Modulation of Movement by the Basal Ganglia

Question 1

What makes up the basal ganglia?

Answer 1

Group of subcortical nuclei

The striatum (caudate nucleus and putamen, nucleus accumbens and olfactory tubercle)
Globus pallidus
Substantia nigra
Subthalamic nucleus

Question 2

What cell type is found in the caudate nucleus?

Answer 2

Medium spiny neurons (all projection neurons)
= Neurons that are densely covered in spines which receive synaptic inputs

Question 3

What does the caudate project to?

Answer 3

Globus pallidus
Substantia nigra

Question 4

What receptors are found in the basal ganglia and which structures has each receptors?

Answer 4

D1 and D2 dopamine receptors

Globus pallidus externa (GPe) (central hub) = Mainly D2 dopamine receptors
Internal globus pallidus (GPi) (output nuclei) = Mainly D1 dopamine receptors
Substantia nigra pars reticulata (SNpr) = Mainly D1 dopamine receptors

Question 5

What type of receptor are the D1 and D2 dopamine receptors in the basal ganglia?

Answer 5

GABAergic - all inhibitory to the structures they project to

Question 6

What substances do D2 dopamine receptors release in addition to GABA?

Answer 6

Enkephalin

Question 7

What substances do D1 dopamine receptors release in addition to GABA?

Answer 7

Substance P
Dynorphin

Question 8

What structures receive the input to the basal ganglia?

Answer 8

Striatum
Subthalamic nucleus

Question 9

What is the ‘Go pathway’ in the basal ganglia?

Answer 9

Cortex sends an excitatory output to the striatum D1 (Glutamatergic). The neurons from the striatum are GABAergic send their axons to the GPi and SNr causing inhibition which inhibits the cells which are tonically active. This releases the thalamus which in turn activates the cortex

Question 10

What is the ‘Stop pathway’ in the basal ganglia?

Answer 10

Cortex sends excitatory outputs to the subthalamic nucleus and the striatum D2

Striatum D2 neurons have an inhibitory input to the GPe which has an inhibitory input to the subthalamic nucleus which has an excitatory output to the GPi and SNr.
The GPi has tonic inhibition of the thalamus.

When the indirect pathway is activated, the striatal neurons inhibit the GPe neurons, thus disinhibiting the subthalamic neurons meaning the GPi neurons inhibit the thalamus thereby producing a net inhibition on the motor cortex

Question 11

How have these two pathways in the basal ganglia been confirmed?

Answer 11

Optogenetics
Can either turn on or off the D1 and D2 receptors and assess behavioural changes
Mice have been bred with channelrhodopsin, mice are exposed to light with the wavelength corresponding to either D1 or D2
When the mice are exposed to a wavelength activating the D1 dopamine receptors (go pathway), the mean velocity of the animal increases (overall movement)
When mice are exposed to light activating the D2 dopamine receptors, there is a reduction in mean velocity

Question 12

What is the hypothesis for basal ganglia function?

Answer 12

Redgrave et al., (1999)
= The BG is the central switch in the vertebrate brain that enables action selection

Question 13

How does the basal ganglia mediate the competition between actions?

Answer 13

A computational imperative
Central switch has a wiring advantage over the distributed alternative

Question 14

What is the action selection hypothesis?

Answer 14

Basal ganglia circuits are organised to select desired actions and to inhibit potentially competing unwanted actions
This is accomplished through a complex circuitry that is modified through development and learning

Question 15

What evidence is there for the action selection hypothesis?

Answer 15

Clues of function of BG from its disorders
Damage to BG is the cause of the classical symptoms of:
Parkinson’s disease (bradykinesia, rigidity, tremor)
Huntington’s disease (involuntary movements)
Dystonia (abnormal fixed postures)
Tourette’s disorder

Question 16

If the action selection hypothesis is true then we require that…

Answer 16

1. The BG must take input from a wide variety of brain areas
   –> Putative ‘command centres’ for ‘action requests’ should be cortical and subcortical
2. There must be some mechanism by which the BG can switch on selected resources
3. There must be evidence of a flow of information between command centres, BG, and associated motor centres
4. The BG must be able to extract the ‘salience’ or ‘urgency’ of each request
5. There must be evidence of neuronal selection mechanisms in BG

Question 17

Does the BG receive input from a wide variety of brain areas?

Answer 17

Main input nucleus is neo-striatum composed of the putamen and caudate nuclei
Receives input from all over the brain including the cerebral cortex and subcortical nuclei such as the superior colliculus

Question 18

Is there some mechanism by which the BG can switch on selected resources?

Answer 18

Disinhibition gating hypothesis
When activity is relatively quiet with little excitation to the striatum, the GPi and SNr tonically inhibit the thalamus keeping it in an inhibited state
However, if an action request is made to the BG, this increases activity in the striatum driving inhibitory outputs to the GPi/SNr, driving down tonic activity, releasing the thalamus causing excitation

BG makes its selections by removing the tonic inhibition to the thalamus

Question 19

What evidence is there for the disinhibition gating hypothesis?

Answer 19

Data from glutamate injections in monkeys, record multi-unit activity (Alexander et al. 1990)
Glutamate injection causes an increase in the output from the striatum which inhibits the SNr which releases the thalamus causing excitation

Question 20

What are the main loops of the basal ganglia?

Answer 20

Five main loops according to primary cortical input area:
1. Motor (supplementary motor area)
2. Oculomotor (frontal eye fields)
3. Prefrontal 1 (dorsolateral prefrontal cortex)
4. Prefrontal 2 (lateral orbitofrontal prefrontal cortex)
5. Limbic (anterior cingulate area)

Question 21

How can we conclude that the BG represents actions in discrete channels? (evidence of neuronal selection mechanisms)

Answer 21

Evidence of 5 main loops
and
Different body parts represented by different parts of BG and related structures
and
There are subcortical BG loops
–> Superior colliculus, pedunculopontine tegmental nucleus (PPN), periaqueductal grey (PAG)

Question 22

How does salience extraction happen in the striatum?

Answer 22

Spiny projection neurons (SPNs) have on the order of 50,000 synapses
Pattern matching on SPN to command requests extracts their salience

(The louder the inputs shout, the more likely that particular action will be selected)

Question 23

What evidence is there for multiple selection mechanisms in the BG?

Answer 23

Up-down states of spiny projection neurons in the striatum with local inhibitory circuits
Diffuse/focused projection onto output nuclei
Recurrent inhibition in output nuclei