| Substantia nigra | |
|---|---|
 Substantia nigra highlighted in red. | |
 Section throughsuperior colliculus showing substantia nigra. | |
| Details | |
| Part of | Midbrain,basal ganglia |
| Identifiers | |
| Latin | substantia nigra |
| Acronym | SN |
| MeSH | D013378 |
| NeuroNames | 536 |
| NeuroLex ID | birnlex_789 |
| TA98 | A14.1.06.111 |
| TA2 | 5881 |
| FMA | 67947 |
| Anatomical terms of neuroanatomy | |
Thesubstantia nigra (SN) is abasal ganglia structure located in themidbrain that plays an important role inreward andmovement.Substantia nigra isLatin for "black substance", reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels ofneuromelanin indopaminergicneurons.[1]Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigrapars compacta.[2]
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: thepars compacta (SNpc) and thepars reticulata (SNpr). The pars compacta serves mainly as a projection to the basal ganglia circuit, supplying thestriatum with dopamine. The pars reticulata conveys signals from thebasal ganglia to numerous other brain structures.[3]
The substantia nigra, along with four other nuclei, is part of thebasal ganglia. It is the largestnucleus in the midbrain, lying dorsal to thecerebral peduncles. Humans have two substantiae nigrae, one on each side of the midline.
The SN is divided into two parts: thepars reticulata (SNpr) and thepars compacta (SNpc), 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 (SNpr) and the internalglobus pallidus (GPi) are separated by theinternal capsule.[4]
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 mainlyGABAergic.[5][6]
The main input to the SNpr derives from thestriatum. It comes by two routes, known as thedirect andindirect 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 theglobus pallidus; aGABAergic projection from the globus pallidus to thesubthalamic nucleus, and aglutamatergic projection from the subthalamic nucleus to the pars reticulata.[6][7][better source needed] Thus, striatal activity via the direct pathway exerts an inhibitory effect on neurons in the (SNpr) 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.
Significant projections occur to the thalamus (ventral lateral and ventral anterior nuclei),superior colliculus, and other caudal nuclei from the pars reticulata (the nigrothalamic pathway),[8] 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.[9]
The substantia nigra is an important player in brain function, in particular, ineye movement,motor planning,reward-seeking,learning, andaddiction. Many of the substantia nigra's effects are mediated through thestriatum. The nigraldopaminergic input to the striatum via thenigrostriatal pathway is intimately linked with the striatum's function.[10] 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 ofGABAergic inhibition to various brain targets.
Thepars 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 thebasal ganglia to thethalamus andsuperior colliculus. In addition, the pars reticulata also inhibits dopaminergic activity in thepars compacta via axon collaterals, although the functional organization of these connections remains unclear.
The GABAergic neurons of the pars reticulata spontaneously fireaction potentials. In rats, the frequency of action potentials is roughly 25 Hz.[11] The purpose of these spontaneous action potentials is to inhibit targets of the basal ganglia, and decreases in inhibition are associated with movement.[12] 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,[13] as exemplified by the pars reticulata's role insaccadic eye movement. A group of GABAergic neurons from the pars reticulata projects to the superior colliculus, exhibiting a high level of sustained inhibitory activity.[14] Projections from thecaudate 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 inParkinson's disease[15] andepilepsy.[16]
The most prominent function of the pars compacta ismotor control,[17] 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. The pars compacta sends excitatory input to the striatum via D1 pathway that excites and activates the striatum, resulting in the release of GABA onto the globus pallidus to inhibit its inhibitory effects on the thalamic nucleus. This causes the thalamocortical pathways to become excited and transmits motor neuron signals to the cerebral cortex to allow the initiation of movement, which is absent in Parkinson's disease. 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.[18]
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.[19] Dopaminergic activity decreases with repeated stimulus presentation.[19] However, behaviorally significant stimulus presentation (i.e. rewards) continues to activate dopaminergic neurons in the substantia nigra pars compacta. Dopaminergic projections from theventral tegmental area (bottom part of the "midbrain" or mesencephalon) to the prefrontal cortex (mesocortical pathway) and to the nucleus accumbens (mesolimbic pathway – "meso" referring to "from the mesencephalon"... specifically theventral tegmental area) are implicated in reward, pleasure, and addictive behavior. 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,[20] and some studies point to its involvement in a dorsal striatal-dependent, response-based memory system that functions relatively independent of thehippocampus, which is traditionally believed to subserve spatial orepisodic-like memory functions.[21]
The pars compacta also plays a role intemporal processing and is activated during time reproduction.Lesions in the pars compacta leads to temporal deficits.[22] As of late, the pars compacta has been suspected of regulating the sleep-wake cycle,[23] which is consistent with symptoms such asinsomnia andREM sleep disturbances that are reported by patients withParkinson'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 thehippocampus.[24]
The substantia nigra is critical in the development of many diseases and syndromes, includingparkinsonism andParkinson's disease. There exists a study showing that high-frequency stimulation delivery to the left substantia nigra can induce transient acute depression symptoms.[25]
Parkinson's disease is aneurodegenerative disease characterized, in part, by the death of dopaminergic neurons in the SNpc. The major symptoms of Parkinson's disease includetremor,akinesia,bradykinesia, and stiffness.[26] Other symptoms include disturbances to posture,fatigue,sleep abnormalities, anddepressed mood.[27]
The cause of death of dopaminergic neurons in the SNpc is unknown. However, some contributions to the unique susceptibility of dopaminergic neurons in the pars compacta have been identified. For one, dopaminergic neurons show abnormalities inmitochondrial complex 1, causing aggregation ofalpha-synuclein; this can result in abnormal protein handling and neuron death.[28] Secondly, dopaminergic neurons in the pars compacta contain lesscalbindin than other dopaminergic neurons.[29]Calbindin is a protein involved incalcium ion transport within cells, and excess calcium in cells is toxic. Thecalbindin theory would explain the high cytotoxicity of Parkinson's in the substantia nigra compared to the ventral tegmental area. Regardless of the cause of neuronal death, the plasticity of the pars compacta is very robust; Parkinsonian symptoms do not generally appear until at least 30% of pars compacta dopaminergic neurons have died.[30] Most of this plasticity occurs at the neurochemical level; dopamine transport systems are slowed, allowing dopamine to linger for longer periods of time in the chemical synapses in the striatum.[31]
Menke, Jbabdi, Miller, Matthews and Zari (2010) used diffusion tensor imaging, as well as T1 mapping to assess volumetric differences in the SNpc and SNpr, in participants with Parkinson's compared to healthy individuals. These researchers found that participants with Parkinson's consistently had a smaller substantia nigra, specifically in the SNpr. Because the SNpr is connected to the posterior thalamus, ventral thalamus and specifically, the motor cortex, and because participants with Parkinson's disease report having a smaller SNprs (Menke, Jbabdi, Miller, Matthews and Zari, 2010), the small volume of this region may be responsible for motor impairments found in Parkinson's disease patients. This small volume may be responsible for weaker and/or less controlled motor movements, which may result in the tremors often experienced by those with Parkinson's.[32]
Oxidative stress and oxidative damage in the SNpc are likely key drivers in the etiology ofParkinson's disease as individuals age.[33]DNA damages caused by oxidative stress can berepaired by processes modulated byalpha-synuclein.[34] Alpha synuclein is expressed in the substantia nigra, but itsDNA repair function appears to be compromised inLewy body inclusion bearingneurons.[34] This loss may trigger cell death.[35][36][37]
Increased levels of dopamine have long been implicated in the development ofschizophrenia.[38] However, much debate continues to this day surrounding thisdopamine hypothesis of schizophrenia. Despite the controversy, dopamine antagonists remain a standard and successful treatment for schizophrenia. These antagonists includefirst generation (typical) antipsychotics such asbutyrophenones,phenothiazines, andthioxanthenes. These drugs have largely been replaced bysecond-generation (atypical) antipsychotics such asclozapine andpaliperidone. In general, these drugs do not act on dopamine-producing neurons themselves, but on the receptors on the post-synaptic neuron.
Other, non-pharmacological evidence in support of the dopamine hypothesis relating to the substantia nigra include structural changes in the pars compacta, such as reduction in synaptic terminal size.[39] Other changes in the substantia nigra include increased expression ofNMDA receptors in the substantia nigra, and reduceddysbindin expression. Increased NMDA receptors may point to the involvement ofglutamate-dopamine interactions in schizophrenia. Dysbindin, which has been (controversially) linked to schizophrenia, may regulate dopamine release, and low expression of dysbindin in the substantia nigra may be important in schizophrenia etiology.[40] Due to the changes to the substantia nigra in the schizophrenic brain, it may eventually be possible to use specific imaging techniques (such as neuromelanin-specific imaging) to detect physiological signs of schizophrenia in the substantia nigra.[41]
Wooden chest, also called fentanyl chest wall rigidity syndrome, is a rare side effect of syntheticopioids such asFentanyl, Sulfentanil,Alfentanil,Remifentanil. It results in a generalised increase in skeletalmuscle tone. The mechanism is thought to be via increased dopamine release and decreased GABA release in the nerves of the substantia nigra/striatum. The effect is most pronounced on the chest wall muscles and can lead to impaired ventilation. The condition is most commonly observed in anaesthesia where rapid and high doses of these drugs are given intravenously.[42][43][44]
Multiple system atrophy characterized by neuronal degeneration in the striatum and substantia nigra was previously calledstriatonigral degeneration.
Chemical manipulation and modification of the substantia nigra is important in the fields ofneuropharmacology andtoxicology. 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.
Studies have shown that, in certain brain regions, amphetamine and trace amines increase the concentrations of dopamine in thesynaptic cleft, thereby heightening the response of the post-synaptic neuron.[45] The various mechanisms by which amphetamine and trace amines affect dopamine concentrations have been studied extensively, and are known to involve bothDAT andVMAT2.[45][46][47] Amphetamine is similar in structure to dopamine and trace amines; as a consequence, it can enter the presynaptic neuron viaDAT as well as by diffusing through the neural membrane directly.[45] Upon entering the presynaptic neuron, amphetamine and trace amines activateTAAR1, which, throughprotein kinase signaling, induces dopamine efflux,phosphorylation-dependentDATinternalization, and non-competitive reuptake inhibition.[45][48] 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.[45]
In addition, amphetamine and trace amines are substrates for the neuronal vesicular monoamine transporter,vesicular monoamine transporter 2 (VMAT2).[47] When amphetamine is taken up byVMAT2, the vesicle releases (effluxes) dopamine molecules into the cytosol in exchange.[47]
Cocaine's mechanism of action in the human brain includes the inhibition of dopamine reuptake,[49] which accounts for cocaine's addictive properties, as dopamine is the critical neurotransmitter for reward. However, cocaine is more active in the dopaminergic neurons of theventral tegmental area than the substantia nigra. Cocaine administration increases metabolism in the substantia nigra, which can explain the altered motor function seen in cocaine-using subjects.[50] The inhibition of dopamine reuptake by cocaine also inhibits the firing of spontaneous action potentials by the pars compacta.[51] The mechanism by which cocaine inhibits dopamine reuptake involves its binding to thedopamine transporter protein. However, studies show that cocaine can also cause a decrease in DATmRNA levels,[52] most likely due to cocaine blocking dopamine receptors rather than direct interference with transcriptional or translational pathways.[52]
Inactivation of the substantia nigra could prove to be a possible treatment for cocaine addiction. In a study of cocaine-dependent rats, inactivation of the substantia nigra via implantedcannulae greatly reduced cocaine addiction relapse.[53]
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 theneurotoxicity of dopamine and L-DOPA.[54] The drug is especially effective in treating patients in the early stages of Parkinson's, although it does lose its efficacy over time.[55] Levodopa can cross theblood–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 aneurotoxin 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 usingMPPP 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.[56] The proposed mechanism of MPTP involves disruption ofmitochondrial function, including disruption ofmetabolism and creation offree radicals.[57]
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.[58] 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 method to induce Parkinson's disease inanimal models.[57][59]
The substantia nigra was discovered in 1784 byFélix Vicq-d'Azyr,[60] andSamuel Thomas von Sömmerring alluded to this structure in 1791.[61] The differentiation between the substantia nigra pars reticulata and compacta was first proposed by Sano in 1910.[62] In 1963,Oleh Hornykiewicz concluded from his observation that "cell loss in the substantia nigra (of Parkinson's disease patients) could well be the cause of the dopamine deficit in the striatum."[63]
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