Cerebellum (Week 3--Otis) Flashcards
Major anatomical divisions of cerebellum
Anterior lobe
Posterior lobe
Flocculonodular lobe
Vermis: central strip that runs through anterior and posterior lobes
What kinds of information does the cerebellum receive?
Somatosensory
Visual
Auditory
Vestibular
Proprioceptive
In general, what does the cerebellum do?
Rapid, corrective feedback loop, smoothing and coordinating movements
What can lesions of the cerebellum cause?
Nystagmus
Ataxia
Dysdiadochokinesia
Dysmetria
Intention tremor
Deficits in motor learning
SCA1
Causes atrophy of the cerebellum
Functional regions of the cerebellum
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
Inputs to the cerebellum
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
Outputs from cerebellar cortex
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
Two inputs to cerebellar cortex
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
Complex spike
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
Do Purkinje cells fire spontaneously?
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
How does Purkinje neuron firing affect movement?
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
Conditioned eyeblink reflex
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
Associative motor learning
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)
What do complex spikes indicate?
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”
What do climbing fiber inputs do?
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!
What happens when errors no longer occur?
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
Long-term depression
Complex spikes trigger reductions in strengths of coactive parallel fiber inputs to Purkinje cells
How does LTD work at a molecular level?
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!
Which NT do Purkinje neurons use and how?
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
Associative forms of motor learning in the cerebellum
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
How are parallel fiber synapses weakened?
Removal of AMPA glutamate receptors weakens parallel fiber synapses onto Purkinje cells
Regions important for eye movements
Flocculus and nodulus
Regions important for balance, vestibular input, body position
Vermis
Where do Purkinje neurons synapse before exiting the cerebellum?
Deep cerebellar nuclei
What do mossy fibers and climbing fibers do?
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
Granule cells
Always excitatory
Axons are called parallel fibers
Mossy fibers –> granule cells –> Purkinje cells
Mossy fibers –> granule cells –> inhibitory interneurons --I Purkinje cells
