21.4 and 21.5. Basal Ganglia and Cerebellum (HT) Flashcards
1
Q
Summarise the organisation of the sensory-motor pathway.
A
- Sensory systems and the limbic/reticular system are responsible for our motivation to make movement, both due to sensory input and due to our emotions
- The basal ganglia and pre-motor cortical areas are involved in planning of movement
- The motor cortex programs this movement
- The cerebellum and brainstem are involved in integration
- The spinal cords and muscles execute the movement
2
Q
What are the basal ganglia and where are they found?
A
- A group of subcortical nuclei in the brain.
- They are found at the base of the forebrain and top of the midbrain (i.e. they are subcortical).
3
Q
Draw diagrams to show the subcortical loops that the basal ganglia and cerebellum are involved in.
A
4
Q
Describe simply the subcortical loops that basal ganglia form.
A
- Receive information from various cortical areas
- They then process this information and pass it back to the cortex via the thalamus (ventral anterior and vental lateral nuclei)
5
Q
The basal ganglia are ………, ………. structures.
A
- Extrapyramidal (meaning that they do not pass through the pyramids of the medulla)
- Subcortical
6
Q
Summarise simply the function of the basal ganglia.
A
- They are involved in selection of internally-generated goal-driven movements.
- This is done because they receive information from the cortical areas and then output back to the pre-motor cortical areas via the thalamus
(In other words, the basal ganglia select motor activity that is not reflex, although it may be almost automatic due to learning)
7
Q
Describe in depth the functions of the basal ganglia.
A
- Solve the problem of multiple competing inputs from the limbic/reticular system and cortical areas:
- There are multiple sensory, motivational and emotional inputs, as well as short and long-term goals, to the basal ganglia
- They must weight up these needs and put them in context, in order to decide which motor program is appropriate for the circumstances
- This is done by:
- Selecting the goal to respond to (e.g. quenching thirst)
- Selecting actions that will achieve that goal (e.g. movement)
- Select the exact movements required with regards to important sensory stimuli (e.g. how to move to get the water)
- Learn the outcome of actions (Outocome-Action) and the sensory cues that are associated with those outcomes (Stimulus-Outcome)
- This allows adaptation, so that efficient responses can be managed in the future
- This is called reinforcement learning
- Establish habits (Stimulus-Response)
8
Q
Draw the general appearance of the basal ganglia in 3D.
A
9
Q
What are the different basal ganglia you need to know about?
[IMPORTANT]
A
- Striatum
- Caudate
- Putamen
- Globus pallidus
- Internal segment
- External segment
- Subthalamic nucleus
- Substantia nigra
- Pars compacta
- Pars reticulata
10
Q
Label this.
A
11
Q
What is number 1?
A
Thalamus (Ventral anterior and ventral lateral nuclei)
12
Q
What is number 2?
A
Caudate nucleus (part of striatum)
13
Q
What is number 3?
A
Putamen (part of striatum)
14
Q
What is number 4?
A
Globus pallidus (internal and external segments)
15
Q
What is number 5?
A
Subthalamic nuclei
16
Q
What is number 6?
A
Substantia nigra pars compacta
17
Q
What is number 7?
A
Substantia nigra pars reticulata
18
Q
Label this.
A
19
Q
Label this.
A
20
Q
Draw a diagram to show the relative 3D positions of all of the basal ganglia.
A
21
Q
Draw and describe the subcortical loops that the basal ganglia are involved in.
[IMPORTANT]
A
- The blue box shows all of the basal ganglia
- The striatum receives input from the cortex
- It then outputs to the substantia nigra pars reticulata and internal globus pallidus (which are considered together), as well as the external globus pallidus
- The external globus pallidus and subthalamic nucleus are interconnected, and the subthalamic nucleus also outputs to the substantia nigra pars reticulata and internal globus pallidus
- Output from the basal ganglia is from the substantia nigra pars reticuluta and internal globus pallidus, to the thalamus and brainstem nuclei
- The substantia nigra compacta also outputs back to the striatum
- The thalamus outputs to the cortex and striatum, completing the loop
22
Q
Which part of the basal ganglia is most input from the cortex and thalamus from?
A
Striatum
23
Q
Which part of the basal ganglia is most output from the basal ganglia from and to?
A
- From the substantia nigra pars reticulata and internal globus pallidus.
- To the thalamus and to the brainstem nuclei.
24
Q
Which two parts of the basal ganglia are frequently considered together and why?
A
- Substantia nigra para reticulata and internal globus pallidus
- This is because they contain similar neurons and have similar inputs/outputs
25
What neurons in the striatum receive input from the cortex?
Medium spiny neurons (a.k.a. spiny projection neurons)
26
What do medium spiny neurons in the striatum fire in response to?
* They fire in relation to cues for movement or intended movement, not movement itself.
* This is consistent with the idea that the basal ganglia are responsible for selection of motor programs.
27
What are the principle neurotransmitters involved in the basal ganglia that you need to know? Where is each used?
[IMPORTANT]
* Glutamate (excitatory)
* From cortex to striatum
* From subthalamic nucleus to internal globus pallidus (and internal globus pallidus + substantia nigra pars reticulata, although not mentioned)
* From thalamus to cortex and striatum (*not in spec*)
* GABA (inhibitory)
* From striatum, external globus pallidus and internal globus pallidus (+ substantia nigra pars reticulata)
* Dopamine (excitatory or inhibitory)
* From substantia nigra pars compacta to striatum
28
What are the two types of medium spiny neurons in the striatum?
[IMPORTANT]
* D1
* Enriched in D1 dopamine receptors
* Make substance P and dynorphin opioid
* D2
* Enriched in D2 dopamine receptors
* Have A2A receptors
* Make enkephalin opioid
This is because they also receive dopaminergic input from the substantia nigra pars compact (aside from the glutamatergic input from the cortex).
29
What neurotransmitters act on the striatum?
[IMPORTANT]
* Glutamate from the cortex
* Dopamine from the substantia nigra pars compacta
30
What neurotransmitters does the striatum (medium spiny neurons) use?
[IMPORTANT]
GABA
31
Summarise where glutamate is used in the basal ganglia system.
[IMPORTANT]
* From cortex to striatum
* From subthalamic nucleus to internal globus pallidus (and internal globus pallidus + substantia nigra pars reticulata, *not in spec*)
* From thalamus to cortex and striatum (*not in spec*)
32
Summarise where GABA is used in the basal ganglia system.
[IMPORTANT]
* From striatum to the internal globus pallidus (+ substantia nigra pars reticulata) and external globus pallidus
* From external globus pallidus to the subthalamic nucleus
* From internal globus pallidus (+ substantia nigra pars reticulata) to the thalamus and brainstem nuclei
33
Summarise where dopamine is used in the basal ganglia system.
[IMPORTANT]
From substantia nigra pars compacta to striatum
34
Which synapses in the basal ganglia are important in reinforcement learning in movement?
Corticiostriatal synapses, which undergo plasticity
35
Which parts of the thalamus does the internal globus pallidus/substantia nigra pars reticulata output to?
Ventral anterior and ventral lateral thalamic nuclei.
(VA and VL)
36
What are some brainstem nuclei that the internal globus pallidus and substantia nigra pars reticulata ouput to?
[EXTRA?]
* Superior colliculus
* Reticular formation
* Pedunculopontine nucl.
* Habenular nucl.
37
Describe the principle by which the basal ganglia feedback on the cortex (allowing them to perform their function).
* When the striatum is excited by glutamate from the cortex, it releases GABA on the substantia nigra pars reticulata/internal globus pallidus
* This in turn reduces firing of the substantia nigra pars reticulata/internal globus pallidus, so that there is less inhibitory GABA signalling onto the thalamus
* This increases firing in the thalamus, so it stimulates the cortex
* If the substantia nigra pars reticulata/internal globus pallidus is stimulated instead by the subthalamic nucleus, the opposite happens and the thalamus/cortex is inhibited
Therefore, the basal ganglia perform cortical feedback via **disinhibition**.
38
Give some experimental evidence for how the basal ganglia feedback on the cortex.
[EXTRA]
(Deniau & Chevalier, 1984):
* Stimulated the striatum using glutamate
* Measured the activity at:
* (1) Substantia nigra pars reticulata/internal globus pallidus -\> This showed that there was decreased activity caused by release of GABA from the striatum
* (2) Thalamus -\> This showed that there was increased activity caused by decreased release of GABA from the substantia nigra parts reticulata/internal globus pallidus
* Thus, this showed that the basal ganglia feedback on the cortex via a process of disinhibition
39
What are the two main pathways of transmission through the basal ganglia?
[IMPORTANT]
* Direct pathway (1) -\> Passes from the striatum to the substantia nigra pars reticulata/internal globus pallidus
* Indirect pathway (2) -\> Passes from the striatum to the external globus pallidus to the subthalamic nucleus to substantia nigra pars reticulata/internal globus pallidus to the
There is also the hyperdirect pathway (3), which bypasses the striatum entirely, but this is not mentioned in the spec.
40
Can the neurons in the striatum that pass to the direct and indirect pathway be mapped?
No, they are all interspersed throughout the striatum.
41
Which neurons in the basal ganglia are dopaminergic?
Substantia nigra pars compacta
42
What sort of pathway is the nigrostriatal pathway?
Ascending dopaminergic
43
Describe the concept of various basal ganglia loops.
[EXTRA]
* The substantia nigra in the midbrain is topographically mapped, so that different parts receive input from different parts of the striatum, which in turn receives input from different parts of the cortex
* These loops may have different functions
* Pre-motor and motor loops involve:
* Pre-motor and motor cortex
* Dorso-lateral striatum areas
* Lateral substantia nigra
* Limbic loops involve:
* Orbital and medial prefrontal cortex
* Ventro-medial striatum areas
* Medial substantia nigra
* Cognitive/associative loops are between these two
* Note that these pathways loop back to the cortical areas via the thalamus
44
Which basal ganglia pathway do D1 and D2 striatum neurons link to?
* D1 -\> Direct
* D2 -\> Indirect
45
Summarise the functions of the direct and indirect pathways.
[IMPORTANT]
Direct (1):
* The striatum releases GABA on the substantia nigra pars reticulata/internal globus pallidus
* This in turn reduces firing of the substantia nigra pars reticulata/internal globus pallidus, so that there is less inhibitory GABA signalling onto the thalamus -\> i.e. There is disinhibition
* This increases firing in the thalamus, so it stimulates the cortex
* Thus, it **facilitates** movement
Indirect (2):
* The striatum releases GABA on the external globus pallidus
* This in turn reduces firing of the external globus pallidus, so that there is less inhibitory GABA signalling onto the subthalamic nucleus
* This increases glutamate release onto the substantia nigra pars reticulata/internal globus pallidus
* This increases substantia nigra pars reticulata/internal globus pallidus firing, so it inhbits the thalamus and thus inhibits the cortex
* Thus, it **inhibits** movement
46
What effect does dopamine release on the striatum have?
[IMPORTANT]
* Dopamine is excitatory at D1 receptors, so it stimulates the direct pathway
* Dopamine is inhibitory at D2 receptors, so it inhibits the indirect pathway
Since the indirect pathway is inhibitory, the dopamine leads to an increase in movement via both pathways.
47
Give some experimental evidence for the distrubution and function of D1 and D2 neurons in the striatum.
* Expression of GFP in either D1 or D2 neurons (Gerfen, 2011)
* Optogenetics to explore the consequences on mouse movement of stimulating either D1 or D2 neurons -\> D1 stimulation leads to more movement (Kravitz, 2010)
48
What are some examples of basal ganglia diseases?
* Parkinson’s disease [IMPORTANT]
* Drug-induced parkinsonism [IMPORTANT]
* Huntington’s disease [IMPORTANT]
* Hemiballismus [IMPORTANT]
* Multiple system atrophy
* Tourette syndrome
* Dystonias
* Manganism
* Sydenham’s chorea
* Wilson’s disease
* Hatters disease
* Hallevorden Spatz
* Tardive dyskinesia
49
What are the symptoms of basal ganglia
There can be either:
* Deficiency of movement -\> e.g. Akinesia, Bradykinesia
* Involuntary movements -\> e.g. Tremor at rest (contrast with cerebellum), chorea, athetosis/dystonias, ballismus, tics, stereotypies, dyskinesias, hyperactivity
The symptoms vary with disease and site of problem.
50
Compare the tremors seen in basal ganglia and cerebellum disease.
* Basal ganglia -\> Tremors at rest
* Cerebellum -\> Tremors during movement
51
What is chorea?
Involuntary dance-like movements seen in basal ganglia diseases.
52
What are dystonias?
Involuntary twisting or writhing movements of the limbs, seen in basal ganglia diseases.
53
What is ballismus?
Involuntary irregular flinging movements seen in basal ganglia diseases.
54
What is the prevalence of Parkinson's disease?
The second most common neurodegenerative disorder after Alzheimer's (1% prevalence over 60 yrs, 5% over 85 yrs).
55
Who discovered Parkinson's disease?
James Parkinson (1817)
56
What is the age of onset of Parkinson's disease?
5th or 6th decade
57
What are the symptoms of Parkinson's disease?
* Motor symptoms (TRAP):
* Tremor at rest [IMPORTANT]
* Rigidity [IMPORTANT]
* Akinesia (hypokinesia, bradykinesia) [IMPORTANT]
* Postural instability
* Problems with sleep behaviour (RBD)
* Non-motor dynsfunction:
* Olfaction
* Bowels
* Depression
* Pain
* Cognition
* Motivation
* Dementia
58
Draw a diagram to show the progression of Parkinson's disease.
59
What acronym can be used to remember the motor symptoms of Parkinson's disease?
TRAP:
* Tremor at rest
* Rigidity
* Akinesia (hypokinesia, bradykinesia)
* Postural instability
60
What is the mechanism of Parkinson's disease?
[IMPORTANT]
* Progressive loss of dopaminergic substantia nigra pars compacta neurons
* This means there is a loss of dopaminergic control of the striatum, which is usually required to promote movement
61
How does Parkinson's disease present in histology?
There is the loss of the black stripe in the midbrain (caused by the loss of the substantia nigra neurons).
62
Give some experimental evidence for the mechanism of Parkinson's.
(Hornykiewicz, 1960):
* 60 - 80% of the dopamine supply to the striatum is lost (via the nigrostriatal pathway) when Parkinson's presents
(Poewe, 2017):
* F-dopa PET scanning can be used to show loss of dopaminergic innervation in the putamen
63
What are Lewy bodies?
[IMPORTANT]
* Cytoplasmic depositions in neurons
* Made of aggregations of insoluble components, including α-synuclein and ubiquitin
* They are part of Parkinson's disease pathogenesis, but dopaminergic neurons are not the only ones affected
64
What component of Lewy bodies does the spec mention?
[IMPORTANT]
α-synuclein
65
Draw the mechanism of Parkinson's disease.
66
What are the causes of Parkinson's disease?
[EXTRA]
* Genetic components -\> ~15% contribution, PARK genes
* Intrinsic physiology promotes selective vulnerability -\> Neuronal architecture, high metabolic demand, DA oxidation, oxidative stress, Ca2+/mitochondrial/ER stress, neuroinflammation, protein misfolding and accumulation
* Acquired/environmental contributions -\> Neuroinflammation, pesticides + genetics, toxin exposure
67
Give an example of a toxin that can give rise to Parkinson's disease.
MPTP
68
What is MPTP toxicity?
[IMPORTANT]
* MPTP is a prodrug to the neurotoxin MPP+
* It causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain
* It does this by entering via dopamine transporters and being sequestered into mitochondria, where it inhibits complex I and leads to cell death
* It is very rarely found in street drugs that are poorly synthesised (e.g. when trying to synthesise MPPP, an opioid)
69
What is the clinical usefulness of MPTP?
[EXTRA]
It can be used in models of Parkinson's disease, although it doesn't show Lewy bodies and is not progressive.
70
What are some models that can be used to study Parkinson's disease?
* MPTP and other toxins (e.g. 6-OHDA)
* Transgenic animals (e.g. overexpression/mutations in α-synuclein, LRRK2, GBA, or other PARK genes)
* α-synuclein aggregation models (injection of α-synuclein pre-formed fibrils to form Lewy body-like aggregates)
* Human patient iPSC-derived dopamine neurons
71
How can Parkinson's disease treated?
[IMPORTANT]
Using L-DOPA (a precursor to dopamine) and carbidopa (an inhibitor of peripheral DOPA decarboxylase).
72
What are some problems with use of L-DOPA to treat Parkinson's disease?
[IMPORTANT]
* The effects wear off after a few years -\> On/off effects, such as gait freezing
* There are also L-DOPA-induced dyskinesias (involuntary movements)
73
What are some alternative therapies to Parkinson's disease, apart from L-DOPA?
[EXTRA]
* Other dopamine replacement strategies:
* Dopamine agonists
* MAO inhibitors
* COMT inhibitors
* Non-dopamine strategies:
* mACh antagonists (benztropine)
* nAChR/5-HT/glu/adenosine receptor ligands
* Neurotrophic factors
* Autophagy/mitophagy modifiers
* Molecular therapies:
* Antibodies/RNAi to α-synuclein
* Gene therapy
* Surgery:
* Transplants
* Depp brain stimulation (DBS)
74
How does deep brain stimulation work for Parkinson's disease?
* A stimulating electrode is surgically permanently implanted into the basal ganglia (e.g. the subthalamic nuclei), allowing stimulation of movement.
* In the subthalamic nucleus, this may seem counterintuitive since you would expect feedback to the thalamus to be reduced, but it appears that the electrical stimulation actually reduces subthalamic firing.
75
What are the symptoms of Huntington's disease?
They vary, but tend to be hyperkinetic:
* Chorea (involuntary dance-like movements)
* Dystonias (involuntary twisting or writhing movements of the limbs)
* Rigidity
* Cognitive decline
76
Compare the symptoms of Parkinson's and Huntington's disease.
Parkinson's is usually considered hypokinetic, while Huntington's is usually hyperkinetic.
77
Describe the mechanism of Huntington's disease.
* Atrophy of the striatum (loss of the medium spiny neurons in the caudate nucleus)
* Atrophy of the cortex
This causes increased feedback to the brain (via dowregulation of the indirect pathway), so there is hyperkinesia.
78
What is the cause of Huntington's disease?
* It is an autosomal dominant disorder
* It is a codon-repeat disease, caused by repeating CAGs in the huntingtin gene
* Age of presentation depends inversely on the number of repeats
* The huntingtin product aggregates, causing the striatum and cortex atrophy
79
How can Huntington's disease be treated?
[IMPORTANT]
Using an anti-dopaminergic, such as:
* Tetrabenazine
* Neuroleptics
* Benzodiazepines
This combats the imbalance between the direct and indirect pathways, so that the feedback to the cortex is reduced.
80
What is ballism (a.k.a. ballismus)?
[IMPORTANT]
* A rare basal ganglia disorder resulting from damage to the subthalamic nucleus in the basal ganglia
* Symptoms include ballistic violent flinging of limbs
* Usually occurs on one side (hemiballism)
81
What is the mechanism of ballism?
Damage to the subthalamic nucleus leads to downstream events that increase feedback to the cortex. This causes ballistic, violent movements.
82
What is the cause of ballism?
Stroke that causes subthalamic nucleus lesion.
83
How can ballism be treated?
Using anti-dopaminergic drugs.
84
Describe simply the subcortical loops that the cerebellum forms.
* Receives input from various cortical areas via the pons
* It also receives input from the spinal cord and brainstem nuclei
* It then relays this information back to the cortex via the ventral lateral thalamus
85
Summarise simply the functions of the cerebellum.
* It is involved in the modification of ongoing non-reflex movements and central motor plans
* This is because it receives information about motor planning/intention and also sensory feedback, so it can relay any fine tuning and calibration of movements back to the cortex
86
Compare the functions of the basal ganglia and cerebellum in movement.
* Basal ganglia are involved in the selection of voluntary movements
* Cerebellum is involved in the co-ordination and fine-tuning of ongoing movements
In other words, the basal ganglia are more involved in deciding, while the cerebellum is more involved in doing.
87
Describe in depth the functions of the cerebellum.
The co-ordination, calibration, learning and automating of skilled movements (non-reflex):
* Initiation and co-ordination of multi-joint movement and posture
* Calibration of movements -\> By comparing motor instruction from cortex with sensory feedback from performance (e.g. vestibular apparatus) to correct errors and modify movements to be more successful
* Learning for automation of fast movements
88
The cerebellum is a .......... structure.
Extrapyramidal (meaning it does not pass through the pyramids of the medulla)
89
What are the different functional subdivisions of the cerebellum? What is the function of each?
[IMPORTANT]
* Vestibulocerebellum -\> Balance/posture + Eye movement
* Spinocerebellum -\> Motor execution (i.e. control of axial and limb muscles)
* Cerebrocerebellum (a.k.a. pontocerebellum) -\> Motor planning (i.e. planning and timing precise movements)
90
What is another name for the cerebrocerebellum?
Pontocerebellum (this is because the input from the cerebellum goes via the pontine nuclei)
This is the name used in the spec.
91
Which side of the body does the cerebellum work with?
* The ispilateral side (think about the ascending spinocerebellar tract).
* This is unlike the cortex and basal ganglia, which work with the contralateral side.
92
Label this superior view of the cerebellum.
Note that the part at the top is the brainstem, so it is not part of the cerebellum.
93
Label the different functional parts of the cerebellum and give their functions.
[IMPORTANT]
* Spinocerebellum
* Occupies vermis
* Responsible for motor execution
* Cerebrocerebellum (a.k.a. pontocerebellum)
* Occupies lateral hemispheres
* Responsible for motor planning
* Vestibulcerebellum
* Occupies flocculonodular lobe
* Responsible for balance and eye movement
Note that this is an unfolded diagram. The cerebellum is folded so that the top of this diagram is the superior side, while the bottom of this diagram is the inferior side.
94
How does this diagram of the cerebellum compare to the actual structure of the cerebellum?
The cerebellum is usually shown unfolded, whereas in reality it is folded like this.
95
Describe the output nuclei that the cerebellum outputs to and what the function of each of these is.
[IMPORTANT]
Spinocerebellum outputs to:
* Fastigial nucleus -\> To medial descending systems
* Interposed nuclei (globose and emboliform nuclei) -\> To lateral descending systems + Red nucleus
Cerebrocerebellum (pontocerebellum) outputs to:
* Dentate nucleus -\> To motor and premotor cortices (via ventral anterior and ventral lateral thalamus)
Vestibulocerebellum outputs to:
* Fastigial nucleus -\> To vestibular nuclei
* Vestibular nuclei (directly)
96
How many deep cerebellar nuclei are there?
4:
* Fastigial nucleus
* Interposed nuclei (globose and emboliform nuclei)
* Lateral nucleus
These are also known as the medial, intermediate and lateral nuclei respectively.
97
What does the fastigial nucleus (a.k.a. medial nucleus) of the cerebellum output to?
To medial descending systems and vestibular system.
98
What do the interposed nuclei (a.k.a. intermediate nuclei) of the cerebellum output to?
To lateral descending systems + Red nucleus
99
What does the dentate nucleus (a.k.a. lateral nucleus) of the cerebellum output to?
To motor and premotor cortices (via ventral anterior and ventral lateral thalamus).
100
Which parts of the thalamus does the dentate nucleus of the cerebellum output to?
Ventral anterior and ventral lateral thalamus
101
Label the different deep cerebellar nuclei.
They are in the inner white matter of the cerebellum.
102
Describe the different input/output tracts of the cerebellum.
There are three main tracts/peduncles:
* Superior peduncle -\> Efferent information from the deep cerebellar nuclei
* Middle peduncle -\> Afferent information from the pons
* Inferior peduncle -\> Afferent information from the vestibular nuclei, spinal cord and inferior olive
103
Is there somatotopy in the cerebellum?
It is thought that there might be, but it is fractured such that there are multiple representations of the same body part.
104
Describe the function, location, inputs and outputs of the vestibulocerebellum.
Functions:
* Controls balance via axial and proximal limb muscles
* Controls eye movement
Location:
* Flocculonodular lobe (little tail on the inferior side that has been curled up)
Inputs:
* Direct input from primary sensory afferents from vestibular system (only sensory system that doesn't have to relay in the brainstem)
* Input from the vestibular nuclei (secondary afferents)
Outputs (from flocculus):
* To the fastigial nucleus and vestibular nuclei, which then output to:
* Medial and lateral vestibulospinal tracts to neck and back muscles (for posture/balance)
* Oculomotor nuclei for the ‘vestibulo-ocular reflex (VOR)’ which moves eyes accordingly (not illustrated)
Note that the vestibular nuclei output to descending tracts, not to the vestibular apparatus or anything like that.
105
What are the symptoms of vestibulocerebellum lesion?
* Poor balance
* Nystagmus (eye drift and jump)
106
What is the vestibulo-ocular reflex (VOR) and how is it enabled?
* A reflex acting to stabilize gaze during head movement, with eye movement due to activation of the vestibular system.
* This is mediated by the vestibulocerebellum
107
Describe the function, location, inputs and outputs of the spinocerebellum.
Functions:
* Controls posture and locomotion via axial and proximal limb muscles
Location:
* Vermis (including paravermis)
Inputs:
* Sensory and motor cortex (instructions for movement)
* Spinocerebellar tracts:
* From neck and trunk
* From limbs
* Inferior olivary nucl.\*
Outputs:
* Vermis outputs to fastigial nucleus, which outputs to:
* Ventromedial brainstem descending systems (vestibulo-spinal, reticulo-spinal and cortico-spinal tracts (via thalamo-cortical relay))
* Paravermis outputs to interposed nuclei, which outputs to:
* Dorsolateral brainstem descending systems (rubro-spinal and cortico-spinal tracts)
108
What are the symptoms of spinocerebellum lesion?
* Medial lesions (vermis) -\> Problems standing and walking
* Lateral lesions (paravermis) -\> Poor accuracy and action tremor (3-5Hz)
109
What is an action tremor?
It is where a patient's movements are resolved into their 3D x, y and z components, due to a lack of smooth integration by the spinocerebellum.
110
Describe the function, location, inputs and outputs of the cerebrocerebellum (a.k.a. pontocerebellum).
Functions:
* Initiation, planning and timing of movements
Location:
* Lateral hemispheres
Inputs:
* From cortex, via the pons
Outputs:
* Dentate nucleus -\> To VL thalamus and then motor cortical areas + prefrontal cortex
111
What is some evidence for the cerebellum having a role in cognitive functions?
112
What is remarkable about the cerebellum and how does it achieve this?
* It contains 100 thousand million neurones, which is about half of all the neurons in the brain, but it is only 10% of the volume of the brain
* It does this up utilising highly-ordered repeating modules
113
What are the two main input types into the cerebellum?
[IMPORTANT]
* Mossy cells
* From vestibular system, spinal cord and pons
* To granule cells and deep cerebellar nuclei
* Climbing fibre inputs
* From inferior olive
* To Purkinje neurons and deep cerebellar nuclei
114
What is the principle cell type in the outer cortex of the cerebellum? What is their function?
[IMPORTANT]
* Purkinje neurons
* They provide the only output from the cerebellar cortex to the deep cerebellar nuclei, which in turn output this information
115
What are the different types of interneurons in the outer cerebellar cortex?
[IMPORTANT]
* Golgi
* Stellate
* Basket
116
Draw and describe the structure of a module in the cerebellum.
[IMPORTANT]
Mossy fibre input (main input):
* Carry information from the vestibular system, spinal cord and pons
* Mossy fibre neurons stimulate granule cells and send stimulatory collaterals to deep cerebellar nuclei
* Granule cells stimulate Purkinje neurons
* These inhibit the deep cerebellar nuclei (this is the only cortical output to the deep cerebellar nuclei)
* Interneurons receive stimulatory input from the granule cells and send inhibitory output to the granule and Purkinje cells
Climbing fibre input (lesser input):
* Carry information from the inferior olive
* Climbing fibres stimulate Purkinje neurons and deep cerebellar nuclei
* Purkinje neurons inhibit the deep cerebellar nuclei (this is the only cortical output to the deep cerebellar nuclei)
117
What is the function of the inferior olive and how does it interact with the cerebellum?
* It receives input from both the cerebellar output (motor) and also from spinal ascending afferents (sensory)
* When there is mismatch between these two, it can feedback to the cerebellum
118
How many layers are there in the outer cerebellar cortex?
3
(The red here is the white matter of the cerebellum)
119
What are the different layers of the cerebellum and what is found in each?
[IMPORTANT]
* Inner layer (Granule cell layer):
* Granule cells
* Mossy fibre inputs
* Golgi interneurons
* Middle layer (Purkinje cell layer):
* Purkinje cells
* Outer layer (molecular layer):
* Purkinje cell dendrites
* Granule cell parallel fibres (note the perpendicular fibres)
* Climbing fibres
* Stellate and basket interneurons
120
Describe the principle of the molecular layer of the cerebellar cortex.
* It is the outer layer where the Purkinje fibres send their dendrites to receive information from climbing fibres and granule cell parallel fibres. None of these cells actually have their cell bodies here.
* There are also stellate and basket interneurons here.
121
Describe how the granule and Purkinje neurons in the cerebellum are connected.
* The Purkinje neurons send dendrites to the molecular layer (outer layer) of the cerebellar cortex
* Granule cells have parallel fibres that run along the axis of folia, so that each Purkinje neuron can receive input from multiple granule cells.
122
What neurotransmitter do Purkinje neurons use?
GABA
123
Why are climbing fibres called that?
The climbing fibres wind around the dendritic tree of a Purkinje neuron.
124
How many granule cell parallel fibres and climbing fibres does each Purkinje cell receive input from?
* Granule cell parallel fibres -\> 200,000
* Climbing fibres -\> 1 (but at 300 different synapses)
125
Draw another schematic diagram of the connectivity in the cerebellum.
126
Which inferior olive do climbing fibres arise from?
Contralateral -\> This is because the inferior olive communicates with the contralateral side of the body (so there is double decussation and therefore the cerebellum controls the ipsilateral side of the body).
127
Compare the type of firing that mossy fibres/granule cells and climbing fibres stimulate in the Purkinje neurons.
[IMPORTANT]
Mossy fibres and granule cells:
* Generate **simple spikes** in Purkinje cells
* The mossy fibres and therefore granule cells fire at around 50-100Hz
* Each Purkinje cell receives input from 200,000 granule cell parallel fibres
* When around 200 (0.1% of the total) of these fire simultaneously on a Purkinje cell, they summate to trigger an action potential in the Purkinje cell (simple spike)
Climbing fibres:
* Generate **complex spikes** in Purkinje neurons
* The climbing fibres fire at around 1-10Hz
* Each Purkinje cell receives input from only 1 climbing fibre, but at 300 synapses
* An action potential in the climbing fibres triggers a calcium-dependent EPSP (not action potential) in the Purkinje cell
128
Draw the shape of a complex spike in a Purkinje fibre.
129
What ions enable a simple spike and complex spike in a Purkinje neuron?
* Simple spike -\> Na+ and K+ (normal action potential)
* Complex spike -\> Ca2+
130
What is the function of simple spikes in Purkinje neurons?
Calibration/optimisation:
* Each Purkinje cell is sensitive to a particular source/type of input, based on the sensory and motor inputs it receives
* The frequency of simple spikes is determined by granule cell parallel fibre firing, which in turn is determined by sensory/motor inputs (from visual, vestibular, etc.)
* Thus, when the frequency of Purkinje cell simple spikes is increased, negative feedback on the deep cerebellar nuclei is increased, correcting any motor overshoot
131
What is the function of complex spikes in Purkinje neurons?
Long-term depression of mossy fibre/granule cell inputs:
* The number of complex spikes is relatively small compared to the frequency of firing of simple spikes, so climbing fibres have only a small effect on Purkinje cell firing
* However, the complex spikes involve calcium influx, which has downstream effects
* The calcium causes long term depression of the synapses between granule cell parallel fibres and Purkinje cells, so that their firing is decreased
* This is shown in the diagram, where complex spikes lead to long-term decreases in EPSPs caused by granule cells
132
Summarise the function of climbing fibres from the inferior olive.
Motor learning -\> Recalibration, optimisation and automation:
* They respond to mismatches between sensory feedback and motor activity (i.e. when there is motor error)
* In response, they stimulate the Purkinje fibres, producing complex spikes, leading to calcium influx
* This leads to long-term depression of the signals from the granule cell parallel fibres that have fired in the last 200ms
* So the Purkinje cell learns to be less responsive to the sets of granule cell parallel fibres that have caused the recent motor imbalance
133
What neurotransmitter do interneurons in the cerebellum use?
GABA -\> It is inhibitory.
134
Where in the cerebellum are the different types of interneurons found?
* Golgi -\> In the granule cell layer (innermost)
* Basket + Stellate -\> In the molecular layer (outermost)
135
Describe the function of basket cells in the cerebellum.
* Receive excitatory granule cell input in the molecular layer
* Send inhibitory GABAergic axons to Purkinje cells that correspond to other nearby granule cell parallel fibres
* In other words, this is LATERAL INHIBITION
136
Describe the function of stellate cells in the cerebellum.
Short range inhibition of Purkinje cells (via GABA) that correspond to the same granule cell parallel fibre.
(CHECK what input the stellate cells receive)
137
Describe the function of Golgi cells in the cerebellum.
* Receive input from parallel fibres in the molecular layer
* Send inhibitory GABAergic axons to the granule cells in the granule cell layer
* This is essentially FEEDBACK INHIBITION, so that temporal events are terminated and do not go on for too long
138
Give some experimental evidence relating to the VOR and the role of the cerebellum in motor learning.
[EXTRA]
* The vestibulo-ocular reflex usually means that when you turn your head to the right, your eyes move to the left, to maintain focus on an object.
* However, if image-flipping glasses are worn, then the eyes need to turn to the right, which is learned over time (this is called VOR reversal).
* In animals with vestibulocerebellar lesions, this VOR reversal is not possible since motor learning is inhibited.
139
Give some experimental evidence for how the cerebellum enables learning of a new task.
[EXTRA]
(Gilbert and Thach 1977):
* Monkeys are doing a simple task, such as a reach-and-grab task
* The task is made more difficult, which is shown by the "Novel task" arrow
* This is accompanied by a rise in complex spike frequency, which results in a gradual decrease in simple spikes
* Eventually, then frequency of complex spikes returns to the control, while the frequency of simple spikes remains low -\> This shows that the complex spikes have enabled learning
140
Summarise the principle of motor learning in the cerebellum.
* The cerebellum builds up and improves internal models of certain movements and cognitive skills, so that they can be automated (e.g. walking)
* In real time, it adjusts movements by comparing the motor instructions with sensory feedback
* After the movement, it cerebellum corrects any error and stores these changes (learning) by changing Purkinje cells' responsiveness to specific sensorimotor situations
141
Give some experimental evidence that challenges the long-term depression model of cerbellar learning.
[EXTRA]
(Schonewille, 2011):
* Impaired the process of LTD in the cerebellum of monkeys
* However, motor learning was still intact in a blinking task
142
What are some examples of cerebellar disorders?
* Alcoholic cerebellar degeneration
* Essential tremor, intention tremor, postural tremor
* Hereditary ataxias (Friedrich’s, spinocerebellar)
* Acquired ataxia
* Multiple sclerosis
* Hereditary cerebellar atrophy
* Tumours (childhood, adult)
* Vascular damage (stroke, trauma)
* Tonsillar herniations
* Paraneoplastic cerebellar syndrome
* Cerebellar Cognitive Affective Syndromes
* Some dyslexias, dyspraxias
143
What are some examples of the symptoms of cerebellar disorders?
* Incoordination of fine movement -\> Movements break down to subcomponents [IMPORTANT]
* Postural ataxia -\> Incoordination of axial muscles, postural instability, staggering wide-based ataxic gait cf. alcohol [IMPORTANT]
* Intention tremor -\> Low frequency high amplitude oscillations of a limb as it approaches target (intention tremor) (overshooting, overcompensating, 'hunting' to find target) [IMPORTANT]
* Nystagmus -\> Involuntary, rapid oscillation of the eyeballs [IMPORTANT]
* Postural tremor -\> Oscillation of proximal limb in fixed posture
* Dysdiadochokinesis -\> Poor rapid alternating movements
* Hypotonia -\> Decreased muscle tone
* Dysarthria -\> Slurred speech
* Dysmetria -\> Poor accuracy of movement
144
What is postural ataxia?
[IMPORTANT]
* Incoordination of axial muscles, postural instability, staggering wide-based ataxic gait (similar to being drunk)
* This is a symptoms of cerebellar disorders
145
What is intention tremor?
[IMPORTANT]
* Low frequency high amplitude oscillations of a limb as it approaches target (this is due to overshooting and overcompensating as the individual 'hunts' to find the target)
* Seen in patients with cerebellar disorders
146
What is nystagmus?
[IMPORTANT]
* Involuntary, rapid oscillation of the eyeballs
* Seen in patients with cerebellar disorders
147
Give an example of a clinical condition that can lead to cerebellar dysfunction.
* Multiple sclerosis can lead to demyelination of the cerebellar neurons
* This means that dysmetria and tremor are commonly seen in MS patients
148
What nucleus is this?
Interposed (with the globose more medial and emboliform more lateral)
149
What nucleus is this?
Fastigial
150
What nucleus is this?
Dentate
151
Draw a diagram to show how the cerebellum and pons are connected.
152
Draw a diagram to show the position of the cerebellar peduncles.
153
What are the two components of the ventral striatum?
Nucleus accumbens and the olfactory tubercle
154
Draw the location of the nucleus accumbens.
