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{{short description|Small lens-shaped nucleus in the brain}}

factoids

The subthalamic nucleus (STN) is a small lens-shaped nucleus in the brain where it is, from a functional point of view, part of the basal ganglia system. In terms of anatomy, it is the major part of the subthalamus. 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,BOOK, Luys JB, Jules Bernard Luys, 1865, Recherches sur le système cérébro-spinal, sa structure, ses fonctions et ses maladies, Baillière, Paris, fr, and the term corpus Luysi or Luys' body is still sometimes used.

Anatomy

File:Ultra-High-Field-MRI-Post-Mortem-Structural-Connectivity-of-the-Human-Subthalamic-Nucleus-Video1.ogv|thumb|Structural connectivity of the human subthalamic nucleus as visualized through diffusion-weighted MRIdiffusion-weighted MRI

Structure

The principal type of neuron found in the subthalamic nucleus has rather long, sparsely spiny dendrites.JOURNAL, Afsharpour S, Light microscopic analysis of Golgi-impregnated rat subthalamic neurons, The Journal of Comparative Neurology, 236, 1, 1–13, June 1985, 4056088, 10.1002/cne.902360102, 12482772, JOURNAL, Rafols JA, Fox CA, The neurons in the primate subthalamic nucleus: a Golgi and electron microscopic study, The Journal of Comparative Neurology, 168, 1, 75–111, July 1976, 819471, 10.1002/cne.901680105, 11962279, In the more centrally located neurons, the dendritic arbors have a more ellipsoidal shape.JOURNAL, Yelnik J, Percheron G, Subthalamic neurons in primates: a quantitative and comparative analysis, Neuroscience, 4, 11, 1717–43, 1979, 117397, 10.1016/0306-4522(79)90030-7, 40909863, The dimensions of these arbors (1200 Î¼m, 600 Î¼m, and 300 Î¼m) are similar across many species—including rat, cat, monkey and human—which is unusual. However, the number of neurons increases with brain size as well as the external dimensions of the nucleus. 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; however, the dendritic arbors of subthalamic neurons shy away from the border and primarily interact with one another.JOURNAL, Lévesque JC, Parent A, GABAergic interneurons in human subthalamic nucleus, Movement Disorders, 20, 5, 574–84, May 2005, 15645534, 10.1002/mds.20374, 9551517, The structure of the subthalamic nucleus has not yet been fully explored and understood, but it is likely composed of several internal domains. The primate subthalamic nucleus is often divided in three internal anatomical-functional domains. However, this so-called tripartite model has been debated because it does not fully explain the complexity of the subthalamic nucleus in brain function.JOURNAL, Alkemade, Anneke, Forstmann, Birte U., July 2014, Do we need to revise the tripartite subdivision hypothesis of the human subthalamic nucleus (STN)?,weblink NeuroImage, en, 95, 326–329, 10.1016/j.neuroimage.2014.03.010, 24642281, 11010595, JOURNAL, Lambert, Christian, Zrinzo, Ludvic, Nagy, Zoltan, Lutti, Antoine, Hariz, Marwan, Foltynie, Thomas, Draganski, Bogdan, Ashburner, John, Frackowiak, Richard, March 2012, Confirmation of functional zones within the human subthalamic nucleus: Patterns of connectivity and sub-parcellation using diffusion weighted imaging, NeuroImage, en, 60, 1, 83–94, 10.1016/j.neuroimage.2011.11.082, 3315017, 22173294,

Afferent axons

The subthalamic nucleus receives its main input from the external globus pallidus (GPe),JOURNAL, Canteras NS, Shammah-Lagnado SJ, Silva BA, Ricardo JA, Afferent connections of the subthalamic nucleus: a combined retrograde and anterograde horseradish peroxidase study in the rat, Brain Research, 513, 1, 43–59, April 1990, 2350684, 10.1016/0006-8993(90)91087-W, 22996045, 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). These afferents are GABAergic, inhibiting neurons in 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.JOURNAL, Cragg SJ, Baufreton J, Xue Y, Bolam JP, Bevan MD, Synaptic release of dopamine in the subthalamic nucleus, The European Journal of Neuroscience, 20, 7, 1788–802, October 2004, 15380000, 10.1111/j.1460-9568.2004.03629.x, 14698708, amp, free, It also receives inputs from the pedunculopontine nucleus.

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.JOURNAL, Nauta HJ, Cole M, Efferent projections of the subthalamic nucleus: an autoradiographic study in monkey and cat, The Journal of Comparative Neurology, 180, 1, 1–16, July 1978, 418083, 10.1002/cne.901800102, 43046462, Some send axons to the substantia nigra medially and to the medial and lateral nuclei of the pallidum laterally (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.JOURNAL, Smith Y, Hazrati LN, Parent A, Efferent projections of the subthalamic nucleus in the squirrel monkey as studied by the PHA-L anterograde tracing method, The Journal of Comparative Neurology, 294, 2, 306–23, April 1990, 2332533, 10.1002/cne.902940213, 9667393, When all axons reaching this target are added, the main efference of the subthalamic nucleus is, in 82.7% of the cases, clearly the internal globus pallidus (GPi).Some researchers have reported internal axon collaterals.JOURNAL, Kita H, Chang HT, Kitai ST, The morphology of intracellularly labeled rat subthalamic neurons: a light microscopic analysis, The Journal of Comparative Neurology, 215, 3, 245–57, April 1983, 6304154, 10.1002/cne.902150302, 32152785, amp, However, there is little functional evidence for this.

Physiology

File:Basal ganglia circuits.svg|thumb|320px|Anatomical overview of the main circuits of the basal ganglia. Subthalamic nucleus is shown in red. Picture shows 2 coronal slices that have been superimposed to include the involved basal ganglia structures. + and - signs at the point of the arrows indicate respectively whether the pathway is excitatory or inhibitory in effect. {{color|green|Green arrows}} refer to excitatory (:en:Glutamic acid|glutamatergic) pathways, {{color|red|red arrows}} refer to inhibitory (:en:gamma-Aminobutyric acid|GABAergic) pathways and {{color|turquoise|turquoise arrows}} refer to (:en:dopamine|dopaminergic) pathways that are excitatory on the direct pathway and inhibitory on the indirect pathway.]]

Subthalamic nucleus

The first intracellular electrical recordings of subthalamic neurons were performed using sharp electrodes in a rat slice preparation.{{Citation needed|date=May 2010}} 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",JOURNAL, Surmeier DJ, Mercer JN, Chan CS, Autonomous pacemakers in the basal ganglia: who needs excitatory synapses anyway?, Current Opinion in Neurobiology, 15, 3, 312–8, June 2005, 15916893, 10.1016/j.conb.2005.05.007, 42900941, amp, D. James Surmeier, since they can generate spontaneous action potentials at rates of 80 to 90 Hz in primates.Oscillatory and synchronous activityJOURNAL, Levy R, Hutchison WD, Lozano AM, Dostrovsky JO, High-frequency synchronization of neuronal activity in the subthalamic nucleus of parkinsonian patients with limb tremor, The Journal of Neuroscience, 20, 20, 7766–75, October 2000, 11027240, 6772896, 10.1523/JNEUROSCI.20-20-07766.2000, amp, JOURNAL, Lintas A, Silkis IG, Albéri L, Villa AE, Dopamine deficiency increases synchronized activity in the rat subthalamic nucleus, Brain Research, 1434, 3, 142–51, January 2012, 21959175, 10.1016/j.brainres.2011.09.005, 14636489,weblink is likely to be a typical pattern of discharge in subthalamic neurons recorded from patients and animal models characterized by the loss of dopaminergic cells in the substantia nigra pars compacta, which is the principal pathology that underlies Parkinson's disease.

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"JOURNAL, Plenz D, Kital ST, A basal ganglia pacemaker formed by the subthalamic nucleus and external globus pallidus, Nature, 400, 6745, 677–82, August 1999, 10458164, 10.1038/23281, 1999Natur.400..677P, 4356230, amp, 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 measures 808 mm3, the subthalamic nucleus only 158 mm3.JOURNAL, Yelnik J, Functional anatomy of the basal ganglia, Movement Disorders, 17, Suppl. 3, S15-21, 2002, 11948751, 10.1002/mds.10138, 40925638, This translated in numbers of neurons represents a strong compression with loss of map precision.Some axons from the lateral pallidum go to the striatum.JOURNAL, Sato F, Lavallée P, Lévesque M, Parent A, Single-axon tracing study of neurons of the external segment of the globus pallidus in primate, The Journal of Comparative Neurology, 417, 1, 17–31, January 2000, 10660885, 10.1002/(SICI)1096-9861(20000131)417:13.0.CO;2-I, 84665164, amp, The activity of the medial pallidum is influenced by afferences from the lateral pallidum and from the subthalamic nucleus.JOURNAL, Smith Y, Wichmann T, DeLong MR, Synaptic innervation of neurones in the internal pallidal segment by the subthalamic nucleus and the external pallidum in monkeys, The Journal of Comparative Neurology, 343, 2, 297–318, May 1994, 8027445, 10.1002/cne.903430209, 24968074, amp, The same for the substantia nigra pars 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.JOURNAL, Bevan MD, Magill PJ, Terman D, Bolam JP, Wilson CJ, Move to the rhythm: oscillations in the subthalamic nucleus-external globus pallidus network, Trends in Neurosciences, 25, 10, 525–31, October 2002, 12220881, 10.1016/S0166-2236(02)02235-X, 8127062, amp,

Pathophysiology

Chronic stimulation of the STN, called 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 modify the activity of subthalamic neurons. However, it has been shown in thalamic slices from mice,JOURNAL, Bekar L, Libionka W, Tian GF, Xu Q, Torres A, Wang X, Lovatt D, Williams E, Takano T, Schnermann J, Bakos R, Nedergaard M, 6, Adenosine is crucial for deep brain stimulation-mediated attenuation of tremor, Nature Medicine, 14, 1, 75–80, January 2008, 18157140, 10.1038/nm1693, 7107064, that the stimulus also causes nearby astrocytes to release adenosine triphosphate (ATP), a precursor to adenosine (through a catabolic process). In turn, adenosine A1 receptor activation depresses excitatory transmission in the thalamus, thus mimicking ablation of the subthalamic nucleus.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.As one of the STN's suspected functions is in impulse control, dysfunction in this region has been implicated in obsessive–compulsive disorder.BOOK, Carter R, The Human Brain Book, 58,233, Artificially stimulating the STN has shown some promise in correcting severe impulsive behavior and may later be used as an alternative treatment for the disorder.JOURNAL, Mallet L, Polosan M, Jaafari N, Baup N, Welter ML, Fontaine D, du Montcel ST, Yelnik J, Chéreau I, Arbus C, Raoul S, Aouizerate B, Damier P, Chabardès S, Czernecki V, Ardouin C, Krebs MO, Bardinet E, Chaynes P, Burbaud P, Cornu P, Derost P, Bougerol T, Bataille B, Mattei V, Dormont D, Devaux B, Vérin M, Houeto JL, Pollak P, Benabid AL, Agid Y, Krack P, Millet B, Pelissolo A, 6, Subthalamic nucleus stimulation in severe obsessive-compulsive disorder, The New England Journal of Medicine, 359, 20, 2121–34, November 2008, 19005196, 10.1056/NEJMoa0708514, free,

Function

The function of the STN is unknown, but current theories place it as a component of the basal ganglia control system that may perform action selection. It is thought to implement the so-called "hyperdirect pathway" of motor control, contrasting with the direct and indirect pathways implemented elsewhere in the basal ganglia. STN dysfunction has also been shown to increase impulsivity in individuals presented with two equally rewarding stimuli.JOURNAL, Frank MJ, Samanta J, Moustafa AA, Sherman SJ, Hold your horses: impulsivity, deep brain stimulation, and medication in parkinsonism, Science, 318, 5854, 1309–12, November 2007, 17962524, 10.1126/science.1146157, 2007Sci...318.1309F, 2718110, free, Research has suggested that the subthalamus is an extrapyramidal center. It holds muscular responses in check, and damage may result in hemiballism (a violent flinging of the arm and leg on one side of the body).BOOK, Bruce H. Robinson, Biomedicine - A textbook for Practitioners of Acupuncture & Oriental Medicine, 2007, 126, 978-1-891845-38-3, 2006940894, Blue Poppy Press, The physiological role of the STN has been for long hidden by its pathological role. But lately, the research on the physiology of the STN lead to the discovery that the STN is required to achieve intended movement, including locomotion, balance and motor coordination. It is indeed involved in stopping or interrupting on-going motor tasks. Moreover, STN excitation was generally correlated with significant reduction in locomotor activity, while in contrast, STN inhibition enhanced locomotion.JOURNAL, Aron AR, Behrens TE, Smith S, Frank MJ, Poldrack RA, Triangulating a cognitive control network using diffusion-weighted magnetic resonance imaging (MRI) and functional MRI, The Journal of Neuroscience, 27, 14, 3743–52, April 2007, 17409238, 6672420, 10.1523/JNEUROSCI.0519-07.2007, JOURNAL, Fife KH, Gutierrez-Reed NA, Zell V, Bailly J, Lewis CM, Aron AR, Hnasko TS, Causal role for the subthalamic nucleus in interrupting behavior, eLife, 6, e27689, July 2017, 28742497, 10.7554/eLife.27689, 5526663, Uchida N, free, JOURNAL, Guillaumin A, Serra GP, Georges F, Wallén-Mackenzie Å, Experimental investigation into the role of the subthalamic nucleus (STN) in motor control using optogenetics in mice, Brain Research, 1755, 147226, March 2021, 33358727, 10.1016/j.brainres.2020.147226, free,

Additional images

See also

{{Commons category|Subthalamic nucleus}}

• Primate basal ganglia
• Mesencephalic locomotor region

References

{{Reflist}}{{Diencephalon}}{{Neural tracts}}{{Authority control}}