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RUNNING HEAD: THE NIGROSTRIATAL PATHWAY

The Nigrostriatal Pathway

Elainna Simpson

Loras College
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The Nigrostriatal Pathway

Introduction

        The nigrostriatal pathway is one of the four major dopaminergic pathways of the brain. It

is the connection of the substantia nigra pars compacta within the midbrain to the caudate

nucleus and putamen of the striatum via the projection of dopaminergic neurons. This

dopaminergic neurotransmission allows for action of movement or inhibition of movement and

to ensure the correct movement is being initiated. Reward and reinforcement of memory

consolidation are also small behavioral aspects of the nigrostriatal pathway (Wise, 2009). The

most well-known disorder that has aberrant activity within the nigrostriatal pathway is

Parkinson’s which is characterized by rigidity, shaking, and bradykinesia (slowness of

movement). These symptoms occur when about 50% of the dopamine neurons that project from

the substantia nigra to the striatum are lost (Caminiti et al., 2017). There are approximately

60,000 Americans who are diagnosed with Parkinson’s disorder each year and since its

neurodegenerative its likelihood increases with age. It is also more likely to occur in men than in

women (“Statistics,” 2017). Parkinson’s affects many worldwide and a better understanding of

its neuroanatomical deficits is an important way to create treatments as well as a better

understanding of its progression.

Structure

        The Nigrostriatal pathway is the connector between the substantia nigra pars compacta

and the dorsal striatum (See Figure 1). The substantia nigra is located in the midbrain and is

divided into two main sections: pars compacta and pars reticulata. The pars compacta, more

dorsal, sends dopamine to the striatum and is the main output to the basal ganglia circuit. Where
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the pars reticulata, more ventral, is the main input and can send signals from the basal ganglia to

other brain (“Basal Ganglia (Section 3, Chapter 4)”) structures such as the thalamus (Nolte). The

substantia nigra is ventral to the red nucleus but dorsal to the midbrain peduncles and is

separated in the brainstem by the interpeduncular nucleus. The substantia nigra pars compacta

sends dopamine to the striatum in a very topographic manner. The dopamine distribution within

the striatum is massive and when used fluorescence makes the entire striatum glow (See Figure

2). The dorsal striatum consists of the caudate nucleus and the putamen and the striations that are

made between the two. The striatum is the largest part of the basal ganglia which is involved

primarily in motor control. Separating the caudate from the putamen is the internal capsule, a

white matter nerve tract, and this creates the striations of grey matter and white matter

(Avgevine, J. B. & Cotman, C. W. 1981). The putamen receives motor and somatosensory areas

of the cortex through the globus pallidus. The putamen is most likely the most central for most

motor functioning of the basal ganglia. Where the caudate is more involved in inputs from

association areas of the cortex but also uses the globus pallidus and the thalamus to send

projections to most often the prefrontal cortex. Neurons within the caudate do not seem to

respond to movements of positions but rather are more involved in cognitive functioning (Nolte).

The ventral striatum which consists of the nucleus accumbens and the olfactory tubule is

involved in reward processing. The flow of information of these structures as a whole it that all

parts of the cortex send projections to the striatum which is also receiving dopamine projections

from the substantia nigra pars compacta. The striatum is then sending projections to the globus

pallidus or the substantia nigra pars reticulata. These structures also communicate with the

intraluminal thalamic nuclei which will send information back to the striatum. The globus

pallidus and substantia nigra then uses GABA to communicate to the sub thalamic nuclei to
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inhibit motor functioning which will send GABA signaling back again. The globus pallidus and

substantia nigra pars compacta also can project to the ventral anterior nucleus of the thalamus

which will send information to the premotor area of the cortex where the movement can then be

planned. The nigrostriatal pathway of dopamine to the striatum from the substantia nigra then

plays an important role on motor functioning as well as can affect this loop of information which

can cause the motor symptoms of Parkinson’s disorder.

        It is also important to know that the striatum splits into two pathways: the direct pathway

and the indirect pathway.The normal function of these two pathways is to work in balance and

when there is a lack of dopamine it causes favor to the indirect pathway which then causes the

motor symptoms of Parkinson’s (“Basal Ganglia (Section 3, Chapter 4)”; FitzGerald M. J. T.,

1996).

        The cells of the nigrostriatal pathway are dopaminergic and then synapse on GABAergic

neurons. Dopamine neurons can be multipolar and have axons that project distance (such as that

of the nigrostriatal pathway) and others that are small cells without axons and dendrites that are

involved in small circuits (retinal). About 99% of dopamine projections have specific target areas

and have an ordered topography and often progress unilaterally (Avgevine, J. B. & Cotman, C.

W. 1981).  The major cell type in the striatum are called spiny projection neurons which make up

about 95% of striatal neurons and the other 5% are interneurons. The spiny projection neurons

tend to normalize striatal functioning and half express D1 dopamine receptors that project mostly

to the substantia nigra pars reticulata and the entopeduncular nucleus to create a feedback loop

with the striatum. The other half of the spiny projection neurons express D2 receptors which

project predominantly to the globus pallidus. These spiny neurons are the principal target of the

dopaminergic afferents of the midbrain, mostly from the substantia nigra but also the ventral
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tegmental area (Kaminer et al., 2019; Tepper & Plenz.; Zhai, Shen, Graves, & Surmeier, 2019).

The interneurons of the striatum are usually subdivided by their neurotransmitter such as GABA

and Ach; they have control striatal functioning and influence behaviors but have dopamine

receptors (Zhai et al., 2019). One type of the interneurons within the striatum are tyrosine-

hydroxylase interneurons (THINs) which are not dopaminergic but they do respond to dopamine.

Zhai, Shen, Graves, Surmeier (2019) studied the importance of THINs in a study where they

lesioned mice and looked at the behavioral changes that were a result. They found that THINs

are important in goal-directed behavior which may also effect Parkinson’s symptoms (Kaminer

et al., 2019). All of these cells have a specific role within the nigrostriatal pathway and the motor

functions of it.

Function

        The most frequent example of function of the nigrostriatal pathway is its importance in

both action of movement but also inhibition of movement. Parkinson’s disorder is the main

disorder with dysfunction in the nigrostriatal pathway and the symptoms of it can be dependent

on onset and severity. The hallmark symptoms of Parkinson’s disease is tremor, rigidity, and

bradykinesia. It is a resting tremor where hands are involved in a “pill-rolling” movement that

diminishes during any voluntary movement but increases during emotional stress. Often patients

will have increased muscle tone and experience rigidity but no issues with strength or reflexes.

There are common movements of the uniform rigidity of Parkinson’s. “Plastic” or “led-pipe”

rigidity can be interrupted by brief relaxations (“cog-wheel rigidity”). The rigidity is due to the

lack of dopamine within the substantia nigra. This rigidity is very different from spasticity seen

in other motor disorders where there is increased muscle tone specifically in the flexors of the
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arm which can cause “clasp-knife” reaction. Bradykinesia is slowed movements which can be

seen in increased eye-blinking, an expressionless face, abnormal stillness and absence of arm

movements when walking (Nolte). Another neuropathological aspect of Parkinson’s is that the

surviving substantia nigra pars compacta neurons create inclusions called Lewy bodies which are

mainly composed of a-synuclein. These inclusions help to cause the motor symptoms of

Parkinson's. A decrease in dopamine can happen through natural aging and where the striatal

neurotransmitters can cause slow or irregular movements, this also seen in animals when they

age.

A region of interest PET scan was used to examine differences between controls and

Parkinson’s patients (See figure 3). The levels of dopamine were analyzed and indicated that

those with Parkinson’s had a decrease in dopamine connectivity of the nigrostriatal pathway

(substantia nigra to dorsal putamen) which supports derangement in the pathway.

Neurodegeneration of dopamine pathways is originally more distinguishable in afferent axons

and more critical within the nigrostriatal pathway. This could lead to a possible research on

neuroprotective interventions for Parkinson’s disease (Caminiti et al., 2017). Chronic disruption

of the dopamine levels in Parkinson’s can cause cell-type specific changes to homeostasis within

the spiny projection neurons. Yet disruptions in dopamine signaling can cause deviations in

synaptic plasticity with can lead to Parkinson’s symptoms. Altered dopamine signaling can cause

more issues in the direct and indirect pathways but also neuronal activity as a whole (Zhai et al.,

2019).

Another study that analyzed PET imaging in brains of Parkinson’s patients using striatal

dopamine transporter (DAT) availability (11c-altropane DVR), this was found to be lower in

patients with nigrostriatal dopamine loss compared to age matched controls. An fMRI was used
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to analyze the putamen-midbrain fMRI functional connectivity. It was found to be proportional

to DAT loss in patients (SeeFigure 2). (Rieckmann, Gomperts, Johnson, Growdon, & Van Dijk,

2015). One attempt to treat Parkinson’s in its early stages is through dopamine replacement

therapy called levodopa but as the disease progresses more is needed which causes a maladaptive

change that causes hyperkinetic movements, levodopa-induced dyskinesia (Zhai et al., 2019).

Levodopa is the main drug used within Parkinson’s patients and can be very helpful during the

early stages but as this study demonstrates the effects can “wear off” overtime which is why

other potions need to be evaluated.

Parkinson's’ disorder has also been widely researched through animal studies. One way to

do this is to use a pharmacological model called rotenone. Ureshino et al. (2018) Analyzed

whether this is an accurate method to use when studying Parkinson’s concluding that it was a

accurate method especially when analyzing age related differences in Parkinson’s disorder.

Another way to analyze Parkinson-like symptoms is to inject lactacystin to the substantia nigra in

order to create a nigrostriatal lesion which then cause motor related behaviors. Rodents with this

lesion showed impaired contralateral forelimb grip strength and increased contralateral circling

in response to apomorphine, a dopaminergic agonist. MRIs were able to identify overall

reduction in brain volume, deformation of ipsilateral ventral midbrain, shrinkage in the ipsilateral

striatum and hypertrophy of lateral ventricles. All of these correspond for idiopathic Parkinson’s

disease (Vernon, Johansson, & Modo, 2010). This could create a way to study idiopathic

Parkinson’s and create more treatment options.

The presence of a-synuclein that is often found in abnormal clusters called Lewy bodies

and the loss of dopamine neurons are both characteristic of Parkinson’s disease. Abeliovich et al.

(2000) made comparisons of wild type mice compared to a-synuclein -/- mice. There was no
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apparent morphological differences but a-synuclein -/- mice has significant neurochemical,

electrophysiological, and behavioral deficits. They also exhibited a lower total striatal dopamine

levels and reduced locomotor response. This shows that a-synuclein is a vital, activity dependent

negative regulator of dopamine transmission (See figure 4).

Conclusion

The nigrostriatal pathway is incredibly important to our activation of wanted movement

and the inhibition of unwanted movement. The relationship between the substantia nigra and the

striatum is well-known but there is still more to learn about the neuroanatomy and

neuropathology of the pathway. Parkinson’s is a mass effecting disorder that can progress to

inability to walk or talk. It is extremely important for research within this area to create a long

lasting treatment for those who suffer from it. The levodopa is a treatment that has shown

substantial progress in early onset but perhaps more research can lead to the development of a

version of it that can create lasting treatment to Parkinson’s patients. There is a new theory being

studied about alpha-synuclein causes the immune system to attack the brain which could end in

Parkinson’s disorder (“Groundbreaking Parkinson’s research at La Jolla Institute funded by

Michael J. Fox Foundation | La Jolla Institute for Immunology,” ). More research on a-synuclein

is important for understanding its role and then trying to apply therapies that help to alleviate the

dysfunction. It would be interesting to look more at the gene level and see what else could be

contributing to the loss of dopamine. Overall there is general understanding of the nigrostriatal

pathway and the effects of aberrant activity within it.

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References
Abeliovich, A., Schmitz, Y., Fariñas, I., Choi-Lundberg, D., Ho, W. H., Castillo, P. E., …
Rosenthal, A. (2000). Mice lacking alpha-synuclein display functional deficits in the nigrostriatal
dopamine system. Neuron, 25(1), 239–252.
Angevine, J. B. & Cotman, C.W. (1981). Principles of Neuroanatomy. Oxford University Press.
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Basal Ganglia (Section 3, Chapter 4) Neuroscience Online: An Electronic Textbook for the
Neurosciences | Department of Neurobiology and Anatomy - The University of Texas Medical
School at Houston. (n.d.). Retrieved May 6, 2019, from
https://nba.uth.tmc.edu/neuroscience/m/s3/chapter04.html
Caminiti, S. P., Presotto, L., Baroncini, D., Garibotto, V., Moresco, R. M., Gianolli, L., …
Perani, D. (2017). Axonal damage and loss of connectivity in nigrostriatal and mesolimbic
dopamine pathways in early Parkinson’s disease. NeuroImage. Clinical, 14, 734–740.
https://doi.org/10.1016/j.nicl.2017.03.011
FitzGerald, M. J. T. (1996). Neuroanatomy: Basic and Clinical. W. B. Saunders Company.
Groundbreaking Parkinson’s research at La Jolla Institute funded by Michael J. Fox Foundation |
La Jolla Institute for Immunology. (n.d.). Retrieved May 6, 2019, from https://www.lji.org/news-
events/news/post/groundbreaking-parkinsons-research-at-la-jolla-institute-funded-by-michael-j-
fox-foundation/
Kaminer, J., Espinoza, D., Bhimani, S., Tepper, J. M., Koos, T., & Shiflett, M. W. (2019). Loss
of striatal tyrosine-hydroxylase interneurons impairs instrumental goal-directed behavior. The
European Journal of Neuroscience. https://doi.org/10.1111/ejn.14412
Nolte.
Rieckmann, A., Gomperts, S. N., Johnson, K. A., Growdon, J. H., & Van Dijk, K. R. A. (2015).
Putamen–midbrain functional connectivity is related to striatal dopamine transporter availability
in patients with Lewy body diseases. NeuroImage: Clinical, 8, 554–559.
https://doi.org/10.1016/j.nicl.2015.06.001
Tepper, J. M., & Plenz, D. (n.d.). MICROCIRCUITS IN THE STRIATUM STRIATAL CELL
TYPES AND THEIR INTERACTION. The MIT Press, 12.
Ureshino, R. P., Costa, A. J., Erustes, A. G., Pereira, G. J. da S., Sinigaglia-Coimbra, R., &
Smaili, S. S. (2018). Effects of Aging in the Striatum and Substantia Nigra of a Parkinson’s
Disease Animal Model. Toxicologic Pathology, 46(3), 348–358.
https://doi.org/10.1177/0192623318767065
Vernon, A. C., Johansson, S. M., & Modo, M. M. (2010). Non-invasive evaluation of
nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson’s disease.
BMC Neuroscience, 11(1), 1. https://doi.org/10.1186/1471-2202-11-1
Zhai, S., Shen, W., Graves, S. M., & Surmeier, D. J. (2019). Dopaminergic modulation of striatal
function and Parkinson’s disease. Journal of Neural Transmission (Vienna, Austria: 1996),
126(4), 411–422. https://doi.org/10.1007/s00702-019-01997-y
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Figure 1: The location of the important structures of the

Nigrostriatal pathway.
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Figure 2: Demonstrates the different imaging of dopamine. Also shows the relationship between

striatal dopamine transporter availability and midbrain-putamen functional connectivity. Proves

that an fMRI is a useful biomarker in dopamine loss.

Figure 3:
Region of
interest MRIs
from Camaniti
et. al
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Figure 4: Morphology of the Nigrostriatal Pathway in

wt and α-Syn−/− Mice (Abeliovich et al., 2000)
(A) In situ hybridization of coronal brain sections
with a probe for TH, the rate-limiting enzyme in DA
synthesis.
(B–E) Staining of coronal sections through the SN
(B) and the striatum (C–E) with antibodies for TH (B
and C), neuropeptide Y (D), or calbindin (E). No
deficits or abnormalities in neuronal number,
morphology, or innervation pattern are observed in
the α-Syn−/− mice.
Abbreviations: patch, striatal matrix patch, and neu,
neuron. Scale bar, 1 mm (A); 104 μm (B); 44 μm
(C); 147 μm (D); and 139 μm (E)