BASAL GANGLIA

The basal ganglia consists of a group of subcortical nuclei, located deep beneath the cerebral cortex in what may be described as the base of the forebrain. Consisting of four nuclei, the basal ganglia functions to regulate movement, facilitating intended actions and inhibiting unintended actions. It is important to note that the basal ganglia does not directly cause motor output, but instead influences the processing and modulates the output of the descending pathways the body uses to execute movement. Movements are initiated in the motor cortex, however, the basal ganglia plays a vital role in determining which of these movements are appropriate to send to lower levels of the motor hierarchy (the spinal cord, alpha motor neurons, interneurons, etc.). [1, 4, 5]

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Figure 1

Functional Anatomy

As stated, the basal ganglia consists of four nuclei that function together as an intertwined network; they are (1) the striatum, (2) the globus pallidus, (3) the substantia nigra, and (4) the subthalamic nucleus (STN). The striatum consists of both the caudate and the putamen. The large, centrally located, lateral, oval shaped structure (Figure 2a) is the putamen. Encircling the putamen is the C-shaped caudate, consisting of the head at the most anterior end, followed by the body, and the tail at the most posterior. Small projections, called cellular bridges, connect the caudate and putamen along their length. Because of this “striated” appearance, the caudate and putamen are collectively known as the neostriatum, or more simply, the striatum.

[1, 4]


The putamen fuses with the caudate anteriorly and ventrally, forming what is called the ventral striatum. This structure plays a role in the limbic circuitry, with most of the ventral striatum consisting of the nucleus accumbens. Just medial to the putamen is the globus pallidus (Figure 2b) consisting of two components, the internal segment (GPi), and the external segment (GPe). The globus pallidus combined with the putamen are called the lenticular, or lentiform nucleus.

[1, 4]

Also having two components is the substantia nigra, consisting of both the substantia nigra pars reticulata (SNr), and the substantia nigra pars compacta (SNc). The substantia nigra are located at the inferior/posterior side of the basal ganglia, along with the subthalamic nucleus. The substantia nigra nuclei are located inferior to the subthalamic nuclei with the substantia nigra pars compacta being superior to the substantia nigra pars reticulata. [1, 4]


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Figure 2a

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Figure 2b

Functionally, the globus pallidus internus and the substantia nigra pars reticulata are grouped together as they both serve as “output nuclei,” with neurons exiting the basal ganglia. If the brain were to be cut transversely, one would see that the basal ganglia form a mirror image. On each side, left and right, there is one of each nucleus (Figure 3).

[1, 4]



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Figure 3

Internal Circuitry

The nuclei within the basal ganglia have connections to one another that are either excitatory or inhibitory. Input comes to the basal ganglia, into the striatum, from multiple areas of the cerebral cortex. This information is always excitatory, using the neurotransmitter glutamate, on the caudate and putamen. The corpus striatum has projections to other nuclei that are GABAergic, meaning they utilize the neurotransmitter GABA and are inhibitory on the nuclei they innervate. The striatum sends inhibitory information to both the GPe via the neurotransmitters GABA and enkephalin, and to the output nuclei via the neurotransmitters GABA and substance P. [1, 4]

The GPe has projections to the STN which are inhibitory via the neurotransmitter GABA. The STN has projections to the output nuclei that are excitatory via the neurotransmitter glutamate. [1, 4]

The output nuclei have projections leaving the basal ganglia circuitry that are inhibitory via the neurotransmitter GABA. Lastly, the SNc has projections to the striatum that can be either excitatory or inhibitory based on the receptor within the caudate or putamen; the neurotransmitter used here is dopamine. There are also projections returning to the SNc from the striatum that are inhibitory via the neurotransmitter substance P. All of this is depicted in Figure 4. Here, it is also evident that there are two pathways of information traveling through the basal ganglia, each affecting the output nuclei in different ways. [1, 4]


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Figure 4

Relating to motor function, there are two pathways that traverse the basal ganglia. The direct pathway, allows for the correct motor program to be elicited. Meaning, the body is allowing for the action that we intend. Conversely, the indirect pathway is inhibiting, or suppressing, the unintended motor programs, disallowing for movement that is inappropriate. [1, 4, 7]


Direct Pathway

Functionally, the direct pathway travels from the cortex, having excitatory input on the striatum. An excited striatum then sends an increased amount of inhibitory signals to the output nuclei (GPi, SNr). The output nuclei are tonically active, meaning they are always actively sending inhibitory information to the thalamus. When the striatum increases its amount of inhibitory signals to the output nuclei, it is inhibiting the inhibition of the thalamus, thereby allowing the thalamus to send its excitatory signals to cortical motor areas. The cortex will then send descending information down to all levels of the spinal cord to induce movement. In this way, the basal ganglia is indirectly influencing movement of the body. [1, 4]


Indirect Pathway

The indirect pathway travels from the striatum, after receiving excitatory input from the cortex, and is inhibitory on the GPe. The GPe has an inhibitory effect on the subsequent nuclei, the STN. When the inhibition from the striatum increases, the GPe decreased its inhibition on the STN. This allows for the STN to send more of its excitatory input to the output nuclei. When excitation of the output nuclei occurs, increased inhibition is sent out to the thalamus (via the neurotransmitter GABA), thereby decreasing the amount of excitation traveling to the cortical motor areas. With the indirect pathway, due to the inhibition of information to the cortex, movement is not induced and will not descend the spinal cord. Therefore, the basal ganglia is indirectly influencing motor output by inhibiting unintended movement. [1, 4, 7]

Both of the above pathways either allow for (direct) or disallow for (indirect) motor action because the information from the thalamus returns to the cortex where motor planning occurs (within the supplementary motor area, and the premotor cortex), and to the primary motor cortex which initiates movement, selects for the force of movement, and produces the direction of movement. [1, 4, 7]


The Role of Dopamine

Dopamine is a neurotransmitter that is released by the SNc; it has either an excitatory or inhibitory effect on the corpus striatum depending on which pathway (direct or indirect) it is synapsing on (Figure 4). For the direct pathway, dopamine is excitatory, and for the indirect pathway, dopamine is inhibitory. Dopamine functions only to facilitate movement. In this way, it can be seen how exciting the direct pathway (which facilitates movement) would be facilitating the facilitation of movement. Conversely, inhibiting the indirect pathway (which inhibits movement) would be inhibiting the inhibition, thereby allowing for movement. [1, 4]

There is feedback to the SNc to inhibit or decrease the release of dopamine. This feedback occurs via neurons from the striatum traveling to the SNc; the release of substance P causes this inhibition to take place. [1, 4]


Neuron Types in the Striatum

The striatum contains several neuron types, however, 90-95% of them are termed medium spiny neurons. They serve as both the main receptive neurons and the sole source of output, meaning they are the proprietors of the direct and indirect pathways. Other neurons found in the striatum are the large cholinergic interneurons which release acetylcholine as their neurotransmitter to the medium spiny neuron. Also present are other small interneurons which release GABA as their neurotransmitter. Both types of interneurons are inhibitory and although few in number, they are the primary neurons responsible for tonic activity in the striatum. The image below depicts a medium spiny neuron with the multitude of input it receives. [1, 4, 7]


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Figure 5


Input and Output

Most input to the striatum originates in the cerebral cortex. When input comes into the striatum, it synapses on medium spiny neurons in either the matrix or the striosome. Neurons within the matrix are those that project through the direct and indirect pathways. Neurons within the striosome are the ones that project back to the SNc, regulating the release of dopamine to the striatum. [1, 4]

Neurons of the matrix, which project through the direct and indirect pathways, have either D1 or D2 receptors located in the striatum. D1 receptors belong to the direct pathway; dopamine is excitatory to medium spiny neurons yielding D1 receptors. D2 receptors belong to the indirect pathway in which dopamine is inhibitory at this synapse. [1, 4]

Information travels to the output nuclei via the striatum and the STN. The information coming from the striatum to the output nuclei follows the direct pathway. Knowing that the direct pathway facilitates movement, this information is selective for a the intended motor program of the individual; it is the action they intend to make. Because we generally don’t want to make a bunch of different movement at once – we want our movement to be pointed and direct – this information is slow, focused and convergent (multiple neurons synapsing on one neuron). This information is also inhibitory. It may be confusing that the information traveling to the output nuclei of the movement we want to perform is inhibitory, but remember that the output nuclei itself is inhibitory to the thalamus. Therefore, in this scenario, the inhibition of the thalamus to the cortex is being inhibited by the striatum, therefore allowing for the intended movement. When information comes to the output nuclei via the STN, indirect pathway, it is fast, widespread, and divergent (one neuron synapsing on many neurons). This information is also excitatory. Here, this excitation of the inhibitory output nuclei is increasing the inhibition that the output nuclei send to the thalamus; unintended movement is therefore inhibited. [1, 4]

Output from the basal ganglia originates in the GPi and SNr. Most output travels to the ventral lateral (VL) thalamus, and the ventral anterior (VA) thalamus. Whereas input to the striatum synapses on medium spiny neurons, the output nuclei is comprised of what are called aspiny neurons. [1, 4]

Within the circuitry of the basal ganglia there are four parallel channels, each in control of a different function: General motor control, eye movement, cognitive function, emotional function:


Motor channel: This is the most well-known channel, aiding regulation of bodily movement. Originating in the cortex (somatosensory, primary motor, and premotor), this channel runs through the putamen, to the output nuclei (mainly the GPi), exiting the basal ganglia and traveling to the ventrolateral and ventral anterior thalamus (VL and VA respectively), this pathway returns to the cortex terminating in the supplementary motor area, the premotor area, and the primary motor cortex.

Oculomotor channel: Regulation of eye movement is subserved by this channel. This channel begins in the cortex (posterior parietal and prefrontal), traveling through the caudate body to the output nuclei (mainly SNr), to the VA and MD (mediodorsal) thalamus, and terminating in the frontal and supplementary eye fields.

Prefrontal channel: This channel plays an important role in cognitive processing involving the frontal lobes. Beginning in the posterior parietal and prefrontal cortex, this channel passes through the caudate head, to the output nuclei (mainly SNr) to the VA and MD thalamus, terminating in the prefrontal cortex.

Limbic channel: Involving the regulation of emotion and motivational drive, this channel runs through the ventral areas of the basal ganglia. Beginning in the temporal cortex, hippocampus, and amygdala, this channel passes through the ventral caudate and putamen, as well as the nucleus accumbens, to the output nuclei and ventral pallidum. It then travels through the MD and VA thalamus, terminating in the anterior cingulate and orbital frontal cortex. [1, 4]


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Figure 6

Basal Ganglia and the Role of Saccades

The basal ganglia plays a role in all movement, this includes movement of the eyes. The SNr, part of the tonically active, inhibitory output nuclei, has projections to the superior colliculus neurons that control eye movement. When striatal neurons in the direct pathway are excited by the cortical frontal eye fields, the SNr is inhibited, therefore it cannot send inhibitory information to the superior colliculus. The superior colliculus is now released from inhibition, allowing it’s neurons to signal a new target and move the eyes there (i.e. perform a saccade). Once the eyes are in its new appropriate and intended location, the frontal eye fields stop sending excitatory information to the striatum, and the direct pathway no longer inhibits the output nuclei, thereby allowing inhibition of the superior colliculus to continue – eyes will stay fixed. [5]


Habit Formation

Recent research has shown that there is a causal relationship between action and outcome, relating to the control of actions in anticipation of a desired result. It has been proposed that the basal ganglia does not consist of four distinct and disjoint channels, but rather that there are connections between them. During habit-performing studies, it was found that cortical activity switched from ventral areas to dorsal areas during overtraining of a behavior; similar findings were found in the striatum of the basal ganglia. For example, when an individual is learning a new motor program, the caudate is activated (along with the dorsolateral prefrontal cortex). When the behavior becomes well-learned, activation switches to the putamen (and the motor cortices). When individuals are asked to focus and think about the task at hand, the activation switches back to the caudate and dorsolateral prefrontal cortex. [3, 6, 8, 9]

With respect to addictive drugs, the compulsion for and motivation to do drugs may be implemented by links between the limbic channel and the sensorimotor channel. It has also been seen that the effects of addictive drugs progressed from the ventral to dorsal striatum. Further studies have shown that a given stimuli that is predicted to yield a reward, can potentiate the release of dopamine, modulating behavior. [3, 6, 8, 9]

At present, more studies must be done in order to fully comprehend the relationship between habit-forming and the basal ganglia but these findings indicated that there is a correlation that exists. When a reward is anticipated and received, there are changes to the basal ganglia. Similarly, when a reward is anticipated and not received, there are also changes. [3, 6, 8, 9]

Other studies done on monkeys have shown that if the subject receives an unexpected reward, neurons for dopamine fire quickly. The thinking here is that these neurons fire to strengthen the motor program that lent the monkey to that reward. If the subject receives a reward that was expected, no change in neuronal firing is seen. If the monkey expects a reward but does not receive one, neuron firing is inhibited which is thought to weaken the motor program that lead to no reward (Figure 7). [5]

Dopaminergic neurons signal unexpected reward or unexpected absence of reward: [5]

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Figure 7

For more information on the role of the basal ganglia in habit formation, click here.


Disorders of the Basal Ganglia

Hyperkinetic movement disorders are characterized by uncontrolled involuntary movement, often presenting as a random pattern of jerks and twists. The most common hyperkinetic condition is called Huntington’s disease. In this condition, the individual has degeneration to the indirect pathway. Remember that the indirect pathway inhibits unwanted motor programs. When this pathway isn’t functioning correctly, inappropriate motor programs are not inhibited. This condition is characterized by unwanted movement, difficulty with speech, swallowing, and posture. For more information visit the following sites: Huntington's 1, Huntington's 2, or Huntington's 3. [1, 2, 3]


Hypokinetic movement disorders are characterized by marked difficulty in producing movement, slow movement, and rigidity. One of the most common hypokinetic condition is called Parkinson’s disease. In this condition, there is degeneration of the direct pathway. Because the direct pathway is the body’s means by which intended movements are carried out, individuals with this condition have a difficult time performing movements, movement is often slow, and they may have resting tremors. For more information click here, here, or here. [1, 2, 3]


Conclusion

In conclusion, the basal ganglia, a collection of gray matter nuclei located deep beneath the cerebral cortex in the white matter, consists of four nuclei with interconnecting pathways. Most information comes into the striatum of the basal ganglia from the cortex. If that information synapses on medium spiny neurons in the matrix, neural projections travel through the direct and indirect pathways for the purpose of facilitating or inhibiting motor programs respectively. At the output nuclei, the GPi and SNr, inhibitory projections travel to the thalamus. The direct pathway inhibits this inhibition, allowing for movement, whereas the indirect pathway elicits this inhibition, preventing unintended movement. If information coming into the striatum synapses on medium spiny neurons in the striosome, this information travels back to the SNc to regulate the release of dopamine, the neurotransmitter which promotes the facilitation of movement by facilitating the facilitation of the direct pathway, and inhibiting the inhibition of the indirect pathway. There are four channels running through the basal ganglia, the motor, oculomotor, prefrontal, and limbic, which regulate motor control, eye movement, cognitive processing, and emotion and motivational drive respectively. Recent studies have found that there is neuroplasticity (the ability of the workings of the brain to change through one’s lifetime) of the basal ganglia which respond to reward or consequence of behavior. Overall, the basal ganglia plays a large role in the regulation of the body’s motor system, allowing an individual to conduct appropriate and wanted movements while simultaneously inhibiting unwanted and inappropriate movements.


Glossary of Terms

Aspiny neuron - Found in the striatum and project to the SNc.

Caudate - Input nuclei; one of the nuclei of the striatum. Most information that is not part of the motor channel synapses here.

Cholinergic interneuron - Found in the striatum and release acetylcholine as their neurotransmitter, acting as the primary neuron responsible for tonic activity.

Dopamine - Excitatory or inhibitory neurotransmitter utilized by neural projections from the SNc to the striatum; binds to D1 receptors in the direct pathway and is excitatory; binds to D2 receptors in the indirect pathway and is inhibitory. In either pathway this neurotransmitter codes for the facilitation of movement.

Enkephalin - Inhibitory neurotransmitter used by the striatum for the indirect pathway.

GABA - Inhibitory neurotransmitter used by the striatum, the GPe, and the output nuclei (GPi/SNr).

Globus pallidus external segment (GPe) - Indirect pathway nuclei utilizing GABA as its neurotransmitter.

Globus pallidus internal segment (GPi) - Output nuclei utilizing GABA as its neurotransmitter.

Glutamate - Excitatory neurogransmitter used by the cortex, STN and the thalamus.

Matrix - One of two complementary compartments of the striatum; neurons here project to the direct and indirect pathways.

Medium spiny neuron - Found in the striatum and project to the direct and indirect pathways.

Output nuclei - SNr and GPi. Sends excitatory glutaminergic information to the thalamus.


Putamen - Input nuclei; one of the nuclei of the striatum. Most motor channel information synapses here.

Saccade - Rapid, ballistic eye movement to allow fixation on a new area in the environment.

Striatum - The input area of the basal ganglia made up of both the putamen and the caudate nuclei.

Striosome - One of two complementary compartments of the striatum; neurons in this area project back to the SNc to regulate the release of the neurotransmitter dopamine to the striatum.

Substance P - Inhibitory neurotransmitter used by the striatum for the direct pathway.

Substantia nigra pars compacta (SNc) - Has projections to the striatum which release the neurotransmitter dopamine as its synaptic terminals.

Substantia nigra pars reticulata (SNr) - Output nuclei sending projections to the thalamus using glutamate as its neurotransmitter.

Subthalamic nucleus (STN) - Indirect pathway nuclei utilizing glutamate as its neurotransmitter.


Relevant Links

The basal ganglia’s role in saccades:

http://kin450-neurophysiology.wikispaces.com/Saccades+I

Role of the indirect pathway of the basal ganglia in perceptual decision making:

http://www.jneurosci.org/content/jneuro/35/9/4052.full.pdf

A direct GABAergic output from the basal ganglia to the frontal cortex:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425585/


Quiz
True/False

1. The direct pathway travels through the GPe, whereas the indirect pathway travels through the GPi.

2. The striatum is comprised of two areas of input: the striosome and the matrix, with the matrix projecting through the direct and indirect pathways, and the striosome projecting to the SNc.

3. Aspiny neurons are found in the output nuclei, and medium spiny neurons are found in the striatum.

4. D1 receptors are part of the indirect pathway, with dopamine being excitatory to them; D2 receptors are part of the direct pathway, with dopamine being inhibitory at their synapse.

5. Most input to the basal ganglia comes from the thalamus.


Multiple Choice

6. Which channel follows this pathway: Posterior parietal cortex à caudate head à SNr à VA, MD à Prefrontal cortex

a. Motor channel

b. Oculomotor channel

c. Prefrontal channel

d. Limbic channel

7. Which is the correct sequence of the direct pathway?

a. Cortex, striatum, GPi, STN, thalamus

b. Cortex, GPe, STN, output nuclei, thalamus

c. Thalamus, striatum, output nuclei, thalamus

d. Cortex, striatum, output nuclei, thalamus, cortex

8. The basal ganglia is located:

a. In the cerebral cortex

b. Deep beneath the cerebral cortex

c. Above the cerebellum

d. In the brainstem


Short answer

9. Describe the indirect and indirect pathways and how they facilitate or inhibit movement.

10. Describe the effect of dopamine on the indirect and direct pathways.


Essay

11. Describe what you know about the input and output of the basal ganglia.


References
Text

1. Blumenfeld, H. (2014). Neuroanatomy through clinical cases. Sunderland, MA: Sinauer Associates, Inc.

2. Coppen, E. M., Jacobs, M., Berg-Huysmans, A. A., Grond, J. V., & Roos, R. A. (2017). Grey matter volume loss is associated with specific clinical motor signs in Huntingtons disease. Parkinsonism & Related Disorders. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29128164

3. Giovannini, M. G., Rakovska, A., Benton, R. S., Pazzagli, M., Bianchi, L., & Pepeu, G. (2001). Effects of novelty and habituation on acetylcholine, GABA, and glutamate release from the frontal cortex and hippocampus of freely moving rats. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11564415

4. Kandel, E. R., Mack, S. (2014). Principles of neural science. New York, NY: McGraw-Hill Medical.

5. Knierim, J. (n.d). Basal Ganglia. Neuroscience Online. Retrieved from http://nba.uth.tmc.edu/neuroscience/s3/chapter04.html

6. Porrino, L. J., Lyons, D., Smith, H. R., Daunais, J. B., Nadar, M. A. (2004, April 7). Cocaine self-administration produces a progressive involvement of limbic, association, and sensorimotor striatal domains. Journal of neuroscience. Retrieved from http://www.jneurosci.org/content/jneuro/35/9/4052.full.pdf

7. Saunders, A., Oldenburg, I. A., Berezovskii, V. K., Johnson, C. A., Kingery, N. D., Elliott, H. L., . . . Sabatini, B. L. (2015, May 07). A direct GABAergic output from the basal ganglia to frontal cortex. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425585/

8. Wei, W., Rubin, J. E., Xiao-Jing, W., (2015, March 4). Role of the indirect pathway of the basal ganglia in perceptual decision making. J. Neuroscience. 35(9):4052-4064. Retrieved from http://www.jneurosci.org/content/jneuro/35/9/4052.full.pdf

9. Yin, H. H., Knowlton, B. J. (2006 June). The role of the basal ganglia in habit formation. Nature. Neuroscience. Retrieved from

http://www.readcube.com/articles/10.1038/nrn1919?no_publisher_access=1&r3_referer=nature&referrer_host=www.nature.com


Images

1. http://images.huffingtonpost.com/2016-06-15-1466024574-2426318-KatBGImage.jpg

2. http://aibolita.com/nervous-diseases/32-basal-ganglia-system.html

3. http://science-naturalphenomena.blogspot.com/2009/05/basal-ganglia.html

4. http://missinglink.ucsf.edu/lm/ids_104_neurodegenerative/case2/BGPop.htm

5. http://neurology.mhmedical.com/Content.aspx?bookId=1049&sectionId=59138673

6. http://www.cell.com/trends/neurosciences/fulltext/S0166-2236(10)00105-0

7. http://nba.uth.tmc.edu/neuroscience/s3/chapter04.html


Quiz answers

1. F

2. T

3. T

4. F

5. F

6. C

7. D

8. B

9. Direct: Cortex à(E) Striatum à(I) Output nuclei à(I) Thalamus à(E) Cortex

Indirect: Cortex à(E) Striatum à(I) GPe à(I) STN à(E) Output nuclei à(I) Thalamus à(E) Cortex

10. Dopamine is excitatory on the direct pathway to facilitate the facilitation, and inhibitory to the indirect pathway to inhibit inhibition (both facilitating movement).