L22: The Basal Ganglia & Movement Disorders

Question 1

The basal ganglia acts along with the motor cortex to mediate movement. List the primary and secondary subdivisions of the different basal ganglia structures.

Answer 1

1) striatum
1 -dorsal striatum –> 2. caudate + putament
1 -ventral striatum –> 2. nucleus accumbens
1 - —- –> 2. septum, olfactory tubercle

2) Globus pallidus
1 -external segment –> 2. —-
1 -internal segment –> 2. outer/inner portion
1 -ventral pallidum –> 2. –

3) Substantia nigra
1 - pars compacta –> 2. –
1 - pars reticulata –> 2. pars lateralis

4) subthalamic nucleus

Question 2

What are the most common basal ganglia projection neurons? What are 2 other basal ganglia projection neurons?

Answer 2

medium spiny stellate neuron (MSSN) located in striosome & matrix are the most common. They are GABAergic. There are also 2 other basal ganglia projection neurons, which are spindle neurons & pigmented neurons.

Question 3

All the basal ganglia structures can be input or output structure. List ones that are involved in input, output & intermediate structures.

Answer 3

Input structures receive direct projections from cerebral cortex –> striatum, subthalamic nuclei

Output structures project back to cortex via thalamus –> internal segment & external segment of globus pallidus (GPi & GPe), pars reticulata of substantia nigra (SnPr)

Intermediate structures modify the activity of input or output –> substantia nigra pars compacta (SnPc), subthalamic nucleus

Question 4

The brake is always on, meaning there’s always a brake placed on the thalamus, inhibiting it. How to release the brake aka “disinhibition” of the thalamus?

Answer 4

“disinhibition” of the thalamus occurs via activation of direct pathway via basal ganglia. Thalamus is more active so cortex is more active (+ feedback).

Question 5

Explain the direct pathway in the cortico-basal ganglia-thalamo cortical circuit

Answer 5

excitatory neuron with info coming from cortex will excite the inhibitory neuron in the striatum which will inhibit the inhibitory neuron in the globus pallidus internal segment/substantia nigra, which will release the brake. So the excitatory neuron in the thalamus will no longer be inhibited by the inhibitory neuron of the GPi/SNr because that’s being inhibited by inhibitory projection from striatum, which is activated by the excitatory projection from cortex.

Question 6

Explain the indirect pathway in the cortico-basal ganglia-thalamo cortical circuit

Answer 6

Same excitatory cortical information to striatum, activating the inhibitory neuron. This inhibitory neuron will inhibit the inhibitory neuron of the GPe, which means it will activate the excitatory projection in STN which will excite the inhibitory neuron in GPi/SNr, inhibiting the thalamus.

Question 7

It is important to maintain balance btw direct & indirect pathways. Explain what kind of an effect each pathway has on the thalamus.

Answer 7

Direct pathway –> disinhibition of thalamus = active thalamus

Indirect pathway –> activates inhibitory projection on thalamus so thalamus is inhibited.

Question 8

Why is it that the brake is always on if both the direct and indirect pathways need to be in balance?

Answer 8

The indirect pathway operates thru subthalamic nucleus (glutamate rich, excitatory) which will activate the inhibitory projection on the thalamus, putting the brake on. This subthalamic nucleus can be activated via indirect pathway AND can receive input directly from cortex (bypass striatum). Therefore, cortex has 2 different routes to excite inhibitory neuron on thalamus, essentially inhibiting the thalamus at rest.

Question 9

What is the effect of dopamine on cortico-basal ganglia-thalamo cortical circuit?

Answer 9

Dopamine is a great equalizer. It can exert inhibitory or excitatory effect depending on receptors on cells.

Question 10

Dopamine can be a great equalizer in the cortico-basal ganglia-thalamo cortical circuit, depending on the receptors. Explain dopamine’s effect on D1 and D2 receptors.

Answer 10

D1 receptors are present in input layer (striatum) of the direct pathway. The D1 receptors are coupled with EXCITATORY G-PROTEIN and when bound to dopamine will excite neuron inhibiting the inhibitory projection on thalamus, helping to turn the brake off = active thalamus

D2 receptors are present in input layer (striatum) of the indirect pathway and is coupled with INHIBITORY G-PROTEIN. Dopamine will bind to D2 receptors and inhibit the inhibitory neuron, which will release the inhibition on the inhibitory neuron that is on STN. An inhibited STN cannot activate the inhibitory neuron on the thalamus, thus leading to disinhibition of the thalamus.

Question 11

Classic view that basal ganglia output to cortex is only to motor cortex is not true. List and briefly explain the other basal ganglia loops (4)

Answer 11

1) Body Movement Loop
primary motor, premotor, supplementary motor to basal ganglia back to motor areas via thalamus

2) Oculomotor Loop
frontal eye field, supplementary eye field to basal ganglia and back to frontal eye field, supplementary eye field via thalamus

3) Prefrontal Loop
dorsal lateral prefrontal cortex to basal ganglia back to dorsal lateral prefrontal cortex via thalamus

4) Limbic Loop
ACC, orbital frontal cortex to basal ganglia back to ACC, orbital frontal cortex via thalamus

Question 12

How do basal ganglia participate in motor & non-motor function?

Answer 12

basal ganglia structures have neurons very active in simple movements of the limbs & visually guided movements. Therefore, location within basal ganglia determines precise properties that are observed.

Question 13

There are the indirect and direct pathways in cortico-basal ganglia-thalamo cortical circuits. Explain the hyperdirect path and the striosomal path.

Answer 13

the hyperdirect path –> when cortical info goes straight to the subthalamic nucleus, bypassing the striatum. This is what keeps the brake on, inhibiting the thalamus because the STN will excite the inhibitory neuron on the thalamus.

striosomal path –> concerned w/ reward having projections directly to dopamine producing cells.

Question 14

What are the neurons most involved in “habit learning”?

Answer 14

giant cholinergic interneurons called tonically active neurons (TANs) are most involved in “habit learning”. TANs are in striatum and interact with dopamine inputs from substantia nigra pars compacta at the level of the medium spiny stellate neuron (MSSNs).

Question 15

What is the relationship btw tonically active neurons (TANs) & SNpc neurons?

Answer 15

TANs are in striatum and interact with dopamine inputs from SNpc at the level of the MSSNs. TANs and SNpc neurons are activated by rewards or stimuli that predict the occurrence of rewards & modify the activity of MSSNs based on this. Therefore, this reward based shaping of neuronal activity can have profound effects on the prop of cells.

Question 16

T/F: Tonically active neurons (TANs) have ability to cause dopamine release which allows for potential for conditioning.

Answer 16

Yes

Question 17

What are the 2 general groups of dyskinesias? Explain the role of basal ganglia in these 2 groups of dyskinesias and what types of symptoms to expect.

Answer 17

1) hypokinesias (Parkinson’s Disease)
- excessive inhibition of thalamus by basal ganglia
- too much braking
- impairment of initiation of movement (akinesia)
- lack/reduction in amplitude & velocity of movement (bradykinesia)

2) hyperkinesias (Chorea, HD)
- abnormally LOW LEVELS of basal ganglia output
- remember at rest, thalamus is inhibited so if there’s decrease basal ganglia output, then thalamus will be active.
- excessive motor activity
- abnormaly involuntary purposeless movement
- hypertonia
* *seem to take out indirect pathway so there’s disinhibition of thalamus = active thalamus

Question 18

Chorea & Sydenham’s Chorea

Answer 18

Both are hyperkinesias due to low basal ganglia output. Both are characterized by quick, jerky movements. Sometimes, people get this due to autoimmune response to strep infections.

Question 19

Parkinson’s disease

Answer 19

resting tremor, postural abnormalities, muscular rigidity, akinesia, bradykinesia. due to loss of dopamine –> cannot support direct pathway (so no disinhibition of thalamus) & cannot oppose indirect pathway, leading to excessive braking.

Question 20

Are there only motor symptoms associated with basal ganglia disorders?

Answer 20

No, there are also high order consequences.

HD - cognitive defects
chorea -emotional, behavioral, OCD
Parkinsons - cognitive defects

hence there’s a strong evidence that basal ganglia lesions are caused by cognitive defects, hallucinations & OCD

Question 21

What can cause basal ganglia lesions (list 5)?

Answer 21

• CO poisoning
• wasp stings
• adverse drug rxns
• post-infections
• high altitude sickness

Question 22

What are some treatments for hyperkinetic disorders?

Answer 22

• treatment should inhibit thalamus by blocking direct pathway
• use anti-dopa drugs or dopamine-depleting cells so to put the brake on.
• treatment can include abx, immunomodulatns
• consider plasmapheresis

Question 23

What can chronic treatment of hyperkinetic disorders lead to?

Answer 23

tardive dyskinesia (the involuntary movements are tardive, meaning they have a slow or belated onset)

Question 24

How to treat hypokinesia?

Answer 24

In hypokinesia, the brake is on too much so need to relieve it by stimulating direct pathway and inhibiting indirect pathway.

• treat with L-dopa or dopamimetics
• treat with MAO inhibitors to prevent degradation of dopamine
• treat with anti-cholinergics to dampen dopamine release

Question 25

What are some surgical options to treat hypokinesias?

Answer 25

1) pallidotomy
- electrocoagulative or radiofreq lesions are made in globus pallidus or ventrolateral nucleus of thalamus
- globus pallidus removal will increase motor function by reducing rigidity
- ventrolateral nucleus removal will increase motor function by reducing tremor

2) transplants (grafts, stem cells)
- most promising = iPSC-derived dopaminergic cells

3) deep brain stimulation -pacemaking

Question 26

Electrophysiological recording studies of the globus pallidus shows that globus pallidus
neurons:
A) are highly excited by cortical stimulation.
B) are inhibited by dopaminergic inputs.
C) seldom exhibit spontaneous firing.
D) do not change their firing rates during simple arm movements.
E) are involved in remembering sequences of visual stimuli for short periods of time

Answer 26

E

Question 27

Functional imaging studies in human subjects indicate:
A) activity of basal ganglia loops cannot be observed under normal circumstances.
B) there is less involvement of dopaminergic systems than in rodents.
C) the subthalamic nucleus degenerates in children with streptococcal infections.
D) the basal ganglia are not involved in simple motor tasks.
E) considerable activation of the globus pallidus during problem-solving tasks.

Answer 27

E

Question 28

The medications used to treat Parkinson’s disease:
A) are ineffective at improving the motor symptoms.
B) often lead to the development of dyskinesias.
C) cannot be taken by mouth due to effects on the GI tract.
D) are the same class of drugs used to treat Huntington’s disease.
E) are less effective as administering dopamine directly.

Answer 28

B

Question 29

Localized application of a GABA receptor agonist within the SNpr would most likely

Answer 29

result in involuntary saccadic eye movements