggestion is that the interpositus nucleus projects to the inferior olive, completing a LOOP

Cerebellar deep nuclei inactivation disrupts this loop so the system no longer works

So inactivating the interpositus nucleus disinhibits the inferior olive so it fires more, and increases the complex spikes in the cortex
-this means fewer simple spikes = an unintentional inactivation of the relevant area of cerebellar cortex

Question 22

Describe the evidence supporting this loop theory. Zucca et al. (2016)

Answer 22

Electrophysiological evidence =
If you increase inferior olive firing rates, you abolish simple spikes in cerebellar cortex
- this suppresses conditioned eyeblink responses

Question 23

What don’t we know still?

Answer 23

Increasing inferior olive firing abolishes simple spikes and suppresses conditioning
but we don’t know whether inactivating the anterior interpositus nucleus has similar effects- has yet to be conclusively demonstrated

But at least we have a reasonable explanation of the effects of deep nucleus activation