Nigrostriatal pathway

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

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

The connection between the substantia nigra pars compacta and the dorsal striatum is mediated via dopaminergic axons.

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 that, by supplying dopamine to the striatum, relays information to the basal ganglia. In contrast, the pars reticulata contains mostly GABAergic neurons.

The SNc is composed of a thin band of cells 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 neurons contain a black pigment called neuromelanin which is known to accumulate with age. 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. These dopamine cell bodies are localized to one of two chemically defined layers. Those in the upper layer (or dorsal tier) contain a binding protein called calbindin-D28K which can buffer calcium levels inside the cell when it becomes too high or toxic. Dopamine cells in the lower layer (or ventral tier) lack this protein 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.

The axons from dopamine neurons emanate from a primary dendrite and project ipsilaterally (on the same side) 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 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. 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. 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 innervate up to 6% of the striatal volume in a rat. Although all SNc dopamine cells project to both the striosome (or patch) and matrix 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. 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, ventral pallidum, subthalamic nucleus, globus pallidus, amygdala, and thalamus.

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.