| Nigrostriatal pathway | |
|---|---|
 Nigrostriatal pathway (Left and Right in red). | |
 The nigrostriatal pathway is shown here in solid blue, connecting the substantia nigra with the dorsal striatum. | |
| Anatomical terminology |
Thenigrostriatal pathway is a bilateraldopaminergic pathway in the brain that connects thesubstantia nigrapars compacta (SNc) in the midbrain with thedorsal striatum (i.e., thecaudate nucleus andputamen) in the forebrain. It is one of the four majordopamine pathways in the brain, and is critical in the production of movement as part of a system called thebasal ganglia motor loop.Dopaminergic neurons of this pathway release dopamine from axon terminals that synapse ontoGABAergic medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs),[1][2] located in the striatum.
Degeneration of dopaminergicneurons in the SNc is one of the main pathological features ofParkinson's disease,[3] leading to a marked reduction in dopamine function and the symptomatic motor deficits ofParkinson's disease includinghypokinesia,tremors, rigidity, andpostural imbalance.
The connection between the substantia nigra pars compacta and the dorsal striatum is mediated via dopaminergic axons.
Thesubstantia nigra is located in the ventralmidbrain of each hemisphere. It has two distinct parts, thepars compacta (SNc) and thepars reticulata (SNr). The pars compacta containsdopaminergic neurons from theA9 cell group that forms the nigrostriatal pathway that, by supplying dopamine to thestriatum, relays information to thebasal ganglia. In contrast, the pars reticulata contains mostlyGABAergic neurons.
The SNc is composed of a thin band of cells that overlies the SNr and is situated laterally to theA10 group of dopaminergic neurons in theventral tegmental area (VTA) that forms themesolimbic dopamine pathway. The SNc is easily visualized in human brain sections because the dopamine neurons contain a black pigment calledneuromelanin which is known to accumulate with age.[4] The dopaminergic cell bodies in the SNc are densely packed with approximately 200,000 to 420,000 dopamine cells in human SNc and 8,000 to 12,000 dopamine cells in mouse SNc.[5] These dopamine cell bodies are localized to one of two chemically defined layers.[6] Those in the upper layer (ordorsal tier) contain a binding protein calledcalbindin-D28K which can buffercalcium levels inside the cell when it becomes too high or toxic. Dopamine cells in the lower layer (orventral tier) lack this protein and are more vulnerable to the effects ofneurotoxins (e.g.MPTP) that can cause Parkinson disease-like symptoms.[7][8] The dorsal tier dopamine cells havedendrites that radiate horizontally across the pars compacta, whereas ventral tier dopamine cells have dendrites that extend ventrally into the pars reticulata.[6][9]
Theaxons from dopamine neurons emanate from a primary dendrite and projectipsilaterally (on the same side) via themedial forebrain bundle to the dorsal striatum. There is a rough topographical correlation between the anatomical localization of the dopamine cell body within the SNc and the area of termination in the dorsal striatum. Dopaminergic cells in the lateral parts of the SNc project mainly to the lateral and caudal (posterior) parts of the striatum, whereas dopamine cells in the medial SNc project to the medial striatum.[10][9] In addition, dopamine cells in the dorsal tier project to the ventromedial striatum, whereas the ventral tier neurons project to the dorsal caudate nucleus and putamen.[6][9] In general, there is a greater density of dopaminergic input to the dorsolateral striatum.[9]
Each dopamine neuron has an extremely large unmyelinated axonal arborization which can innervate up to 6% of the striatal volume in a rat.[11] Although all SNc dopamine cells project to both thestriosome (or patch) andmatrix neurochemical compartments of the striatum, most of the axonal territory of a dorsal tier neuron is in the matrix compartment while the majority of the axonal field of ventral tier neurons is in the striosomes.[6][10][11] Nigrostriatal dopamine axons can also give rise to axon collaterals that project to other brain regions. For example, some SNc nigrostriatal dopamine axons send axon collaterals to thepedunculopontine nucleus,ventral pallidum,subthalamic nucleus,globus pallidus,amygdala, andthalamus.[6][9][12]
A small number of SNc dorsal tier dopamine neurons also project directly to the cortex, although most of the dopaminergic innervation of the cortex comes from the adjacent VTA dopamine neurons.[9]
Thedorsal striatum is located in the subcortical region of theforebrain. In primates and other mammals, it is divided by the anterior limb of awhite matter tract called theinternal capsule[13] into two parts: thecaudate nucleus and theputamen.[14] In rodents, the internal capsule is poorly developed such that the caudate and putamen are not separated but form one large entity called the caudate putamen (CPu).[15][16] The majority (about 95%) of cells in the dorsal striatum are GABAergic medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs). Approximately half of these MSNs containdopamine D1 receptors and project directly to the substantia nigra to form thedirect pathway of the basal ganglia, whereas the other half expressdopamine D2 receptors that project indirectly to the substantia nigra via the globus pallidus and subthalamic nucleus to form theindirect pathway of the basal ganglia.[17] The remaining 5% of cells areinterneurons that are either cholinergic neurons[18] or one of several types of GABAergic neurons.[19] The axons and dendrites of these interneurons stay within the striatum.
The caudate nucleus and putamen receive excitatory information from all areas of thecerebral cortex.[20] Theseglutamatergic inputs are generally topographically arranged such that the putamen takes information largely from the sensorimotor cortex, whereas the caudate nucleus obtains information largely from the association cortex.[20] In addition, the dorsal striatum receives excitatory inputs from other brain structures like the thalamus,[21] and minor excitatory inputs from thehippocampus andamygdala.
The dorsal striatum contains neurochemically defined compartments called striosomes (also known as patches) that exhibit dense μ-opioid receptor staining embedded within a matrix compartment that contains higheracetylcholinesterase and calbindin-D28K.[22]
The dopaminergic axon terminals of the nigrostriatal pathway synapse ontoGABAergic MSNs in the dorsal striatum. They form synapses on the cell body and dendritic shaft regions but mostly on the necks ofdendritic spines that also receive glutamatergic input to the heads of the same dendritic spines.[1]
The main function of the nigrostriatal pathway is to influencevoluntary movement through basal ganglia motor loops. Along with themesolimbic andmesocortical dopaminergic pathways, the nigrostriatal dopamine pathway can also influence other brain functions, includingcognition,[23]reward, andaddiction.[24] Nigrostriatal dopaminergic neurons exhibit tonic and phasic patterns of neuronal firing activity. This can lead to different patterns of dopamine release from the axon terminals in the dorsal striatum and also from the cell body (soma) and dendrites in the SNc and SNr.[25][26] As well as releasing dopamine, some axons in the nigrostriatal pathway can also co-release GABA.[27][28]
The nigrostriatal pathway influences movement through two pathways, thedirect pathway of movement and theindirect pathway of movement.[29][30]
Thedirect pathway is involved infacilitation of wanted movements. The projections fromdopamine D1 receptors containing medium spiny neurons in the caudate nucleus and putamen synapse onto tonically active GABAergic cells in the substantia nigra pars reticulata and the internal segment of the globus pallidus (GPi), which then project to the thalamus. Because the striatonigral / striatoentopeduncular and nigrothalamic pathways are inhibitory, activation of the direct pathway creates an overall net excitatory effect on the thalamus and on movement generated by the motor cortex.
Theindirect pathway is involved insuppressing unwanted movement. The projections fromdopamine D2 receptors containing medium spiny neurons in the caudate nucleus and putamen synapse onto tonically active GABAergic cells in the external segment of the globus pallidus (GPe), which then projects to the substantia nigra pars reticulata via the excitatorysubthalmic nucleus (STN). Because the striatopallidal and nigrothalamic pathways are inhibitory but the subthalamic to nigra pathway is excitatory, activation of the indirect pathway creates an overall net inhibitory effect on the thalamus and on movement by the motor cortex.
Parkinson's disease is characterized by severe motor problems, mainlyhypokinesia, rigidity,tremors, and postural imbalance.[31] Loss of dopamine neurons in the nigrostriatal pathway is one of the main pathological features of Parkinson's disease.[32] Degeneration of dopamine producing neurons in the substantia nigra pars compacta and the putamen-caudate complex leads to diminished concentrations of dopamine in the nigrostriatal pathway, leading to reduced function and the characteristic symptoms.[33] The symptoms of the disease typically do not show themselves until 80-90% of dopamine function has been lost.
Another hypothesis suggests that Parkinson's disease is an imbalance between dopamine (D.A.) and acetylcholine (ACh) in the dorsal striatum, and not just dopamine deficiency.[34]
Levodopa-induced dyskinesias (LID) is a complication associated with long-term use of the Parkinson's treatmentL-DOPA, characterized by involuntary movement and muscle contractions. This disorder occurs in up to 90% of patients after 9 years of treatment. The use of L-DOPA in patients can lead to interruption of nigrostriatal dopamine projections as well as changes in the post-synaptic neurons in the basal ganglia.[35]
Presynaptic dopamine metabolism is altered inschizophrenia.[36][37]
Other major dopamine pathways include:
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