SUBSTANCE NIGRA: FUNCTIONS, ANATOMY AND DISEASES - NEUROPSYCHOLOGY - 2025

The substantia nigra is a heterogeneous portion of the midbrain, a specific region of the brain. Likewise, it is an important element of the basal ganglia system. It constitutes a dorsal portion of the brain characterized by having neurons that contain neuromelanin, a dark pigment specific to the brain.

The name substantia nigra refers to the appearance of neurons in specific regions of the midbrain. These have a dark color, very similar to black.

In terms of its functions, the substantia nigra is made up of dopaminergic and GABAergic neurons, and plays an important role in the control of motor activities.

Anatomy of the substantia nigra

MRI, horizontal section. The black substance is highlighted in red.

The substantia nigra is a region of the brain that lies dorsal to the cerebral peduncles and extends face-to-head along the midbrain.

The first studies on this particular substance were carried out by Mingazzini in 1888 and by Sano in 1919. Since then, it has been concluded that the black substance is divided into two macroscopic portions.

The first one, known as the dorsal portion, is characterized by being a very rich substance in neurons with neuromelanin. The color of this pigment makes the cells in that region appear darker than normal.

The other portion of the substantia nigra is located in the most ventral region, where the most voluminous substantia nigra structure is found. It has a flattened ovoid shape and is characterized by being poorer in cells.

Finally, some authors defend the existence of a lateral portion of substantia nigra. However, at present this portion is considered part of the ventral portion of the substance.

On the other hand, the two portions of substantia nigra can also be easily differentiated through the type of neurotransmitters they include. While neurons in the dorsal portion contain high concentrations of dopamine, neurons in the ventral portion are richer in GABA.

Features

Location of the substantia nigra marked in red

The functions of the substantia nigra are certainly controversial today. What activities these brain regions perform or what specific functions they perform has not yet been fully examined.

However, the data obtained about its activity suggest that the substantia nigra could be involved in four main processes: learning, motor planning, eye movement and the search for reward.

Learning

The association between learning and substantia nigra lies in the relationship that this structure presents with Parkinson's disease. Today it is well established that alterations in the neurons of the substantia nigra are a sign of degenerative pathology.

Photomicrograph of the substantia nigra in a Parkinson's patient showing loss of dopaminergic cells, as well as Lewy body and Lewy neurite pathology. Source: Suraj Rajan

In this sense, the amnesic alterations that many subjects with Parkinson's present motivated the beginning of the study of the role of the substantia nigra in learning.

Specifically, a team of researchers from the University of Pennsylvania demonstrated that the stimulation of dopaminergic neurons in the substantia nigra can alter the learning process.

The study was carried out in a group of subjects who followed a treatment against Parkinson's disease through deep stimulation, connoting how the intervention improved the associative learning of the participants.

Reward hunt

In the same previous research, it was shown how the stimulation of dopaminergic neurons in the substantia nigra provided rewarding sensations in individuals.

For this reason, it is argued that this brain structure could be closely related to both reward seeking and addiction.

Motor planning

The role of the substantia nigra in motor planning is one of the most well studied and documented functions.

Many studies show how the neurons of the substantia nigra play a vital role in the development of body movements, a fact that is widely reflected in the parkinsonian symptoms caused by their degeneration.

Eye movement

Finally, it has also been shown how the neurons of the substantia nigra intervene in the processes of eye movements. This function appears to be performed mainly by the reticulated black substance.

Neurons of the substantia nigra

Three main types of neurons have been described in the nervous system. These differ mainly by their size and location.

The first type of neurons are large cells, they are found in the ventral region of the substantia nigra and refer to the region known as the reticular substantia nigra.

The second type of neurons are somewhat smaller cells that are classified as "medium neurons." These are found in the dorsal region of the substantia nigra and refer to the compact substantia nigra.

Finally, the third type of neurons are small cells found in the two portions of the substantia nigra, the dorsal and the ventral. That is, both the reticulated substantia nigra and the compact substantia nigra contain small neurons.

Dopamine neurons

Dopamine neurons are very abundant in the compact substantia nigra (dorsal region), however, they can be located in different regions of the midbrain, including the ventral region (reticulated substantia nigra).

Dopamine neurons are distinguished by histofluorescence and immunhistochemical techniques, as well as through Nissl staining, since these types of neurons have high masses of Nissl substance.

Dopaminergic neurons have a median neuronal body, which is located in the compact substantia nigra. It presents several main dendritic processes, usually between 3 and 6 processes that can bifurcate up to 4 times.

One or two dendrites from these neurons enter the reticular substance nigra. The axon of dopaminergic cells originates from one of the main dendrites and is not myelinated.

The axon does not emit collaterals within the substantia nigra, and runs through the lateral hypothalamus, until reaching the striated regions. The other dendrites of the neuron branch within the compact substantia nigra.

In addition, dopamine neurons have a small portion of small, star-shaped "non-dopaminergic" neurons whose dendrites do not exceed nuclear limits.

Types of substantia nigra

Coronal sections of the human brain that mark the basal ganglia. Blue = striatum, green = pale globe (outer and inner segments), yellow = subthalamic nucleus, red = black substance (pars reticulata and pars compacta). The right section is the deepest, closest to the brain stem. Source: Andrew Gillies (User: Anaru)

Substance nigra differs from white matter and gray matter by its appearance, location, structure, and function. However, within the substantia nigra two specific regions can also be distinguished.

This differentiation responds mainly to the types of neurons that the substantia nigra includes. In some regions a certain cell type predominates and in others different neurons are connoted.

Likewise, the two regions of the substantia nigra are associated with different functions, as well as with different types of pathologies.

The two parts of the black substance are the compact part and the reticulated part. The compact part includes adjacent dopamine groups, and the reticulated part also involves the lateral portion of the substantia nigra.

Compact black substance

The compact part of the substantia nigra is characterized by black neurons, stained through the neuromelanin pigment. This pigment increases with age, so that the neurons in this region darken over the years.

This portion of the substantia nigra can be divided between the ventral floor and the dorsal floor. Neurons in the compact part receive inhibitory signals from the collateral axons of neurons in the reticulated part of the substantia nigra.

The dopaminergic cells of this region also innervate other structures of the basal ganglia system such as the medial pallidum, the reticulated part of the substantia nigra, and the subthalamic nucleus.

Its activity is mainly associated with learning processes. However, the functioning of this region is complex and is little studied at present.

Some studies suggest that the degeneration of the pigmented neurons of the substantia nigra compact constitutes the main sign of Parkinson's disease, which is why it is suggested that this region is involved in the development of the pathology.

With regard to electrophysiological studies, several authors point out that neurons in this region are characterized by having triphasic waveform action potentials, with the first positive phase, and with a mean duration greater than 2.5 milliseconds.

Cross-linked black substance

The reticulated substantia nigra differs from the compact substantia nigra by the density of neurons, which is much lower. In fact, it is a somewhat diffuse region and the dendrites of the neurons are preferably perpendicular to the striated afferents.

It is made up of a heterogeneous population of GABAergic neurons, mostly large and medium-sized projection neurons, as well as small star-shaped interneurons.

The low neuronal density of the reticular substance nigra is anatomically very similar to that of the globus pallidus and the entopeduncular nucleus. In fact, due to its cytology, connections, neurochemistry and physiology, the reticular substantia nigra can be considered as an extension of these brain structures.

Medium neurons have a variably shaped neuronal body. It can be triangular, spindle-shaped, ovoid or polygonal, usually containing between 3 and 5 primary dendrites that originate in the neuronal body.

The major dendrites of the reticular substantia nigra form at the poles of spindle neurons, dividing dichotomously at a short distance from the body. Tertiary dendrites usually appear at a great distance, close to the terminal dendrites.

The axons of neurons are milienized and originate in the body or the primary dendrites of the cell. Most of them end in the reticular substantia nigra or in the compact substantia nigra.

Regarding its functions, the reticulated black substance seems to be associated with orientation and oculomotion processes. Likewise, this brain structure has been linked to Parkinson's disease and epilepsy.

References

1. Beckestead, RM; Domesick, VB and Nauta, WJH (1979) Efferent connections of the substantia nigra and ventral tegmental area in the rat. Brain Res. 175: 191-217.
2. Castellano, MA and Rodríguez, M. (1991) nigrostriatal dopaminergic cell activity is under control by substantia nigra of the contralateral brain side: electrophysiological evidence. Brain res. Bull. 27: 213-218.
3. From LONG, MR; CRUTCHER, MD and GEORGOPOULOS, AP (1983) Relations between movement and single cell discharge in the substancia nigra of the substantia nigra of the behaving monkey. J. Neurosc. 3: 1599-1606.
4. Hikosaka, O; Wurtz, RH (1983). »Visual and oculomotor functions of monkey substantia nigra pars reticulata. III. Memory-contingent visual and saccade responses ». Journal of Neurophysiology. 49 (5): 1268–84.