Cerebellum & Classical Conditioning

Question 1

what is a simple form of learning studied to understand the underlying brain changes relating to memory/learning?

Answer 1

classical conditioning

Question 2

Overview of the terminology/ the steps of classical conditioning

Answer 2

• Before training, the unconditioned stimulus (US) e.g. food, produces an unconditioned response (UR) e.g. salivation.
• During training, the conditioned stimulus (CS) e.g. bell, is paired with an unconditioned stimulus e.g. food.
• After training, the CS, e.g. bell, produces a conditioned response (CR) e.g. salivation (without the presence of US)

Question 3

in eyeblink conditioning in humans, what are the US, CS, CR and UR?

Answer 3

US = airpuff in eye
CS= audio tone
CR and UR = eyeblink/eyelid movement

Question 4

name of 3rd eyelid that some animals e.g. rabbits, have

Answer 4

nictitating membrane

Question 5

what is NMR

Answer 5

the nictitating membrane response- involuntary response of nictitating membrane closure to stimulus

Question 6

why is studying NMR often preferred to eyelid CR?

Answer 6

it has no voluntary interference and low levels of spontaneous activity

Question 7

draw graphs showing the development of rabbit NMR to an auditory stimulus and airpuff over time

Answer 7

see drawing/description in notes

Question 8

what are the 2 important features of eyeblink/NMR conditioning

Answer 8

1) US overlaps with the end of CS (delay conditioning
2) US is usually a brief shock or airpuff to skin around eye

Question 9

briefly outline how the parts of the brain involved in eyeblink conditioning were found historically

Answer 9

• since the 50s the role of the hippocampus in memory has been known, with HM’s lesioned hippocampus leading to anterograde amnesia where STM is intact but LTM isn’t (inability to insert new memories into LTM)
• eyeblink conditioning is LTM, however, eyeblink conditioning is intact in patients with hippocampal lesions (anterograde amnesia). This indicates that there is more than one kind of LTM
• rabbits lacking forebrain/hippocampus/decerebrated rabbits maintain eyeblink conditioning
• hence it was clear the Brainstem and cerebellum had a role

Question 10

outline early physiological recording/mapping during conditioning

Answer 10

(researchers systematically recorded units in the cerebellar cortex and deep cerebellar nuclei, with the deep cerebellar nuclei showing activation in eyeblink conditioning
(almost all cerebellar output is via these deep nuclei)

Question 11

outline early lesion work into eyeblink conditioning

Answer 11

• when the entire cerebellum was lesioned, CR was abolished and could not be relearnt
• they found specifically the anterior of interpositus nuclei removed CR. The UR was not affected, indicating the lesion did not cause a motor deficit. To show the lack of CR was not due to deafness, they found unilateral lesions only affect the ipsilateral eyeblink- so the rabbits can hear.

Question 12

draw and label the unconditional reflex pathway for NMR

Answer 12

a basic 3 neuron reflex arc- see diagram in notes

Question 13

draw and label the conditioned reflex circuit for NMRadding in conditioned reflex

Answer 13

see notes
input from cerebellar interpositus via red nucleus to the accessory abducens nucleus

Question 14

where does output for the cerebellum primarily leave from?

Answer 14

the deep cerebellar nuclei

Question 15

where does input for the cerebellum primarily come in?

Answer 15

the cerebellar cortex

Question 16

different regions of the cerebellar cortex project to differing parts of

Answer 16

deep cerebellar nuclei

Question 17

which particular cerebellar cortical region projects to the anterior interpositus and is concerned with eye blink

Answer 17

Hemisphere of lobule VI (HVI)

Question 18

draw the conditioned reflex pathway, including input from the cerebellar cortex

Answer 18

look in notes

Question 19

is cerebellar cortex HVI input to interpositus nucleus excitatory or inhibitory?

Answer 19

inhibitory (tonically active)

Question 20

where does the HVI get its input?

Answer 20

pontine nuclei

Question 21

draw a diagram of the conditional reflex circuit, including the CS pathway

Answer 21

look at notes
CS from light/sound travelling via forebrain and midbrain to pontine nuclei, via mossy fibres to cerebellar cortex etc.

Question 22

draw the overall basic circuitry underlying delay NMR conditioning labelling the CR, US, CS and UR aspects of the pathways

Answer 22

see notes

Question 23

where is the cerebellum found?

Answer 23

base of brain- rostral posterior
next to brainstem

Question 24

what are the 2 parts of the cerebellum?

Answer 24

• cerebellar cortex (extensive)
• deep cerebellar nuclei

Question 25

what is the basic information flow through the cerebellar cortex?

Answer 25

mossy fibres (coming from pontine nuclei) excite
granule cells, whose axons (parallel and ascending fibres) excite
Purkinje cells, which inhibit
cells in deep cerebellar nuclei

Question 26

overview of mossy fibres

Answer 26

• output from pontine nuclei
  in NMR conditioning, they convey info about tone (CS, via vestibulocochlear cranial nerve) with increased firing for increased tone intensity
• input to cerebellar cortex (HVI for NMR) to communicate the current state of body and motor commands
• mossy appearance under staining

Question 27

overview of granule cells

Answer 27

• input from the mossy fibre at the synapse (excitatory)
• axons of GCs form parallel fibres that synapse with Purkinje cell dendrites
• the most numerous cell type in the human brain- ~80% of neurons
• 100:1 ratio with mossy fibres

Question 28

overview Purkinje cells

Answer 28

• middle layer of cerebellar cortex
• sole output of cerebellar cortex
• each PC receives ~150,000 parallel fibre synapses
• largest cell in the cerebellar cortex
• dendritic field flattened out like a fan

Question 29

overview of the layers of the cerebellar cortex from outer to inner

Answer 29

molecular layer- containing stellate cells, basket cells, parallel fibres (of granule cells), Purkinje dendritic tree

purkinje layer- purkinje cell body

granular layer- granule cells

white matter

Question 30

overview Golgi cells

Answer 30

receive input from parallel fibres
project back to synapses between mossy fibres and granule cells (inhibitory- the more PF input they receive, the more they reduce it - posi feedback)
hence, the key function to control expanse recoding

Question 31

overview Stellate and basket cells

Answer 31

in molecular layer
input from parallel fibres
basket cells synapse with Purkinje cell body
stellate cells synapse with Purkinje dendrites
inhibitory
balance average excitatory drive from parallel fibres

Question 32

what kind of spikes does the conditioned stimulus pathway cause to relevant Purkinje cells?

Answer 32

simple spikes

Question 33

outline climbing fibre input to Purkinje cells

Answer 33

• cell body in the inferior olive
• communicates information about the unconditioned stimulus (airpuff/shock)
• low-frequency firing
• fibres wrap around PC dendrites, acting as one large synapse
  -1 wraps around 1 PC (1:1 ratio) (whereas many PF input to PC
• input to PC produces complex spikes- very reliably (whenever CF fires, PC fires)
• thought to be involved in long-term depression by altering parallel fibre synapses on PCs- learning/plasticity

Question 34

what are the 2 candidate sites of plasticity in the cerebellum?

Answer 34

• cerebellar cortex- parallel and climbing fibres synapses on Purkinje cells (of lobule HVI in NMR)
• deep cerebellar nuclei- mossy and climbing fibres synapse onto neurons in the anterior interpositus nucleus

Question 35

what have clinical and experimental observations of cerebellar damage shown about its function?

Answer 35

it does not cause paralysis but makes movements slower, inaccurate/uncoordinated (similar to the effects of alcohol)
this suggests that other parts of the brain control movement (motor cortex), but the cerebellum ensures they are carried out properly- user-friendly/ automation etc.

Question 36

what are cerebellar modules?

Answer 36

individual areas of the cerebellar cortex. The cerebellar cortex has a very uniform structure over its surface with different regions having different inputs/outputs but with the same basic organisation

Question 37

what are cerebellar zones

Answer 37

a parasagittal strip of cortex where Purkinje cells receive climbing fibre input from a unique region of inferior olive and project to a unique region of deep cerebellar nuclei, which in turn project to unique neural targets

Question 38

draw an image of the cerebellar ‘chip’

Answer 38

see notes

Question 39

describe the idea of the cerebellar chip

Answer 39

the idea that the basic cortical microcircuit appears to be very similar for the entire cerebellum, but different regions have different incoming and outgoing connections- hence a chip- the same basic algorithm being used for a wide range of tasks- motor skills, cognitive processing etc.

• this simple algorithm can be applied to NMR conditioning
• mossy fibre input, climbing fibre teaching signal, Purkinje cell output (to deep cerebellar nuclei and beyond)

Question 40

What triggered the start of cerebellar modelling work?

Answer 40

‘The Cerebellum as a Neuronal Machine’ published in 1967 by John Eccles

Question 41

who came up with key theories surrounding cerebellar function

Answer 41

David Marr and James Albus

Question 42

what does the Marr-Albus theory/framework model

Answer 42

the importance of the cerebellum for motor control

Question 43

discuss task analysis and the cerebellum

Answer 43

• complex information processing problems need to be modelled at more than one level
• the first and most abstract is the computational level using a simple task. for example, look straight ahead at the target and move it a certain number of degrees from the centre of vision- we need to know how big a command is sent to eye muscles depending on how far the target is from the original location
• the second level is algorithmic where precise motor commands are learnt using supervised learning in the cerebellum, where command is sent to eye muscles and if motor output is not perfect, error signal send back and response to increase or reduce command (learning rule)
• third level is implementation level- looking at how neural machinery carries out this task. In cerebellum, parallel fibre signals the location of target, when they fire, so does target purkinje cell, with firing amount dependent on synaptic weight between parallel fibre and PC. Climbing fibre then sends error signal and this adjusts the synaptic PF-PC weight. Overtime this is leart to automatically respond to task.

Question 44

what evidence supports the idea of cerebellar motor learning through supervised learning

Answer 44

• there are so many granule cells (which input to parallel fibres (which input to PC), a lot of factors can influence the size of response for accurate motor output, so a lot of info to get the movement right
• unusual climbing fibre input- very reliable- whenever climbing fibre fires, so does PC- strong error signal

Question 45

via which pathway does information about CS (aural tone) arrive at the Cerebellum?

Answer 45

mossy fibres- from pontine nuclei to granule cells (which synapse onto PC dendrites via parallel fibres)

Question 46

via which pathway does info about US (airpuff) arrive in the cerebellum

Answer 46

via climbing fibres from inferior olive to PCs and deep cerebellar nuclei

Question 47

draw a diagram of the cerebellar model of conditioning with notes

Answer 47

see notes

Question 48

what are the 2 issues within the evidence of sites of plasticity?

Answer 48

1) cerebellum vs brainstem
2) cerebellar cortex vs deep cerebellar nuclei

Question 49

outline pro-brainstem argument

Answer 49

• both sides agree that lesion to the anterior interpositus nucleus inhibits CRs, however, they disagree on the mechanism for this. Pro-brainstem believe the lesions are affecting the brainstem input, causing performance deficit as the interpositus nucleus tonically excites the BS pathway via the red nucleus (to accessory abducens nucleus for NMR)
  they believe that the red nucleus and other brainstem areas convey US/CS for CR command

Question 50

outline anti-brainstem argument

Answer 50

• there is weak evidence for the pro-brainstem view- for example, the removal of tonic excitation from the red nucleus in BS only affects UR in a weak and unreliable manner- URs are still present- no clear candidate for the plastic site in BS
• inactivation studies where muscimol has been applied to the red nucleus or interpositus nucleus. Found no CRs when training when applying muscimol to RN, however, CRs appear when muscimol wears off- the animal is still learning, just cannot perform. Whereas, when used on interpositus nucleus, there are no CRs during learning or after muscimol wears off, hence preventing learning and performance

Question 51

what is the overall conclusion on BS vs cerebellum for sites of plasticity

Answer 51

plasticity seems more likely in the cerebellum

Question 52

discuss evidence in the cerebellar cortex vs deep cerebellar nuclei argument for the site of plasticity

Answer 52

• lesions: unilateral cerebellar cortex lesions impair CRs, bilateral lesions abolish them- indicates the role of the cerebellar cortex
• cortical inactivation: parallel fibre->purkinje cell synapses (in the cerebellar cortex) use glutamate as NT AMPA receptors, when blocked with CNQX no CRs are generated both when the drug is active and once the drug has worn off. Further indicates the role of the cerebellar cortex (however CNQX may be having effects at other sites)
• Cortical electrophysiology: a reduction in firing of PC (in HVI eyeblink of cerebellar cortex) is shown after conditioning -further supporting role of cortex
• it is possible that changes in PC in the cerebellar cortex subsequently produce learning in deep nuclei - why does deep nuclear inactivation also block learning? A role for deep nuclei does seem possible as it is part of the activity loop from inferior olive and pontine nuclei. Increasing inferior olive firing rates can abolish simple spiking in the cerebellar cortex and suppress CR

overall likely to be the cortex, but deep nuclei may have a role maybe linked to extended training

Question 53

How does synaptic plasticity produce classical conditioning (relating to eyeblink)?

Answer 53

PCs in HVI reduce firing rate during/ after conditioning in response to the aural tone, before conditioning the tone causes no change- implying that the direct excitatory effect of PC from PFs is balanced with inhibitory stellate/basket cells- which must increase input/PF reduce input during conditioning, so deep cerebellar nuclei are less inhibited.

during conditioning, CS is paired with US so firing in parallel fibres I paired with climbing fibre firing

the prediction that PF-PC become less effective through LTD and the inhibitory pathway is unchanged, therefore PC recieves net inhibitory then CS tone is played

Question 54

overview KO mice in classical conditioning

Answer 54

mice that lack LTD in slices show normal eyeblink conditioning, however, mice lacking LTP do not show classical conditioning

Question 55

what’s the covariance learning rule

Answer 55

applies to supervised learning- if input signal is positively correlated with error, decrease the influence of input signal and vice versa
(correlation is treated as cause)

Question 56

how is the covariance learning rule implemented to the cerebellum?

Answer 56

to decrease the signals positively associated with the error, there’s increased activity of inhibitory interneurons- basket and stellate cells. Seen in classical conditioning and motor learning/control

Question 57

what is meant by cerebellar function being described as an adaptive filter/ analysis synthesis filer?

Answer 57

the operating system of the cerebellum carries out high-level instructions automatically, e.g. walking into a room, which frees up the system for higher cognitive functions to be activated simultaneously

it is receiving input of motor commands from the cerebral cortex alongside information about the state of the body and environment (granule cells)- its output is the detailed motor command to produce the desired output (firing of PC and molecular layer interneurons) (with error signal from climbing fibres)