Cerebellum (Week 3--Otis)

Question 1

Major anatomical divisions of cerebellum

Answer 1

Anterior lobe

Posterior lobe

Flocculonodular lobe

Vermis: central strip that runs through anterior and posterior lobes

Question 2

What kinds of information does the cerebellum receive?

Answer 2

Somatosensory

Visual

Auditory

Vestibular

Proprioceptive

Question 3

In general, what does the cerebellum do?

Answer 3

Rapid, corrective feedback loop, smoothing and coordinating movements

Question 4

What can lesions of the cerebellum cause?

Answer 4

Nystagmus

Ataxia

Dysdiadochokinesia

Dysmetria

Intention tremor

Deficits in motor learning

Question 5

SCA1

Answer 5

Causes atrophy of the cerebellum

Question 6

Functional regions of the cerebellum

Answer 6

Cerebrocerebellum (hemispheres): coordination of voluntary movements of limbs, hypothalamic control, cognitive functions?; inputs from cortex via pons; lateral cerebellum influences ipsilateral limbs

Spinocerebellum (intermediate zone, includes vermis): voluntary movements of limbs, postural control and balance; receives fast feedback from spinal cord

Vestibulocerebellum (includes nodulus and flocculus): balance and posture, eye movements; receives vestibular input and input from other brainstem centers via pons

Question 7

Inputs to the cerebellum

Answer 7

Mossy fibers from pons through middle cerebellar peduncle

Mossy fibers from spinal cord through inferior cerebellar peduncle

Mossy fibers from vestibular nuclei through inferior cerebellar peduncle

Climbing fibers from inferior olive through inferior cerebellar peduncle

Question 8

Outputs from cerebellar cortex

Answer 8

Carried solely by Purkinje cell axons!

First go straight to deep cerebellar nuclei (dentate nucleus (most lateral), interposed nucleus, fastigial nucleus (most medial))

Deep nuclei project to: thalamus (then to cortex), red nucleus (then to spinal cord via rubrospinal tract), inferior olive (to influence climbing fiber input), vestibular nuclei and reticular formation (influence posture and balance)

Vestibular nuclei

Question 9

Two inputs to cerebellar cortex

Answer 9

Mossy fibers: carry info about motor context; contact granule cells whose axons are called parallel fibers and contact Purkinje cells; each Purkinje cell receives >80,000 excitatory parallel fiber inputs; input from everywhere except olive

Climbing fibers: carry info indicating errors in movement; directly contact Purkinje cells; each Purkinje cell receives 1 climbing fiber input (but is a really strong input); input info from inferior olive only

Question 10

Complex spike

Answer 10

Climbing fibers stimulate Purkinje fibers to generate this “special” response

The whole Purkinje neuron “hears” this response/burst of APs

This input from climbing fibers onto Purkinje neurons is a “teacher” that teaches circuit new information

Question 11

Do Purkinje cells fire spontaneously?

Answer 11

Yes, Purkinje cells fire spontaneously, with no synaptic input

So deep cerebellar nuclei always receiving constant inhibition

Intrinsic activity causes them to fire at ~50 spikes/second

Generated by “pacemaking” types of ion channels

Question 12

How does Purkinje neuron firing affect movement?

Answer 12

Purkinje neurons are inhibitory, thus when they slow or stop firing their targets are excited (muscles contract!)

Purkinje cells –> deep nuclei (pre-motor neurons) –> thalamus (to motor cortex), vestibular nuclei, inferior olive, red nucleus –> motor neurons –> voluntary movement or reflex

If can get Purkinje fiber to STOP firing, can get/enhance a movement

Question 13

Conditioned eyeblink reflex

Answer 13

Classic paradigm for studying associative motor learning

Auditory tone at fixed time interval with a puff of air in eye at the end –> then when air puff taken away you still blink your eye

This is because you have reflex memory and anticipate air puff

This learning requires the cerebellum

Question 14

Associative motor learning

Answer 14

Cerebellar cortex is critically important for forms of associative motor learning

Learning uses experience to keep movements (particularly rapidly alternating sequences of movement) coordinated and well-calibrated for their intended purpose

Mossy fiber to granule cell’s parallel fiber inputs to Purkinje cells carry all moment-to-moment sensorimotor info into cerebellar cortex (sensorimotor context)

Question 15

What do complex spikes indicate?

Answer 15

Errors

Rate of complex spikes increases with errors in a novel task

Rate of complex spikes decreases after learning corrects errors in performance

Climbing fibers function as “teachers” providing “error signals”

Question 16

What do climbing fiber inputs do?

Answer 16

Climbing fiber inputs signal errors in movement and have crucial role in instructing changes during learning

When CF input fires, parallel fiber inputs to Purkinje cells that were active in the time immediately before (100ms) are “punished” by having their synaptic strength reduced

Also, parallel fiber inputs to inhibitory interneurons are increased in strength

Also mossy fibers hypothesized to undergo CF-driven long term increases in strength

These experience-driven changes lead to less excitation of Purkinje cells and increase deep nuclear cell output that will occur in response to particular pattern of mossy fiber activity –> increased muscle contraction in muscles that need to act!

Question 17

What happens when errors no longer occur?

Answer 17

Perfection!

Climbing fiber firing drops to baseline levels and no plasticity occurs

System maintains well-calibrated reflexes to visual stimuli, vestibular stimuli, reflexive, sequenced movements, learning how to play a sport

Question 18

Long-term depression

Answer 18

Complex spikes trigger reductions in strengths of coactive parallel fiber inputs to Purkinje cells

Question 19

How does LTD work at a molecular level?

Answer 19

Coincident climbing fiber and parallel fiber activity causes removal of AMPA receptors on Purkinje cell postsynaptic membrane at only those parallel fiber synapses which were active (LTD)

This mechanism explains the 100ms time window where climbing fibers inhibit parallel fibers that have fired 100ms beforehand, because this process of removing AMPA receptors takes time

Specifically:

1) Climbing fiber inputs (error signals) cause complex spikes in Purkinje cell, which increases Ca2+ throughout the entire Purkinje cell via voltage-gated Ca2+ channels
2) In dendritic spines where parallel fiber inputs come in, DAG/PKC from glutamate binding mGluR (G coupled protein receptor) plus Ca2+ phosphorylate the AMPA receptor to remove it from the synapse

Note: this is how climbing fibers reduce, or “punish” parallel fibers that fired when they weren’t supposed to 100ms ago!

Question 20

Which NT do Purkinje neurons use and how?

Answer 20

Purkinje neurons use GABA and inhibit their targets in the deep nuclei

This “sculpting inhibition” of descending motor commands allows cerebellum to smooth and coordinate movement

Lesions cause ataxia, intention tremor and decomposition of movement

Question 21

Associative forms of motor learning in the cerebellum

Answer 21

Climbing fiber inputs drive learning:

1) Instruct coactive parallel fiber inputs to Purkinje neurons to undergo long term decreases in strength
2) Instruct coactive parallel fiber inputs to inhibitory interneurons to increase in strength
3) Instruct coactive mossy fiber inputs to deep cerebellar nucleus neurons to increase in strength

Question 22

How are parallel fiber synapses weakened?

Answer 22

Removal of AMPA glutamate receptors weakens parallel fiber synapses onto Purkinje cells

Question 23

Regions important for eye movements

Answer 23

Flocculus and nodulus

Question 24

Regions important for balance, vestibular input, body position

Answer 24

Vermis

Question 25

Where do Purkinje neurons synapse before exiting the cerebellum?

Answer 25

Deep cerebellar nuclei

Question 26

What do mossy fibers and climbing fibers do?

Answer 26

Mossy fibers can bring in excitatory inputs to Purkinje fibers OR inhibitory (mossy –> granule (excitatory) –> inhibitory to Purkinje cell)

Climbing fibers only excitatory inputs to Purkinje fibers

Remember that Purkinje fibers are always inhibitory though, so excitatory TO Purkinje = inhibitory overall

Question 27

Granule cells

Answer 27

Always excitatory

Axons are called parallel fibers

Mossy fibers –> granule cells –> Purkinje cells

Mossy fibers –> granule cells –> inhibitory interneurons --I Purkinje cells