The substantia nigra is a brain structure located in the midbrain that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for “black substance”, reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons. It was discovered in 1784 by Félix Vicq-d’Azyr, and named after Samuel Thomas von Sömmerring alluded to this structure in 1791. Parkinson’s disease is characterized by the death of dopaminergic neurons in the substantia nigra pars compacta.
Although the substantia nigra appears as a continuous band in brain sections, anatomical studies have found that it actually consists of two parts with very different connections and functions: the pars compacta and pars reticulata. The pars compacta serves mainly as an input to the basal ganglia circuit, supplying the striatum with dopamine. The pars reticulata, on the other hand, serves mainly as an output, conveying signals from the basal ganglia to numerous other brain structures.
The substantia nigra, along with four other nuclei, is part of the basal ganglia. It is the largest nucleus in the midbrain, lying dorsal to the cerebral peduncles. Humans have two substantiae nigrae, one on each side of the midline.
The substantia nigra is divided into two parts: the pars reticulata and pars compacta, which lies medial to the pars reticulata. Sometimes a third region, the pars lateralis, is mentioned, though it is usually classified as part of the pars reticulata. The pars reticulata and the internal globus pallidus are separated by the internal capsule.
The pars reticulata bears a strong structural and functional resemblance to the internal part of the globus pallidus. The two are sometimes considered parts of the same structure, separated by the white matter of the internal capsule. Like those of the globus pallidus, the neurons in pars reticulata are mainly GABAergic.
The main input to the pars reticulata derives from the striatum. It comes by two routes, known as the direct and indirect pathways. The direct pathway consists of axons from medium spiny cells in the striatum that project directly to pars reticulata. The indirect pathway consists of three links: a projection from striatal medium spiny cells to the external part of the globus pallidus; a GABAergic projection from the globus pallidus to the subthalamic nucleus, and a glutamatergic projection from the subthalamic nucleus to the pars reticulata.
Thus, striatal activity via the direct pathway exerts an inhibitory effect on neurons in the pars reticulata but an excitatory effect via the indirect pathway. The direct and indirect pathways originate from different subsets of striatal medium spiny cells: They are tightly intermingled but express different types of dopamine receptors, as well as showing other neurochemical differences.
There are significant projections to the thalamus (ventral lateral and ventral anterior nuclei), superior colliculus, and other caudal nuclei from the pars reticulata (the nigrothalamic pathway), which use GABA as their neurotransmitter. In addition, these neurons form up to five collaterals that branch within both the pars compacta and pars reticulata, likely modulating dopaminergic activity in the pars compacta.
The substantia nigra is an important player in brain function, in particular, in eye movement, motor planning, reward-seeking, learning, and addiction. Many of the substantia nigra’s effects are mediated through the striatum. The nigral dopaminergic input to the striatum via the nigrostriatal pathway is intimately linked with the striatum’s function.
The co-dependence between the striatum and substantia nigra can be seen in this way: when the substantia nigra is electrically stimulated, no movement occurs; however, the symptoms of nigral degeneration due to Parkinson’s is a poignant example of the substantia nigra’s influence on movement. In addition to striatum-mediated functions, the substantia nigra also serves as a major source of GABAergic inhibition to various brain targets.
The pars reticulata of the substantia nigra is an important processing center in the basal ganglia. The GABAergic neurons in the pars reticulata convey the final processed signals of the basal ganglia to the thalamus and superior colliculus. In addition, the pars reticulata also inhibits dopaminergic activity in the pars compacta via axon collaterals, although the functional organization of these connections remains unclear.
The GABAergic neurons of the pars reticulata spontaneously fire action potentials. In rats, the frequency of action potentials is roughly 25 Hz. The purpose of these spontaneous action potentials is to inhibit targets of the basal ganglia, and decreases in inhibition are associated with movement.
The subthalamic nucleus gives excitatory input that modulates the rate of firing of these spontaneous action potentials. However, lesion of the subthalamic nucleus leads to only a 20% decrease in pars reticulata firing rate, suggesting that the generation of action potentials in the pars reticulata is largely autonomous, as exemplified by the pars reticulata’s role in saccadic eye movement.
A group of GABAergic neurons from the pars reticulata projects to the superior colliculus, exhibiting a high level of sustained inhibitory activity. Projections from the caudate nucleus to the superior colliculus also modulate saccadic eye movement. Altered patterns of pars reticulata firing such as single-spike or burst firing are found in Parkinson’s disease and epilepsy.
The most prominent function of the pars compacta is motor control, though the substantia nigra’s role in motor control is indirect; electrical stimulation of the substantia nigra does not result in movement, due to mediation of the striatum in the nigral influence of movement. However, lack of pars compacta neurons has a large influence on movement, as evidenced by the symptoms of Parkinson’s. The motor role of the pars compacta may involve fine motor control, as has been confirmed in animal models with lesions in that region.
The pars compacta is heavily involved in learned responses to stimuli. In primates, dopaminergic neuron activity increases in the nigrostriatal pathway when a new stimulus is presented. Dopaminergic activity decreases with repeated stimulus presentation.
However, behaviorally significant stimulus presentation (such as classical conditioning, where a reward is presented) continues to activate the dopaminergic neurons, which has been used to explain the addictiveness of drugs. The pars compacta is also important in spatial learning, the observations about one’s environment and location in space.
Lesions in the pars compacta lead to learning deficits in repeating identical movements, and some studies point to its involvement in a dorsal striatal-dependent, response-based memory system that functions relatively independent of the hippocampus, which is traditionally believed to subserve spatial or episodic-like memory functions.
The pars compacta also plays a role in temporal processing and is activated during time reproduction. Lesions in the pars compacta leads to temporal deficits. As of late, the pars compacta has been suspected of regulating the sleep-wake cycle, which is consistent with symptoms such as insomnia and REM sleep disturbances that are reported by patients with Parkinson’s disease. Even so, partial dopamine deficits that do not affect motor control can lead to disturbances in the sleep-wake cycle, especially REM-like patterns of neural activity while awake, especially in the hippocampus.
Chemical Modification of the Substantia Nigra
Chemical manipulation and modification of the substantia nigra is important in the fields of neuropharmacology and toxicology. Various compounds such as levodopa and MPTP are used in the treatment and study of Parkinson’s disease, and many other drugs have effects on the substantia nigra.
Amphetamine and Trace Amines
Studies have shown that, in certain brain regions, amphetamine and trace amines increase the concentrations of dopamine in the synaptic cleft, thereby heightening the response of the post-synaptic neuron. The various mechanisms by which amphetamine and trace amines affect dopamine concentrations have been studied extensively, and are known to involve both DAT and VMAT2.
Amphetamine is similar in structure to dopamine and trace amines; as a consequence, it can enter the presynaptic neuron via DAT as well as by diffusing through the neural membrane directly. Upon entering the presynaptic neuron, amphetamine and trace amines activate TAAR1, which, through protein kinase signaling, induces dopamine efflux, phosphorylation-dependent DAT internalization, and non-competitive reuptake inhibition.
Because of the similarity between amphetamine and trace amines, it is also a substrate for monoamine transporters; as a consequence, it (competitively) inhibits the reuptake of dopamine and other monoamines by competing with them for uptake, as well.
In addition, amphetamine and trace amines are substrates for the neuronal vesicular monoamine transporter, vesicular monoamine transporter 2 (VMAT2). When amphetamine is taken up by VMAT2, the vesicle releases (effluxes) dopamine molecules into the cytosol in exchange.
The substantia nigra is the target of chemical therapeutics for the treatment of Parkinson’s disease. Levodopa (commonly referred to as L-DOPA), the dopamine precursor, is the most commonly prescribed medication for Parkinson’s disease, despite controversy concerning the neurotoxicity of dopamine and L-DOPA.
The drug is especially effective in treating patients in the early stages of Parkinson’s, although it does lose its efficacy over time. Levodopa can cross the blood–brain barrier and increases dopamine levels in the substantia nigra, thus alleviating the symptoms of Parkinson’s disease. The drawback of levodopa treatment is that it treats the symptoms of Parkinson’s (low dopamine levels), rather than the cause (the death of dopaminergic neurons in the substantia nigra).
MPTP, is a neurotoxin specific to dopaminergic cells in the brain, specifically in the substantia nigra. MPTP was brought to the spotlight in 1982 when heroin users in California displayed Parkinson’s-like symptoms after using MPPP contaminated with MPTP. The patients, who were rigid and almost completely immobile, responded to levodopa treatment. No remission of the Parkinson’s-like symptoms was reported, suggesting irreversible death of the dopaminergic neurons. The proposed mechanism of MPTP involves disruption of mitochondrial function, including disruption of metabolism and creation of free radicals.
Soon after, MPTP was tested in animal models for its efficacy in inducing Parkinson’s disease (with success). MPTP induced akinesia, rigidity, and tremor in primates, and its neurotoxicity was found to be very specific to the substantia nigra pars compacta. In other animals, such as rodents, the induction of Parkinson’s by MPTP is incomplete or requires much higher and frequent doses than in primates. Today, MPTP remains the most favored neurotoxin to model nigrostriatal degeneration and dopamine depletion in animals, for studying Parkinson’s disease.
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