Basal Ganglia

Question 1

How does information reach the muscles

Answer 1

The motor cortex communicates with the Basal Ganglia, Cerebellum and Thalamus before sending a signal through the pyramids to the lower motor neuron, which innervates striatal muscle.

Question 2

Characteristics of the Basal Ganglia

Answer 2

• Four nuclei
• Primary input from the cerebral cortex.
• No direct input or output connections with the spinal cord or the cerebellum.
• Send their output via the thalamus, back to the prefrontal, premotor, and motor cortices.

Question 3

Three characteristic types of motor disturbances caused by issues in the Basal Ganglia

Answer 3

Tremor and other involuntary movements;
Changes in posture and muscle tone
Poverty and slowness or uncoordination of movement without paralysis.

Question 4

Pyramidal tract vs the extrapyramidal tract

Answer 4

Pyramidal tract: the upper and lower motor neuron

Extrapyramidal tract: Basal Ganglia, Cerebellum and Thalamus

Question 5

Pyramidal tract syndrome

Answer 5

Characterized by spasticity and paralysis

Question 6

Extrapyramidal syndrome

Answer 6

Characterized by involuntary movements/un-controlled voluntary movements, muscular rigidity, and immobility without paralysis

Question 7

The 4 Basal Ganglia nuclei

Answer 7

Striatum: Nucleus caudatus / Putamen
Golbus Pallidus: Pars interna / Pars externa
Substantia nigra: Pars reticulata / Pars compacta
Nucleus subthalamicus

Question 8

What is the only excitatory component of the Basal Ganglia?

Answer 8

The subthalamic nucleus (use glutamate)

Question 9

Striatal interneurons

Answer 9

5% in total
Parvalbumin, ChAT
Most of the tonic activity
extensive axon collaterals that reduce the activity of the striatal output neurons

Question 10

D1/D2 receptor expression in the striatum

Answer 10

MSNs that expresss dopamine receptor D1 (DRD1) project directly over the GPi to the Thalamus (direct)
MSNs that expresss dopamine receptor D2 (DRD2) project to the nucleus subthalamicus to the Thalamus (indirect)

Question 11

Placement of input for the Medium Spiny Neurons

Answer 11

From the cortex: input on the head of the spine
From the substantia nigra: the neck of the spine
From intrinsic inhibitory neurons (striatum): on the soma

Question 12

The direct pathway to initiate movement

Answer 12

Dopaminergic neurons from the substancia nigra and the motor cortex activate DRD1-MSNs. DRD1-MSN in turn block inhibitory neurons which leave the GP to block the thalamus. By this way the thalamus is dis-inhibited (the so-called de-blockade of the thalamus).

Question 13

The indirect pathway to initiate movement

Answer 13

Dopaminergic neurons from the substancia nigra and the motor cortex block DRD2-MSNs. GABAergic neurons are then de-blocked and in turn block the subthalamic nucleus (master regulator). By this way the GPi is not activated anymore and the thalamus is not blocked anymore.

Question 14

Symptoms of hypokinetic disorders

Answer 14

excessive motor activity
involuntary movements (dyskinesias)
decreased muscle tone (hypotonia).

Question 15

Symptoms of hyperkinetic disorders

Answer 15

impaired initiation of movement (akinesia)
reduced amplitude and velocity of voluntary movement (bradykinesia)
usually accompanied by muscular rigidity (increased resistance to passive displacement) and tremor

Question 16

On a neuronal level, what causes movement disorders?

Answer 16

They come from an imbalance in the Direct and Indirect Pathways of the Basal Ganglia

Question 17

Parkinsons symptoms

Answer 17

paucity of spontaneous movement, akinesia, bradykinesia,
increased muscle tone (rigidity)
characteristic tremor (4-5 per second) at rest
shuffling gait
flexed posture
impaired balance
mask-like facial expression

Question 18

Pathway dysfunction in Parkinsons patients

Answer 18

DRD2-MSNs in the striatum are not activated anymore thus leading to an enhanced blockade of the thalamus. In addition, the indirect pathway in not blocked anymore and the subthalamic nucleus is constantly active thus blocking the GPi that in turn blocks the thalamus.

The indirect pathways is acting in the opposite way than in Huntingtons (the D2R signaling are causing the Globus Pallidus(external) to be super inhibited  internal segment is becoming super excited)

Question 19

Epidemiology of Parkinsons

Answer 19

it’s becoming more prenevelent. Between 10-240 per 100 K

Question 20

Histology of Parkinsons

Answer 20

We seem to spot

1) Cell loss of dopamin neruons in the Substancia Nigra
2) Lewy bodies in the Substancia Nigra

Question 21

The role of ROS in Parkinsons

Answer 21

The accumulation of oxygen radicals can cause many issues and are thought to underlie the degeneration of dopamine neurons in the Substancia Nigra.
ROS might also lead to disturbed chaperon function, which leads to misguided protein folding and therefore to protein aggregations (which are toxic)

Question 22

The different forms of Parkinsons

Answer 22

Parkinsons comes in sporadic or mongetic forms. We have dominant and recessive forms and high/low risk loci

Question 23

Genes for recessive Parkinson’s

Answer 23

Parkin 2 and PINK1 – they lead to autophagy of mitochondria

Most ressecive forms for Parkinsons don‘t have Lewy bodies

Question 24

Genes for dominant Parkinson’s

Answer 24

Dominant Parkinson’s can be caused by SCNA and LRRK2.

Mutationes lead to a dominant negative effect (probably) by an increased Phosphorylation.

Question 25

Alpha-synuclein

Answer 25

Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release

Question 26

SCNA in Parkinsons

Answer 26

Mutations of the gene perhaps a cause of dominant Parkinsons. mutated forms of SCNA compromises the lysosomes, and those with lysosomal storage disease are at greater risk of PD.

mutated SCNA also aggregates at:
- mitochondrial membranes
Causes degradation of them, apoptosis and ROS
- cytoskeleton/microtubules
block axonal transport, destabilizes microtubules, reduces polymerization of tubulin.
- presynaptic compartment
decreases vesicle release, disturbes the SNARE complex assembly, disturbes Ca2+ homeostasis

SCNA aggregation might be over the entire body and is released and distributed through dense-core vesicles

Question 27

Gaucher disease

Answer 27

An example of a genetic lysosomal storage disease. Having this increased your risk of Parkinsons. We see glucosylceramide accumulations in multiple organs. Some forms of Gaucher’s disease may be treated with enzyme replacement therapy. The disorder is characterized by bruising, fatigue, anemia, low blood platelets, and enlargement of the liver and spleen.

Question 28

SCNA in the mitochondrial membranes

Answer 28

Causes damage to the mitochondria,

Question 29

Treatment of Parkinson’s

Answer 29

L-DOPA or similar substances

DBS that targets the external segment of the globus pallidus to inhibit the sub-thalamic nucleus

Question 30

Hyperkinetic disorders and their characteristics

Answer 30

Huntington disease and hemiballism
excessive motor activity
involuntary movements (dyskinesias)
decreased muscle tone (hypotonia).

Question 31

hypotonia

Answer 31

decreased muscle tone

Question 32

dyskinesias

Answer 32

involuntary movements

Question 33

akinesia

Answer 33

impaired initiation of movement

Question 34

bradykinesia

Answer 34

reduced amplitude and velocity of voluntary movement

Question 35

chorea (type of dyskinesias)

Answer 35

jerky, random movements of the limbs and orofacial (mouth and face) structures

Question 36

ballism (type of dyskinesias)

Answer 36

violent, large-amplitude, proximal limb movements

Question 37

dystonia (type of dyskinesias)

Answer 37

sustained abnormal postures and slower movements with underlying cocontraction of agonist and antagonist muscles

Question 38

athetosis (type of dyskinesias)

Answer 38

slow, writhing movements of the extremities

Question 39

Causes of Huntington’s

Answer 39

More than 37 The CAG repeats in the first Exon of the Huntingtin gene. It’s autosomal dominant neurodegenerative disorder

Question 40

Epidemiology of Huntington’s

Answer 40

more common in Western countries compared to Asia or Africa (1:100000)
affects both men and women

Question 41

Symptoms of Huntington’s

Answer 41

Primary: lack of coordination & uncoordinated, jerky body movements
But also: problems with mood or cognition, decline in mental abilities until dementia

no cure for HD - full-time care required in the later stages of the disease

Question 42

What does the mutation in the Huntington’s gene do?

Answer 42

We don’t know - might be loss or gain of funciton

However, we do see endocytosis and lysosomal degradation – leads to accumulations and increased concentration of ROS

Question 43

Where do Huntington’s patients lose the most brain tissue?

Answer 43

Putamen (64%) and the Caudate (57%)

Question 44

How does the clinical symptoms of HD connect to the direct/indirect pathway?

Answer 44

We first see hyperkinesia and reduced muscle tone due to GABAergic neurons from the striatum degenerate, leading to issues in the indirect pathway.
Later, we have hypokinesia and increased muscle tone due to issues in the direct pathway
Also, the rigidity and akinesia in advanced Huntington disease are associated with the loss of the striatal neurons that project to the internal pallidal segment.

Question 45

Neuronal cause of Hemiballism?

Answer 45

Lesions in the subthalamic nucleus leading to less activation of the internal Globus Pallidus and thereby decreased thalamus inhibition

Question 46

Pathophysiology of Drug-induced dyskinesias

Answer 46

Mechanisms of L-DOPA
1) excessive dopaminergic inhibition of the striatal neurons that project to GPe, reduced inhibition of Gpi neurons (we’re putting the direct pathway out)
2) excessive inhibition of the subthalamic nucleus
lower output from the GPi segment (we’re also not exciting the GPi through the indirect pathway, leading to more movement)

Question 47

Where do we think L-DOPA side effects (dyskinesia) comes from?

Answer 47

The symptoms probably result from receptor upregulation, supersensitivity, and altered gene expression caused by prolonged administration of the drug.
It’s also believed that we might need just the right dosis not the have these symptoms

Question 48

What mouse models do we use for Huntingtons?

Answer 48

The PolyQ htt mouse.
It exhibits progressive neurological phenotype, intranuclear inclusions, and a disturbed axonal transport

PolyQ htt fly (Drosophila)
When expressed in the photoreceptor neurons, we see a similar degeneration as in the human brain.

C. elegans (worm)
Easy to work with as we know all the physiological components of the model

Question 49

What are characteristic signs for diseases caused by protein aggregations?

Answer 49

Disturbed axonal transport and reduced mitochondrial functions

Question 50

Htt (Huntingtin gene) regulates what?

Answer 50

apoptotic signaling and axonal transport
I has been suggested to regulate neuronal and glial function and is implicated in nuclear import and transcriptional regulation

Question 51

What is the main take aways from the “Impaired TrkB Receptor SignalingUnderlies Corticostriatal Dysfunctionin Huntington’s Disease” paper?

Answer 51

Unlike previous believed, there is no problem with expressing of releasing BDNF in the corticostriatal pathway. The problem occurs as up-regulated PTEN blocks Akt, which is a component of the TrkB system