Subthalamic nucleus

The subthalamic nucleus is a small lens-shaped nucleus in the brain where it is a part of the basal ganglia system. As suggested by its name, the subthalamic nucleus is located ventral to the thalamus. It is also dorsal to the substantia nigra and medial to the internal capsule. It was first described by Jules Bernard Luys in 1865, and the term corpus Luysi or Luys' body is still sometimes used.

Structure
The principal type of neuron found in the subthalamic nucleus has rather long dendrites devoid of spines. The dendritic arborizations are ellipsoid, replicating in smaller dimension the shape of the nucleus. The dimensions of these arborizations (1200,600 and 300 μm) are similar across many species—including rat, cat, monkey and man—which is unusual. However, the number of neurons increases across evolution as well as the external dimensions of the nucleus. Due to the bending of dendrites at the border, the subthalamic nucleus is a close nucleus, able to receive information only in its space. The principal neurons are glutamatergic, which give them a particular functional position in the basal ganglia system. In humans there are also a small number (about 7.5%) of GABAergic interneurons that participate in the local circuitry.

Afferent axons
The subthalamic nucleus receives its main input from the lateral pallidum ( external segment of the globus pallidus) (84.2% of its axons ), not so much through the ansa lenticularis as often said but by radiating fibers crossing the medial pallidum first and the internal capsule (see figure). This afference is GABAergic, inhibiting the neurons of the subthalamic nucleus. Excitatory, glutamatergic inputs come from the cerebral cortex (particularly the motor cortex), and from the pars parafascicularis of the central complex. The subthalamic nucleus also receives neuromodulatory inputs, notably dopaminergic axons from the substantia nigra pars compacta.

Efferent targets
The axons of subthalamic nucleus neurons leave the nucleus dorsally. The efferent axons are glutamatergic (excitatory). Except for the connection to the striatum (17.3% in macaques), most of the subthalamic principal neurons are multitargets and directed to the other elements of the core of the basal ganglia. Some send axons to the substantia nigra medially and to the medial and lateral nuclei of the pallidum lateraly (3-target, 21.3%). Some are 2-target with the lateral pallidum and the substantia nigra (2.7%) or the lateral pallidum and the medial (48%). Less are single target for the lateral pallidum. In the pallidum, subthalamic terminals end in bands parallel to the pallidal border. When all axons reaching this target are added, the main afference of the subthalamic nucleus is, in 82.7% of the cases, clearly the medial pallidum (internal segment of the globus pallidus).

Some researchers have reported internal axon collaterals. However, there is little functional evidence for this.

Subthalamic nucleus
The first intracellular electrical recordings of subthalamic neurons were performed using sharp electrodes in a rat slice preparation (Nakanishi et al., 1987). In these recordings three key observations were made, all three of which have dominated subsequent reports of subthalamic firing properties. The first observation was that, in the absence of current injection or synaptic stimulation, the majority of cells were spontaneously firing. The second observation is that these cells are capable of transiently firing at very high frequencies. The third observation concerns non-linear behaviors when cells are transiently depolarized after being hyperpolarized below –65mV. They are then able to engage voltage-gated calcium and sodium currents to fire bursts of action potentials.

Several recent studies have focused on the autonomous pacemaking ability of subthalamic neurons. These cells are often referred to as "fast-spiking pacemakers", since they can generate spontaneous action potentials at rates of 80 to 90Hz in primates.

Lateropallido-subthalamic system
Strong reciprocal connections link the subthalamic nucleus and the external segment of the globus pallidus. Both are fast-spiking pacemakers. Together, they are thought to constitute the "central pacemaker of the basal ganglia" with synchronous bursts.

The connection of the lateral pallidum with the subthalamic nucleus is also the one in the basal ganglia system where the reduction between emitter/receiving elements is likely the strongest. In terms of volume, in humans, the lateral pallidum mesures 808 mm³, the subthalamic nucleus only 158 mm³. This translated in numbers of neurons represents a strong compression with loss of map precision.

The systemic position of this circuit is particular in the basal ganglia system that may be revealed by contrast versus outputs subsystems. There are two output paths starting from the striatum. The first has a first relay in the medial pallidum (GABAegic inhibitory) and the second in the nigra reticulata (GABA). These two output subsystems do not send regulatory messages to other elements of the basal ganglia system: striatum, lateral pallidum or subthalamic nucleus. The lateropallido-subthalamic subsystem is particular in that it does the reverse. It does not send axons to the thalamus and from there to the cortex. All efferent axons of the subsystem are indeed returning inside the basal ganglia system. This topologically makes it a regulator. Some axons from the lateral pallidum go to the striatum. The activity of the medial pallidum is influenced by afferences from the lateral pallidum and from the subthalamic nucleus. The same for the nigra reticulata. The subthalamic nucleus sends axons to another regulator: the pedunculo-pontine complex (id).

The lateropallido-subthalamic system is thought to play a key role in the generation of the patterns of activity seen in Parkinson's disease.

Physiopathology and interventions
Chronic stimulation of the nucleus, as produced during deep brain stimulation (DBS), is used to treat patients with Parkinson disease. The first to be stimulated are the terminal arborisations of afferent axons which modifies the activity of subthalamic neurons. However trigger zones may also rapidly send the signals to the output axons. The precise effects of stimulation are not understood, although DBS mimics ablation of the subthalamic nucleus.

Pathology
Unilateral destruction or disruption of the subthalamic nucleus – which can commonly occur via a small vessel stroke in patients with diabetes, hypertension, or a history of smoking – produces hemiballismus.

Function
The function of the STN is unknown, but current theories place it as a component of the basal ganglia control system which may perform action selection.