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The nigrostriatal pathway is a bilateral dopaminergic pathway that connects the substantia nigra pars compacta (SNc) with the dorsal striatum (i.e., the caudate nucleus and putamen). It is one of the four major dopamine pathways in the brain, and is particularly involved in the production of movement as part of a system called the basal ganglia motor loop. Dopaminergic neurons of this pathway release dopamine from terminals that synapse onto striatal GABAergic medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs).

Loss of dopamine neurons in the SNc is one of the main pathological features of Parkinson's disease, leading to a marked reduction in dopamine function in this pathway. Depletion of dopamine in this pathway lead to the symptomatic motor deficits of Parkinson's disease including hypokinesia, tremors, rigidity, and postural imbalance.

Anatomy
The following are considered part of the nigrostriatal pathway.

Substantia nigra pars compacta
The substantia nigra is located in the ventral midbrain of each hemisphere. It has two distinct parts, the pars compacta (SNc) and the pars reticulata (SNr). The pars compacta contains dopaminergic neurons from the A9 cell group that forms the nigrostriatal pathway which by supplying dopamine to the striatum relays information to the basal ganglia. The pars reticulata contains mostly GABAergic neurons and in conjunction with the globus pallidus in the basal ganglia allows for inhibition of the thalamus.

The SNc forms a thin band that overlies the SNr and is situated laterally to the A10 group of dopaminergic neurons in the ventral tegmental area (VTA) that forms the mesolimbic dopamine pathway. The SNc is easily visualized in human brain sections because the dopamine cells contain a black pigment called neuromelanin that is know to accumulate with age. The dopaminergic cell bodies are densely packed containing approximately 200,000 to 420,000 dopamine cells in human SNc and 8,000 to 12,000 dopamine cells in mouse SNc. These dopamine cell bodies are localized to one of two neurochemically defined layers. Those in the upper layer or dorsal tier contain proteins like calbindin-D28K and calretinin which buffer intracellular calcium levels when it becomes too high. Dopamine cells in the lower ventral tier lack either one or both of these proteins and are more vulnerable to the effects of neurotoxins (e.g. MPTP) that can cause Parkinson disease-like symptoms. The dorsal tier dopamine cells have dendrites that radiate horizontally across the pars compacta, whereas ventral tier dopamine cells have dendrites that extend ventrally into the pars reticulata.

Dopamine axons
The axons from dopamine cells in both the dorsal and ventral tiers emanate from a primary proximal dendrite and project ipsilaterally via the medial 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 substantia nigra project mainly to the lateral and caudal parts of the striatum, whereas the medial SNc dopamine neurons project to the medial striatum. In addition, dorsal tier neurons project to the ventromedial striatum, whereas the ventral tier neurons project to the dorsal caudate nucleus and putamen. In general, there is a greater density of dopaminergic input to the dorsolateral striatum.

Each dopamine neuron has an extremely large unmyelinated axonal arborization which can occupy up to 6% of the striatal volume in a rat. Although all SNc dopamine cells innervate both the striosome (or patch) and matrix neurochemical compartments of the striatum, most of the axonal territory of a dorsal tier neuron resides in the matrix compartment while the majority of the axonal field of ventral tier neurons reside in striosomes. 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 the pedunculopontine nucleus, the ventral palladium, subthalamic nucleus, globus pallidus, amygdala and the thalamus.

A small number of dorsal tier SNc dopamine neurons also project directly to the cortex, although the majority of the dopaminergic innervation of the cortex comes from adjacent VTA dopamine neurons.

Dorsal striatum
The dorsal striatum is located in the subcortical region of the forebrain. In primates and other mammals it is divided by the anterior limb of a white matter tract called the internal capsule into two parts: the caudate nucleus and the putamen. In rodents, the internal capsule is poorly developed such that the caudate and putamen are not segregated but form one large entity called the caudate putamen (CPu). 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 cells contain dopamine D1 receptors and project directly to the substantia nigra to form the direct pathway of the basal ganglia, whereas the the other half express dopamine D2 receptors that project indirectly to the substantia nigra via the globus pallidus and subthalamic neucleus to form the indirect pathway of the basal ganglia. The remaining 5% of cells are interneurons that are either cholinergic neurons or one of several types of GABAergic neurons. The axons and dendrites of these interneurons stay within the striatum.

The putamen and caudate receive excitatory information from all areas of the cerebral cortex. These inputs are generally topographically arranged such that the putamen takes information largely from the sensorimotor cortex whereas the caudate obtains information largely from the association cortex. In addition, the dorsal striatum receives excitatory inputs from the thalamus, and minor excitatory inputs from the hippocampus and amygdala.

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 higher acetylcholinesterase and calbindin-D28K.

The axon terminals of the nigrostriatal pathway synapse onto GABAergic medium spiny neurons in the dorsal striatum. They form synapses on the cell body and dendritic shaft regions but mostly on the the necks of dendritic spines that also receive glutamatergic input to the heads of the same dendritic spines.

Function
The main function of the nigrostriatal pathway is to influence voluntary movement through basal ganglia loops. Along with the mesolimbic and mesocortical dopaminergic pathways the nigrostriatal dopamine pathway can also influence other brain functions including cognition, reward and addiction. Nigrostriatal dopamine neurons exhibit tonic and phasic patterns of activity. This can lead to differential patterns of dopamine release from axon terminals in the dorsal striatum and also from the soma and dendrites in the SNc and SNr. As well as releasing dopamine some axons in the nigrostriatal pathway can also corelease GABA.

The nigrostriatal pathway influences movement through two pathways, the direct pathway of movement and the indirect pathway of movement.

Direct pathway of movement
The direct pathway is involved in facilitation of wanted movements. The projections from dopamine D1 receptor containing medium spiny neurons in the caudate and putamen synapse onto tonically active GABAergic cells in the substantia nigra pars reticulata and the internal segment of the globus pallidus 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 on the thalamus and on movement.

Indirect pathway of movement
The indirect pathway is involved in suppressing unwanted movement. The projections from dopamine D2 receptor containing medium spiny neurons in the caudate and putamen synapse onto tonically active GABAergic cells in the external segment of the globus pallidus which then projects to the substantia nigra pars reticulata via the excitatory subthalmic nucleus. 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.