Week 5 Topic 2 - The structure and function of the Basal Ganglia

Question 1

Where are the basal ganglia located?

Answer 1

In the forebrain.

Question 2

What are the components of the basal ganglia?

Answer 2

1. the caudate nucleus,
2. the putamen. [Those together form the striatum.]
3. globus pallidus, (external and internal segment).
4. subthalamic nucleus
5. substantia nigra (“The black substance” where dopamine is released from)
   [6. the thalamus
6. the cortex]

Question 3

Which two/three parts of the BG form the “striatum”?

Answer 3

1. the caudate nucleus and
2. the putamen
   [also 3. the ventral striatum, which includes the nucleus accumbens]

Question 4

What are the two parts of the substantia nigra?

Answer 4

1. The pars compacta (SNc)
2. The pars reticulata (SNr).

SNr often works in unison with GPi

SNr-GPi complex inhibits the thalamus

Question 5

What does the tectum do?

Answer 5

The tectum of midbrain is responsible for auditory and visual reflexes.

Question 6

What are reentrant loops?

Answer 6

In the connectivity of the basal ganglia, when loops are repeated several times.

Question 7

What are the three reentrant loops?

Answer 7

1. sensorimotor loop,
2. associative loop,
3. ventral loop

Question 8

What are the three most important features of the basal ganglia connections?

Answer 8

1. excitatory connections, that is, they are activating regions that are connected to it.
2. inhibitory connections. So those activities inhibit the target region.
3. That the striatum has two different ways to reach the GPI and SNR

Question 9

What type of input does the cortex have on the striatum?

Answer 9

the cortex has excitatory inputs to the striatum.

Question 10

What type of connection does the striatum have to the GPI and the SNR?

Answer 10

The striatum has inhibitory connections to the output

nuclei, the GPI and SNR,

Question 11

What type of connection does the striatum have with the internal nuclei, the GPE?

Answer 11

The striatum has inhibitory connections to the internal nuclei, the GPE,

Question 12

What type of connection does the GPE have on the sub thalamus nuclei?

Answer 12

The GPE has inhibitory connection to the STN.

Question 13

What type of connection do the output nuclei have on the thalamus?

Answer 13

Output nuclei have inhibitory connections to the thalamus

Question 14

How is movement modulated in the basal ganglia?

Answer 14

movement is modulated through disinhibition.

Question 15

What type of connection is between the GPI and SNR ?

Answer 15

Inhibitory connection between GPI and SNR,

Question 16

What are the output nuclei to the thalamus?

Answer 16

GPI and SNR

Question 17

What type of connection does the thalamus have to the cortex?

Answer 17

thalamus has an excitatory connection to the cortex

Question 18

What type of output do the GPI and SNR have?

Answer 18

The GPI and SNR are the output nuclei of the basal ganglia and are inhibitory

Question 19

What happens with high tonic activity of the output nuclei (the GPI and SNR)?

Answer 19

This high tonic activity of the output nuclei [and the inhibitory connection of the thalamus] actually
keeps the thalamus quiet, and hence, there cannot be any excitatory activity on the cortex, [which is
the absence of movement.]

Question 20

What causes movement?

Answer 20

Impaired activity of the output nuclei

[which disinhibits the thalamus, which then in turn
can cause an excitatory activity towards the cortex]

Question 21

What is “movement

modulation through disinhibition”

Answer 21

If the activity of the thalamus is disinhibited, it causes
excitatory activity towards the cortex

The basal ganglia mediate
movement through disinhibition

Question 22

How do GPI and SNR cause movement?

Answer 22

The GPI and SNR are inhibitory.

They maintain a high tonic level of discharge, thereby suppressing
the activity in target regions such as the thalamus.

The phasic decrease in firing rate transiently
releases the target regions from inhibition.

It thereby causes disinhibition, which then can lead to
thalamocortical activity, and thereby promote movement.

Question 23

What are the three pathways in the basal ganglia?

Answer 23

1. The direct pathway (increases motor movement)
2. The indirect pathway (stops unwanted motor movement)
3. The NIAGRO STRIATAL Pathway (amplifies motor activity/modulates direct and indirect pathways)

Question 24

What is the direct pathway?

Answer 24

The direct pathway is the direct connection from the striatum
to the output nuclei.

This is an inhibitory connection. So the direct pathway is the direct connection from the striatum to the GPi/SNr.

Question 25

What does it look like when there’s no excitation on the cortex?

Answer 25

The basal firing rates in the striatum are very low, and dependent upon cortical excitation.

That means if the striatum is not activated by excitatory cortical connections, there’s not much activity.

Hence, its inhibitory connection to the output nuclei is low.

Under these conditions, striatal firing has little impact on the output nuclei

The output nuclei show a high rate of tonic firing, which is inhibitory on the thalamus.

Because the striatum is not activated, its inhibitory connection to the GPi/SNr has no effect.

Question 26

What happens to the direct pathway when the cortex is excited?

Answer 26

Phasic cortical excitation drives excitatory discharge in the striatum (action potentials).

The cortex has excitatory connections to the striatum.

This causes activation of the striatum.

Because the striatum has an inhibitory connection to the GPi/SNr, it causes a transient inhibition of GPi/SNr firing.

As a consequence, this activation of the direct pathway promotes action, because in that phase where striatal inhibitory activity inhibits GPi/SNr activity, the output nuclei are not inhibitory on the thalamus.

And this can promote action.

Question 27

What kind of connection does the cortex have on the striatum?

Answer 27

The cortex has excitatory connections to the striatum.

Question 28

What are the intrinsic nuclei?

Answer 28

1. The globus pallidus external segment (GPE), (with the globus pallidus external
   segment having an inhibitory connection to the subthalamic nucleus.)
2. The Subthalamic nucleus (STN) (which has an excitatory connection to the GPi/SNr)

Question 29

What type of connection does the STN have on the output nuclei?

Answer 29

The subthalamic nucleus has an excitatory connection to the GPi/SNr

Question 30

What happens to the indirect pathway with no cortical activity?

Answer 30

without cortical input, the striatum doesn’t have much activity. That is, in
this case of the indirect pathway, it does not impose inhibitory activity on the GPe.

Question 31

High or low: the tonic firing rate of the GPE

Answer 31

The GPe, the external segment of the globus pallidus, has a high tonic firing rate.

Because of inhibitory activity of the GPe neurons, the subthalamic nucleus activity is suppressed [without cortical excitation]

Therefore at rest, firing under these conditions causes high discharge in the output nuclei GPi/SNr because they are
tonically active, and they are inhibitory to the thalamus. So because the STN is not able to have excitatory activity to the GPi/SNr, their inhibitory activity is not suppressed.

Question 32

What happens to the indirect pathway when we have strong phasic cortical excitation

Answer 32

It causes an inhibition of the external globus pallidus because the striatum has an
inhibitory connection on the GPe, and because the GPe shows a high tonic firing rate.

Because the GPe is inhibitory acting on the STN, this leads to the fact that, for a short transient
disinhibition of the STN, this can be active, and thereby excite the output nuclei, GPi and SNr.

Question 33

How do the connections of the indirect pathway differ from the direct pathway?

Answer 33

The indirect pathway suppresses
action, whereas the direct pathway facilitates action.

In contrast to the direct pathway, this activity of the STN onto the output nuclei increases the discharge of the GPi and SNr. And because they are inhibitory, this causes a further inhibition of the
thalamus and cortex, which causes the suppression of action because of the enhanced suppression
of the thalamus.

Question 34

The indirect pathway

Answer 34

Phasic cortical activity activates the striatum, which acts
inhibitory on the external segment of the globus pallidus.

Now, because the external segment of the globus pallidus normally shows a high tonic rate of
discharge, this phasic activity of the striatum causes an inhibition.

Now, as you can see, this inhibition
of the GPe causes a transient activation of the STN. Why? Because the GPe is inhibitory acting on the
STN.

Now, because it has no activity, this inhibitory activity on the STN is released, and the STN itself can
fire excitatory to the output nuclei GPi and SNr.

Now remember, the GPi and SNr also show a high
rate of tonic activity. So they are constantly firing at the thalamus and they are firing inhibitory connections to the thalamus.

And because they are inhibitory to the thalamus, this activity of the STN onto
those output nuclei causes a further inhibition of the thalamus.

When the thalamus is super inhibited then doesn’t action happen? Help?

Question 35

The direct pathway

Answer 35

the direct pathway,

Phasic cortical activity activates the striatum. Now, because the striatum has an
inhibitory connection to the output nuclei, the GPi and SNr, this causes a transient inactivity of the
output nuclei.

Now, because the output nuclei are inhibitory acting onto the thalamus, this causes a
transient inactivity of the inhibition, and thereby action can be facilitated. because the thalamus is able to fire to the cortex?

Question 36

Do the direct and indirect pathway work together, cooperatively?

Answer 36

The indirect pathway suppresses action, whereas the direct pathway facilitates action.

Recent research has
shown that they are both cooperatively active, and regulate motor output. This is very important to
memorise.
In old models, it was always thought that motor activity, for example, would rely on direct pathway
activity, whereas the indirect pathway was silent, whereas when you had no activity, or stopped an
activity, the indirect pathway was active and the direct pathway was silent. This old model is no longer
valid. We now know from experiments that I will show you in a minute that it’s the cooperative activity
of the direct and indirect pathway that regulates adaptive behaviour.
We don’t know yet how this works, but we start to have an idea how they together can mediate
adaptive behaviour.

Question 37

What is one of the most important modulator of basal ganglia activity?

Answer 37

Dopamine

Question 38

Where does dopamine input originate from?

Answer 38

The dopamine input arises from another part of the substantia nigra, which is called pars compacta, abbreviated SNC.

Question 39

How many connections are there from the SNC to the striatum?

Answer 39

we have two connections to the striatum. One connecting to the direct pathway, and
one connecting to the indirect pathway.

Question 40

Which dopamine receptors does the direct pathway express?

Answer 40

the direct pathway expresses D1 receptors,

Question 41

Which dopamine receptor does the indirect pathway express?

Answer 41

whereas the indirect pathway expresses

D2 receptors.

Question 42

Why do we have different responses to the dopamine signalling from the SNC?

Answer 42

Because of the different nature of D1 and D2 receptors

Question 43

What does the D2 signalling do?

Answer 43

D2 signalling suppresses the firing in indirect pathway neurons

Question 44

How does D2 signalling suppress firing in the indirect pathway neurons and what does this mean for movement?

Answer 44

Because of this peculiar activity of the D2 receptors. It results in the reduction of
inward, depolarising currents, and the increase of hyperpolarising currents, and therefore diminishes
the spiking in the indirect pathway.

As a consequence, you have less activity of the GPI. That means dopamine signalling via D2 receptors
diminishes indirect pathway activity, and as a result, dopamine acting on D2 reduces the indirect
pathway inhibitory effect, and thus facilitates movement.

Question 45

How does the D1 signalling pathway work when it receives dopaminergic input? And what does this mean for movement?

Answer 45

In contrast to the D2
dopamine receptor, the D1 receptor acts differently. Dopamine input enhances calcium currents
and reduces potassium currents. The effect of this is to increase the spiking of the neurons in the
striatum. That is, it facilitates striatal signalling on the output nuclei.

That, of course, causes an inhibition of the output nuclei. And as shown here, dopamine acts on D1,
and thereby facilitates the movement in the presence of strong cortical drive.

Question 46

Can the same neurotransmitter have different effects?

Answer 46

Keep in mind that this is due to the fact that D1 and D2 receptors respond differently to dopamine. That is, the very same
neurotransmitter can have opposite effects. Dopamine signalling through D2 receptors in the indirect
pathway suppresses striatal inhibitory activity. Dopamine signalling through D1 receptors in the direct
pathway facilitates strong phasic inputs, it suppresses weak inputs. Thus, dopamine modulates
impact of direct and indirect pathway activity via different differential action of D1 and D2 receptors.

Remember, the overall activity of the indirect pathway
suppresses action. The overall activity of the direct pathway facilitates action. Now dopamine
modulates their impact.

Question 47

How are optogenetics used in studying the basal ganglia?

Answer 47

In the lab of Anatol Kreitzer, they used optogenetics to
activate either the D1, which is the direct pathway, or the D2, the indirect pathway.

You can express a factor in a neuron that allows you to activate that neuron by a pulse of light. And
you can see, on the left bottom side, there are two sources of light that shine onto the striatum,
STR. Now in the middle, the circular line shows when the activity of D1, the direct pathway, has
been modulated. Wherever you see a grey dot, the light was off. Wherever you see a red dot and
connections between the red dot, the light was on. That means the light was switched on and hence
the neurons of the direct pathway were activated. You can clearly see whenever the light was on, this
mouse was running around in the arena, which clearly emphasises the role of the direct pathway in
facilitating movement and thus action.

Now on the right-hand side, you see a similar experimental set-up. But now, light activates the
D2 receptor, which, as you know, is expressed in the indirect pathway. In grey, the light is off. In
green, light is switched on, and thus, activates neurons of the indirect pathway. You can clearly see
that when you switch the light on and thereby activate the neurons of the indirect pathway, you
immediately stop movement and thus inhibit action. This study, which was published in 2010 by Anatol
Kreitzer’s lab, is a very elegant demonstration of the major output of the direct and indirect pathway.

And this work is beautifully illustrated in this video, which you can actually download yourself and
have a look at. It illustrates what happens when you activate, via optogenetic activation, the indirect
pathway. It suppresses action and thus inhibits motor behaviour. Now as you can see from this
study, when you artificially activate the indirect pathway, you suppress action and thus inhibit motor
behaviour. You can well imagine that any problems with the activity of the direct pathway or the
indirect pathway can be related with disease, and this is indeed the case.

Question 48

What is optogenetics?

Answer 48

Optogenetics most commonly refers to a biological technique that involves the use of light to control neurons that have been genetically modified to express light-sensitive ion channels

Question 49

What are the behavioral abnormalities seen in basal ganglia dysfunction?

Answer 49

1. motor abnormalities,
2. impaired memory formation,
3. attention deficits,
4. affective disorders,
5. sleep disturbances.

Question 50

What are some basal ganglia-related disorders?

Answer 50

Dysfunctions can be found either in isolation or sometimes together in a variety of basal ganglia-related disorders, such as 
1.  Parkinson’s disease, 
2.  Huntington’s disease, 
3.  dystonia, 
4.  abulia, 
5.  dementia,
6.  attention deficit hyperactivity
disorder 
7.  schizophrenia.

Question 51

How is Parkinson’s disease characterized?

Answer 51

Parkinson’s disease is characterised by the specific

loss of dopaminergic input into the striatum.

Question 52

What happens in Parkinson’s disease?

Answer 52

In Parkinson’s disease because of the specific loss of dopaminergic
neurons in the pars compacta, you lose the nigrostriatal pathway. That is, dopamine does no longer
have an impact onto the striatum.

What is the consequence of that, if you no longer have dopaminergic modulatory input onto the
striatum? That is, the direct pathway becomes less active, whereas the indirect pathway becomes
more active. Remember, this is due to the fact that the D1 and D2 receptors respond differently to
dopamine.

Because of this absence of dopamine, action selection via the direct pathway is suppressed, whereas
action inhibition via the indirect pathway is facilitated.

And this causes the very typical symptoms of Parkinson’s disease, which is tremor, rigidity,
bradykinesia.

But please be also aware that Parkinson’s disease is characterised by non-motor
symptoms that also can account for basal ganglial dysfunction.

And one of the most important is
sleep disturbances, which occur even before any motor symptoms are visible.

Question 53

What causes abulia, also

called Athymhormia?

Answer 53

It is caused by lesions of the globus pallidus and the connections between the
striatum and the globus pallidus. Remember, this is part of the indirect pathway where you have an
inhibitory connection from the striatum to the external segment of the globus pallidus.

Those patients have been characterised by a profound inertia. Action is impaired in
its initiation and in maintenance as well. Action is also impaired in its progress, since it tends to stop
unless kept up by external stimulation.

Question 54

How does abulia, also

called Athymhormia relate to voluntariness or freedom of activity?

Answer 54

Those patients which have defects in the globus pallidus and the striatal
pathway, they have great difficulties to initiate actions.

And that, of course, directly relates to what we
call voluntary actions or voluntariness.

Now voluntariness, as you know, is a central point when we
regard our freedom of activity, what we want to do and when we want to do it.

Question 55

What does the basal ganglia have to do with voluntariness and free will?

Answer 55

Remember the experiments from that an Anatol Kreitzer’s lab where he used optogenetics to
artificially activate the direct D1 pathway or the indirect D2 pathway, and remember when the indirect
pathway was artificially activated, it suppressed activity of the mouse.

Now, you could ask, does that mean that the mouse was deprived of her freedom to do what she
wants? I’m well aware this is a very anthropocentric view, but nevertheless, isn’t voluntariness
conceived as a key concept of free will?

And in fact, it was the philosopher Kant who said that a person acts freely if he does of his own
accord what must be done.

Now, think of people with basal ganglia dysfunctions. They are impaired in their actions and, if you like,
in a way they are deprived in expressing their free will.

Now, according to Kant, we are on the one hand determined by natural law and on the other hand
free because of our capacity to obey moral law. Now, think of people with basal ganglia dysfunctions
who are impaired in their judgments.

So with that, I would like to end this little thought experiments and I would like to ask you, so, what
is free will, and has it anything to do with the basal ganglia? And just as a reminder, Stan Grillner, a
researcher at the Karolinska Institute once said, “The only output of the nervous system is the motor
system, whether in in cognition or action.” And without the functional basal ganglia, you inevitably
have problems to express voluntariness.

Question 56

Where does the basal ganglia potentially evolve from?

Answer 56

We recently carried out a study where we compared the basal ganglia to a region in the
insect brain which is called the central complex.

When you look into the central brain, there is this ochre region which is called the central complex.

If you inactivate this central complex, you have problems with actions.

The central complex and its sub-components are connected by so-called re-entrant loops. These are parallel projecting loops that integrate and convey sensory motor representations that select and maintain behavioural activity.

Similar genetic programmes actually
underlie their formation and function, and those behavioural manifestations can be regarded as
shared action selections.
Slide 10
This is also re-emphasised by the fact that, if you have a dysfunction of the basal ganglia and the
central complex, you see homologous pathological manifestations such as motor abnormalities,
impaired memory formation, attention deficits, affective disorders, and sleep disturbances.
There is a corresponding circuit organisation of the basal ganglia and the central complex.

This is necessary to explore your environment and to
look out for the new and open.