Primate basal ganglia system
The basal ganglia form a major brain system in all species of vertebrates, but the basal ganglia of primates (including humans) have special features that justify a separate consideration. As in other vertebrates, the primate basal ganglia can be divided into striatal, pallidal, nigral, and subthalamic components. In primates, however, the two pallidal subdivisions are called the external and internal (or sometimes lateral and medial) segments of the globus pallidus, whereas in other species they are called the globus pallidus and entopeduncular nucleus. Also in primates, the striatum is divided by a large tract of white matter called the internal capsule into two masses of gray matter that early anatomists named the caudate nucleus and putamen—in most other species no such division exists, and only the striatum as a whole is recognized. Beyond this, the complex topography of connections between the striatum and cortex means that functions are segregated within the primate striatum in ways that do not apply to other species.
A separate consideration of the primate basal ganglia is also warranted by the fact that different types of information are available than for other species. Large areas of the primate brain are devoted to vision; consequently the role of the basal ganglia in controlling eye movements has been studied almost exclusively in primates. Functional imaging studies have been performed mainly using human subjects. Also, several major degenerative diseases of the basal ganglia, including Parkinson's disease and Huntington's disease, are specific to humans, although "models" of them have been proposed for other species.
- 1 Corticostriatal connection
- 2 Striatum
- 3 Pallido-nigral set and pacemaker
- 4 Substantia nigra compacta (SNc) and nearby dopaminergic elements
- 5 Regulators of the basal ganglia core
- 6 Outputs of the basal ganglia system
- 7 References
- 8 Sources
- 9 See also
The whole system starts as a major output of the cerebral cortex, about the same size as the corticopontine system opening the cerebellar system. The corticostriatal connection represents a significant portion of the whole cortical output. Almost every part of the cortex, except for the primary olfactory, visual and auditory cortices, sends axons to the striatum. The origin of the connection is in the pyramidal neurons of layer V of the cortex. Corticostriate contributors, of the motor cortex at least, may be collaterals of axons descending lower in the nervous system. However, in primates, the majority of corticostriate axons are monotarget, purely cortico-striate, thin and unbranched until they arrive in the striatum. The corticostriatal connection is glutamatergic and excitatory. This connection is not topologically as simple as was initially described by Kemp and Powell (1970), where the frontal lobe projected anteriorly and the occipitotemporal lobes posteriorly. Part of this distribution grossly remains, but the distribution is much more complex. One small cortical site can send terminal arborisations to several and distal striatal places. The cortico-striatal connection is the substrate of cortical information separation and recombination: axons from distinct cortical areas can systematically end together or separately. There is also a spatial reorganisation, a "remapping".
The corticostriate connection is the first in a chain of strong reduction in numbers between emitter and receiver neurons, i.e. a numerical convergence. The effect of this is that if each striatocortical neuron has its own message, this will be mixed or compressed, leading to lesser definition of the input map.
In primates, the striatum has four neuronal genera: medium spiny neurons (96%), leptodendritic neurons (2%), spidery neurons (1%) and microneurons(1%). The dendritic arborisations of the spiny neurons are spherical unless close to a border. Their overall dimensions depend on the animal species. Spines are of the same type as those of two other (telencephalic) acanthodendritic (acanthos means spine) genera, the pyramidal neurons of the cerebral cortex and the spiny neurons of the amygdala. Most of these spines synapse with cortical afferents. The axons of spiny neurons have abundant and dense initial axonal collaterals acting fast on neighbouring neurons. The distal part is long and myelinated. The spiny neurons are GABAergic, constituting the first part of the inhibitory 2-path so particular to the system . The leptodendritic neurons (or Deiter's) stain for parvalbumin and have all the morphological properties of pallidal neurons. The spidery neurons are specific to primates. They have a big soma and short dendritic and axonal branches. They are the cholinergic neurons of the primate, with a morphology entirely different from that of non-primates. This must lead to great care in making physiopathological transfers. They are the "tonically active neurons" or TANs. The microneurons are local circuit neurons similar to those found in the thalamus for instance. They are GABAergic, and some may be dopaminergic.
The spontaneous activity of striatal neurons of awake monkeys is surprisingly "low or absent". Neurons are activated by cortical stimulation. At rest, spiny neurons are left in a state of low excitability by two types of potassium conductance that hyperpolarize the cell. Striatal neurons need strong synchronized input from their excitatory cortical afferences. In the sensorimotor striatum they respond to movements.
Levels of organisation
There are several levels of organization of the striatum:
- Gross anatomical subdivisions and territories
- The long oblique split of the striatum by the internal capsule creates the classic division into Putamen and Caudate. The striatum is a continuous mass. The gross anatomical division does not correspond exactly with the presently accepted anatomofunctional subdivision of the striatum in primates; relying on the differentiated territories of the corticostriatal axons. Endings of axons from the central region of the cortex, primary somatosensory, motor, premotor, accessory motor and anterior parietal, constitute a sensorimotor territory (or for short sensorimotor striatum) essentially putaminal, but does not cover the total extent of the putamen and slightly includes intracapsular fringes and the inferolateral border of the caudate. It is grossly somatotopically arranged with three oblique bands, one dorso-lateral related to the inferior limb, one intermediate to upper limb, and one medio-inferior to face. This is supposed an "associative" territory (the term is imperfect), located essentially in the caudate, above all orally and dorsally, which, however, does not cover the entire caudate volume. The separation between the two, sensorimotor and associative, territories may be in some places clearcut and observed using calbindin immunochemistry (the sensorimotor territory being negative). The isolation of a third ventral striatal part often qualified as "limbic" is more difficult. There is no general agreement on the position of its limit with the associative territory. Only one part is distinctive, the "nucleus accumbens" (in fact a pars and not a nucleus) having the same morphological features as elsewhere but with particular immunostaining properties and, above all, a selectivity for the reception of axons from the subiculum. A "shell" and a "core" are said to be also present in primates. They are however of small size relative to the other parts.
- Histochemistry has shown inhomogeneities with regards to the distribution of different molecules. The major compartment, the matrix, as its name indicates, is considered as the basic element. It contains contrasting islands or striosomes that contain opiate receptors, D1 binding sites, and stain for acetylcholinesterase. This opposition, obvious in the head of the caudate, is not clear everywhere. Striosomes have no simple links with amygdalar afferents in primates. Striosomes rather represent the insular segregation of particular frontal axonal endings (posterior orbitofrontal/anterior insula and mediofrontal/anterior cingulate cortex). Matricial neurons are those contained in the matrix. Striosomal neurons are those contained in the striosome. They have been opposed as sources of distinctive efferents, which will be shown below.
Basal ganglia core
Hodology to targets
There have been disputes concerning the origin of striatal axons projecting to different targets. In most parts of the neocortex, GABAergic neurons only send local connections, conversely inhibitory neurons in the striatum send long axons to their targets in the pallidum and the substantia nigra. Due to difficulties linked to the geometry of the system, the first data relying on tracing techniques led to the belief that there were specialised striato-pallidal or striato-nigral neurons each having histochemical particularities. A recent study in macaques (following another one on the rat) has drastically changed the situation. Spiny neurons, generally, have several targets. This is not an archaic pattern since it is found in 90% of the cases in macaque monkeys versus 63,6% in the rat. Virtually all striatal axons have the lateral pallidum (the most voluminous) as their first target. 24/27 of the studied axons projected to the three consecutive targets, lateral pallidum, medial pallidum and nigra (lateralis and reticulata). There are no striatal axons projecting to the medial pallidum alone, to the nigra alone or only to both. Between matricial and striosomal axons, the only difference in axonal hodology is that striosomal axons cross the whole lateral to medial extent of the nigra and emit (in macaques) 4 to 6 vertical collaterals, forming vertical columns entering deep inside the pars reticulata. The matricial neurons emit more sparsely branched axons. This general pattern of connectivity raises new problems. The main mediator of the striato- pallidonigral system is GABA, but with cotransmitters. The lateral pallidum stains for met-enkephalin, the medial for substance P and/or dynorphin and the nigra for both. This likely means that a single axon is able to concentrate different comediators in different subtrees depending on the target. This considerably modifies several decades-old schemes and raises new questions.
Selectivity of striatal territories for targets
A study of the percentage of striatal axons from the sensorimotor and associative striatum distributed to targets found important differences. The lateral pallidum for instance receives mainly (68%) axons from the associative territory. On the reverse the medial pallidum is strongly sensorimotor (63%). The nigra is at first associative. This is confirmed by the effects of striatal stimulations.
Pallido-nigral set and pacemaker
The pallidonigral set comprises the direct targets of the striatal axons: the two nuclei of the pallidum and the pars lateralis and pars reticulata of the "substantia" nigra". One character of this ensemble is given by the very dense striato-pallidonigral bundle giving it its whitish aspect (pallidus means pale). In no ways has the pallidum the shape of a globe. After Foix and Nicolesco (1925) and some others, Cécile and Oskar Vogt (1941) suggested the term pallidum - also used by the Terminologia Anatomica (1998). They also proposed the term nigrum for replacing nigra, which is indeed not a substance; but this is generally not followed. The whole pallidonigral set is made up the same neuronal components. The majority is made up of very large neurons, poorly branched, strongly stained for parvalbumin, having very large dendritic arborisations (much larger in primates than in rodents) with straight and thick dendrites. Only the shape and direction of the dendritic arborizations differ between the pallidum and the nigra neurons. The pallidal dendritic arborisations are very large flat and discoidal. Their principal plane is parallel to the others and also parallel to the lateral border of the pallidum; thus perpendicular to the axis of the afferences. Since the pallidal discoidal discs are thin, they are crossed only for a short distance by striatal axons. On another hand, since they are wide, they are crossed by many striatalaxons from wide striatal parts. Since they are loose, the chances of contact are not very high. Striatal arborisations, in anotherhand, emit perpendicular branches participating in flat bands parallel to the lateral border, which increases the density of synapses in this direction. This is true for the striatal afferent but also for the subthalamic (see below). The synaptology of the set is uncommon and characteristic. The dendrites of the pallidal or nigral axons are entirely covered by synapses, without any apposition of glia. More than 90% of synapses are of striatal origin. One noticeable property of this ensemble is that not one of its elements receives cortical afferents. Initial collaterals are present. However, in addition to the presence of various appendages at the distal extremity of the pallidal neurons that could act as elements of local circuitry, there are weak or no functional interrelations between pallidal neurons.
The lateral pallidum is the lateral nucleus of the pallidum, the external "segment" of the globus pallidus (GPe, ). It is flat, curved and very extended (parasagittally and dorsoventrally). The three-dimensional shape of arborisations is discoid and flat. The arborisations are parallel to one another and to the lateral border of the pallidum. They are perpendicular to the striatal afferences. In addition to the striato-pallidal afference, the lateral pallidum receives a major connection from the subthalamic nucleus (see below). It also receives dopaminegic afferences from the nigra compacta. Contrary to two other elements of the basal ganglia core, the lateral pallidum is not a source of output to the thalamus as it sends its axons essentially to other basal ganglia elements (intrasystemic connections). To some extent, it may be seen as an inner basal ganglia regulator. Its mediator is GABA. The very fast spontaneous activity (contrary to that of medial pallidal neurons) is discontinuous with long intervals of silence "lasting up to several seconds or more". Some have low-frequency discharge. The responses to upstream stimulation of striatal neurons on pallidal (2 nuclei) in waking monkeys "consist of an initial inhibition at a mean latency of 14ms, followed by excitation, at a mean latency of 35ms". The excitation was essentially located close to the stimulation electrode and curtailed by excitation. "This arrangement suggests that excitation is used temporarily, to control the magnitude of the central striato-pallidal inhibitory signal and, spatially to focus and contrast it into a restricted number of pallidal neurons". This should be compared to morphological data. Lateral pallidal neurons are often multitargets and may correspond to several hodotypes (neuronal varieties according to the topology of their ways to their targets). From in macaques, the lateral pallidal neurons sends axons in the direction of the striatum only in 15.8%. The other lateral pallidal neurons (84,2%) project to three consecutive targets (medial pallidum, nigra reticulata and subthalamic nucleus) in 13,2% of the cases. The neurons projecting to the medial pallidum and subthalamic targets are 18,4%. Those projecting to the subthalamic nucleus and nigra reticulata 52,6%. The subthalamic nucleus is thus, in 84,2% of the cases, the target of lateral pallidal neurons. In return, the subthalamic nucleus, the privileged target of the lateral pallidum sends the majority of its axons to it (see below).
The medial pallidum is the internal "segment" of the globus pallidus (GPi, Pallidum mediale), though absolutely similar to the lateral, is phylogenetically younger, as it appears only in primates. The entopeduncular nucleus of non-primate is not its equivalent. It does not have indeed a separate territory in the thalamus since its axons end together with nigral ones. In this respect the entopeduncular nucleus would rather be a lateral intracapsular extension of the nigra. The medial pallidum is separated into two parts (medial and lateral) by the lamina intermedia (with no known functional difference yet). As well as the lateral pallidum and the nigra lateralis and reticulata, see below), the medial pallidum is a "fast-spiking pacemaker" with spontaneous discharges in awake monkeys at about 90 Hz, or 70 to 80 for Filion and Tremblay (1991). In opposition to that of the lateral pallidum, the activity is continuous devoid of long intervals of silence. In addition to the massive striatopallidal connection, the medial pallidum receives a dopaminergic innervation from the nigra compacta. Contrary to the lateral pallidum, it is one of the two major source of basal ganglia outputs. The first axonal component (10%) in macaque is in the direction of the habenula. The main group (90%) sends long axons directed posteriorly that, through collaterals, furnish several successive targets: the lateral region of the thalamus (VO) (see human thalamus), the pars media of the central complex (see below), the pedunculopontine complex and to the retrorubral area. The major phylogenetic increase of the medial pallidum carries along that of a major output, the pallido-thalamic bundle, (successively the ansa and fasciculus lenticularis, the comb system, Forel's fields H2, H and H1) and, above all, the appearance of a distinct nucleus in the lateral region of the thalamus, the nucleus ventralis oralis, VO (see thalamus). The mediator is GABA, forming the second segment of the inhibitory 2-path.
The substantia nigra was first called the "tache noire" or "locus niger" (black spot) by Vicq d'Azyr (1786), then "substantia nigra" ('black substance', although it is not actually a substance). Only the melanin could be one, which would mean that the term only qualified the dopaminergic part (since only the dopaminergic neurons darken with age). The "nucleus substantiae nigrae", the nigrum, or nigra in fact comprises two adjoining but contrasted components one of which is not black but pale. A fundamental distinction must be made between the dopaminergic ensemble (including the pars compacta) and the GABAergic ensemble continuing the pallidum in the other side of the capsule. The similarity of the neuronal type of the pallidum and that of the nigra was emphazised as soon as in 1896 by Mirto. The nigral neurons also are sparsely branched and long. The difference between pallidal and nigral neurons is only in the three-dimensional extension of their dendritic arborizations. The continuity of the bundle from the striatum to the pallidum and to the nigra (striato-pallidonigral bundle) was known. The particular synaptology is also the same. Nigral dendrites, as well as pallidal, but not as strictly, tend to be perpendicular to the arriving stiatal axons. However, in spite of so many solid arguments, it still appears today very difficult to convince scientific opinion to mentally extract the substantia nigra from the mesencephalon (where it is indeed located) and to place it fully in the basal ganglia system. Another problem in the primate substantia nigra is that the pale part does not constitute a single entity. There are two subparts that belong to the basal ganglia core (i.e. receiving a dense projection from the striato-pallido-nigral bundle): the pars lateralis and the pars reticulata.
Nigra lateralis (SNl)
There are important interspecific differences in the organization of the substantia nigra. "The monkey nigrotectal cells" ... (become) a spatially ... distinct subpopulation within the pars reticulata. Not all atlas trace a pars lateralis but others do, e.g., Riley, 1960 in man and Paxinos et al. (2000), in macaque. The pars lateralis is the most lateral part of the substantia nigra. It is frequently not considered separately from the pars reticulata. It is, however, on most of its dorsal border not covered by the substantia nigra compacta. But its main difference with the pars reticulata is that it sends axons to the superior colliculus. The border between the two basins is not clearcut but their difference in the participation of distincts subsystems is a sufficient reason for considering the two apart. The neurons that send axons to the superior colliculus have high discharge rates (80 to 100) (hence also a fastspiking pacemaker) and "the signal conveyed by the cells is a decrease in discharge rate" These neurons are involved in occular saccades that have taken a major interest in the last years.
Nigra reticulata (SNr)
The pars reticulata or diffusa, is most often considered as a single entity with the pars lateralis. The term pars reticulata may thus describe either only the most medial part of the nigral ensemble, when a pars lateralis is retained, or the addition of the pars lateralis and reticulata. This must be carefully checked in papers. Due to major interspecific differences, the studied animal species must be verified. The name reticulata is simply an opposition to the dense pars compacta located above it. The border between the two is highly convoluted with deep fringes. Its neuronal genus is the same as that of the pallidum, with the same thick and long dendritic trees. It receives its synapses from the striatum in the same way as the pallidum. Striatonigral axons from the striosomes may form columns vertically oriented entering deeply in the pars reticulata. The ventral dendrites of the pars compacta from the reverse direction go also deeply in it. The nigra also send axons to the pedunculo-pontine complex and to the parafascicular part of the central complex. The substantia nigra reticulata is another "fast-spiking pacemaker" Stimulations provoke no movements. Confirming anatomical data, few neurons respond to passive and active movements (there is no sensorimotor map) "but a large proportion shows responses that may be related to memory, attention or movement preparation" that would correspond to a more elaborate level than that of the medial pallidum. In addition to the massive striatopallidal connection, the nigra reticulata receives a dopamine innervation from the nigra compacta and glutamatergic axons from the pars parafascicularis of the central complex. It sends nigro-thalamic axons. There is no conspicuous nigro-thalamic bundle. Axons arrive medially to the pallidal afferences at the anterior and most medial part of the lateral region of the thalamus: the nucleus ventralis anterior (VA, differentiated from the VO receiving pallidal afferences, see Thalamus). The mediator is GABA.
The striato-pallidonigral connection is a very particular one. It engages the totality of spiny striatal axons. Estimated numbers are 110 million in man, 40 in chimpanzees and 12 in macaques. The striato-pallido-nigral bundle is made up of thin, poorly myelinated axons from the striatal spiny neurons grouped into pencils "converging like the spokes of a wheel" (Papez, 1941). It gives its "pale" aspect to the receiving areas. The bundle strongly stains for iron using Perls technique (in addition to Fe it contains many heavy metals among which: Co, Cu, Mg, Pb ...).
Convergence and focusing
After the huge reduction in number of neurons between the cortex and the striatum (see corticostriate connection), the striatopallido-nigral connection is a further reduction in the number of transmitting compared to receiving neurons. Numbers indicate that, for 31 million striatal spiny neurons in macaques, there are only 166000 lateral pallidal neurons, 63000 medial pallidal, 18000 lateral nigral and 35000 in the pars reticulata. If the number of striatal neurons is divided by their total number, as an average, each target neuron may receive information from 117 striatal neurons. (Numbers in man lead to about the same ratio). A different approach starts from the mean surface of the pallidonigral target neurons and the number of synapses that they may receive. Each pallidonigral neuron may receive 70000 synapses. Each striatal neuron may contribute 680 synapses. This leads again to an approximation of 100 striatal neurons for one target neuron. This represents a huge, infrequent, reduction in neuronal connections. The consecutive compression of maps cannot preserve finely distributed maps (as in the case for instance of sensory systems). The fact that a strong anatomical possibility of convergence exists does not means that this is constantly used. A recent modeling study starting from entirely 3-d reconstructed pallidal neurons showed that their morphology alone is able to create a center-surround pattern of activity. Physiological analyses have shown a central inhibition/peripheral excitation pattern, able of focusing the pallidal response in normal conditions. Percheron and Filion (1991) thus argued for a "dynamically focused convergence". Disease, is able to alter the normal focusing. In monkeys intoxicated by MPTP, striatal stimulations lead to a large convergence on pallidal neurons and a less precise mapping. Focusing is not a property of the striatopallidal system. But, the very particular and contrasted geometry of the connection between striatal axons and pallidonigral dendrites offers particular conditions (the possibility for a very large number of combinations through local additions of simultaneous inputs to one tree or to several distant foci for instance). The disfocusing of the system is thought to be responsible for most of the parkinsonian series symptoms. The mechanism of focusing is not known yet. The structure of the dopaminergic innervation does not seem to allow it to operate for this function. More likely focusing is regulated by the upstream striatopallidal and corticostriatal systems.
Synaptology and combinatory
The synaptology of the striato- pallidonigral connection is so peculiar as to be recognized easily. Pallidonigral dendrites are entirely covered with synapses without any apposition of glia. This gives in sections characteristic images of "pallissades" or of "rosettes". More than 90% of these synapses are of striatal origin. The few other synapses such as the dopaminergic or the cholinergic are interspersed among the GABAergic striatonigral synapses. The way striatal axons distribute their synapses is a disputed point. The fact that striatal axons are seen parallel to dendrites as "woolly fibers" has led to exaggerate the distances along which dendrites and axons are parallel. Striatal axons may in fact simply cross the dendrite and give a single synapse. More frequently the striatal axon curves its course and follow the dendrite forming "parallel contacts" for a rather short distance. The average length of parallel contacts was found to be 55 micrometres with 3 to 10 boutons (synapses). In another type of axonal pattern the afferent axon bifurcates and gives two or more branches, parallel to the dendrite, thus increasing the number of synapses given by one striatal axon. The same axon may reach other parts of the same dendritic arborisation (forming "random cascades") With this pattern, it is more than likely that 1 or even 5 striatal axons are not able to influence (to inhibit) the activity of one pallidal neuron. Certain spatio-temporal conditions would be necessary for this, implying more afferent axons.
What is described above concerned the input map or "inmap" (corresponding to the spatial distribution of the afferent axons from one source to one target). This does not correspond necessarily to the output map or outmap (corresponding to the distribution of the neurons in relation to their axonal targets). Physiological studies and transsynaptic viral markers have shown that islands of pallidal neurons (only their cell bodies or somata, or trigger points) sending their axons through their particular thalamic territories (or nuclei) to one determined cortical target are organized into radial bands. These were assested to be totally representative of the pallidal organisation. This is certainly not the case. Pallidum is precisely one cerebral place where there is a dramatic change between one afferent geometry and a completely different efferent one. The inmap and the outmap are totally different. This is an indication of the fundamental role of the pallidonigral set: the spatial reorganisation of information for a particular "function", which is predictably a particular reorganisation within the thalamus preparing a distribution to the cortex. The outmap of the nigra (lateralis reticulata) is less differentiated.
Substantia nigra compacta (SNc) and nearby dopaminergic elements
In strict sense, the pars compacta is a part of the core of basal ganglia core since it directly receives synapses from striatal axons through the striatopallidonigral bundle. The long ventral dendrites of the pars compacta indeed plunge deep in the pars reticulata where they receive synapses from the bundle. However, its constitution, physiology and mediator contrast with the rest of the nigra. This explains why it is analysed here between the elements of the core and the regulators. Ageing leads to the blackening of its cell bodies, by deposit of melanin, visible by naked eye. This is the origin of the name of the ensemble, first "locus niger" (Vicq d'Azyr), meaning black place, and then "substantia nigra" (Sömmerring), meaning black substance.
The densely distributed neurons of the pars compacta have larger and thicker dendritic arborizations than those of the pars reticulata and lateralis. The ventral dendrites descending in the pars reticulata receives inhibitory synapses from the initial axonal collaterals of pars reticulata neurons (Hajos and Greefield, 1994). Groups of dopaminergic neurons located more dorsally and posteriorly in the tegmentum are of the same type without forming true nuclei. The "cell groups A8 and A10" are spread inside the cerebral peduncule. They are not known to receive striatal afferences and are not in a topographical position to do so. The dopaminergic ensemble is thus also on this point inhomogeneous. This is another major difference with the pallidonigral ensemble. The axons of the dopaminergic neurons, that are thin and varicose, leave the nigra dorsally. They turn round the medial border of the subthalamic nucleus, enter the H2 field above the subthalamic nucleus, then cross the internal capsule to reach the upper part of the medial pallidum where they enter the pallidal laminae, from which they enter the striatum. They end intensively but inhomogeneously in the striatum, rather in the matrix of the anterior part and rather in the striosomes dorsalwards. These authors insit on the extrastriatal dopaminergic innervation of other elements of the basal ganglia system: pallidum and subthalamic nucleus.
Contrarily to the neurons of the pars reticulata-lateralis, dopaminergic neurons are "low-spiking pacemakers", spiking at low frequency (0,2 to 10 Hz) (below 8, Schultz). The role of the dopaminergic neurons has been the source of a considerable literature. As the pathological disappearance of the black neurons was linked to the appearance of Parkinson's disease, their activity was thought to be "motor" . A major discovery has been that the stimulation of the black neurons had no motor effect. Their activity is in fact linked to reward and prediction of reward. In a recent review (Schultz 2007), it is demonstrated that "phasic responses to reward-related events , notably reward-prediction errors, ...lead to ..dopamine release..." While it is thought that there could be different behavioral processes including long time regulation. Due to its widespread distribution, the dopaminergic system may regulate the basal ganglia system in many places.
Regulators of the basal ganglia core
Subthalamic nucleus, or corpus Lyuisi
As indicated by its name, the subthalamic nucleus is located below the thalamus; dorsally to the substantia nigra and medial to the internal capsule. The subthalamic nucleus is lenticular in form and of homogeneous aspect. It is made up of a particular neuronal species having rather long ellipsoid dendritic arborisations, devoid of spines, mimicking the shape of the whole nucleus. The subthalamic neurons are "fast-spiking pacemakers" spiking at 80 to 90 Hz. There are also about 7,5% of GABA microneurons participating in the local circuitry. The subthalamic nucleus receives its main afference from the lateral pallidum. Another afference comes from the cerebral cortex (glutamatergic), particularly from the motor cortex, which is too much neglected in models. A cortical excitation, via the subthalamic nucleus provokes an early short latency excitation leading to an inhibition in pallidal neurons. Subthalamic axons leave the nucleus dorsally. Except for the connection to the striatum (17.3% in macaques), most of the principal neurons are multitargets and ffed axons to the other elements of the core of the basal ganglia. Some send axons to the substantia nigra medially and 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%). Fewer are single target for the lateral pallidum. If one adds all those reaching this target, the main afference of the subthalamic nucleus is, in 82.7% of the cases, the lateral pallidum (external segment of the globus pallidus. While striatopallidal and the pallido-subthalamic connections are inhibitory (GABA), the subthalamic nucleus utilises the excitatory neurotransmitter glutamate. Its lesion resulting in hemiballismus is known for long. Deep brain stimulation of the nucleus suppress most of the symptoms of the Parkinson' syndrome, particularly dyskinesia induced by dopamine therapy.
As said before, the lateral pallidum has purely intrinsic basal ganglia targets. It is particularly linked to the subthalamic nucleus by two-way connections. Contrary to the two output sources (medial pallidum and nigra reticulata), neither the lateral pallidum or the subthalmic nucleus send axons to the thalamus. The subthalamic nucleus and lateral pallidum are both fast-firing pacemakers. Together they constitute the "central pacemaker of the basal ganglia" with synchronous bursts. The pallido-subthalamic connection is inhibitory, the subthalamo-pallidal is excitatory. They are coupled regulators or coupled autonomous oscillators, the analysis of which has been insufficiently deepened. The lateral pallidum receives a lot of striatal axons, the subthalamic nucleus not. The subthalamic nucleus receives cortical axons, the pallidum not. The subsystem they make with their inputs and outputs corresponds to a classical systemic feedback circuit but it is evidently more complex.
Central region of the thalamus (C)
The central complex is the so-called centre-médian- parafascicular complex. Contrary to the current claim it does not topographically, histologically or functionally belong to the intralaminar group. Located at the inferior part of the thalamus, it is almost everywhere surrounded by a capsule making it a closed region. In upper primates, starting from the cercopithecidae, it is made up not of two but of three parts with their own neuronal species. From there, two opposed interpretations were proposed concerning the belonging of the intermediate part: either to the centre médian or to the parafascicular nucleus. This is undecided. It has thus been proposed to group the three elements together in the regio Centralis (since it is a classical nucleus) and to name them from medially to laterally: n. centralis pars parafascicularis, pars media and pars paralateralis. The whole is parvalbumin rich. The first two medial parts are acetylcholinesterase rich. They are the source of the major, centralo-striatal, part of the thalamo-striatal connection, with glutamate as the mediator. The pars parafascicularis sends axons essentially to the associative striatum. The pars media sends axons to the matrix compartment of the sensorimotor striatum through an important bundle. In addition to cortical (see below), the pars parafascicularis receives afferences from the substantia nigra and the superior colliculus. The main afference of the pars media is the medial pallidum. The pars media is a part of the subcortical Nauta-Mehler's circuit (striatum-medial pallidum-pars media-striatum). The pars paralateralis has essentially cortical relations particularly with the motor cortex. There are thus strong interconnections of the complex with the basal ganglia. The structure of the complex being different from that of the close intralaminar formation and having different connections, it has been proposed two decades ago to remove the central complex from the intralaminar elements and to link it to the basal ganglia system, where it may be classified among the regulators of the core. Lesions of the complex have no known clinical effects. There are few physiological data in awake monkeys. For Matsumoto et al. (2001) the axons of the complex would supply striatal neurons with information about behaviorally significant sensory events. For Minamimoto and Kimura (2002) the region plays a role in attentional orienting to events occurring in the contralateral side.
The pedunculopontine complex (nucleus tegmenti pedunculopontinus) is not a primary part of the basal ganglia. It is a part of the reticulate formation having strong interrelations with the basal ganglia system. As indicated by its name, it is located at the junction between the pons and the cerebral peduncle, lateral to the decussation of the brachium conjunctivum. The complex is not homogeneous. An important part is made up of cholinergic (Ch5)(excitatory) neurons, which is also the case for the laterodorsal tegmental nucleus (Ch6). Other neurons are GABAergic. The tracing of axons from the pedunculopontine complex has shown that they end intensively in the nigra reticulata first and to the compacta. Another strong innervation is observed in the subthalamic nucleus. Other targets are the pallidum (mainly medial) and the striatum. The complex receives direct afferences from the cortex and above all abundant direct afferences from the medial pallidum (inhibitory). It sends axons to the pallidal territory of the lateral region VO. The activity of the neurons is modified by movement, and precede it. All this led Mena-Segovia et al. (2004) to propose that the complex be linked in a way or another to the basal ganglia system. A review on its role in the system and in diseases is given by Pahapill and Lozano (2000). It plays an important role in awakeness and sleep. The complex must be left its double position and function. It is a part of the reticular formation. It is a regulator (regulating and being regulated) of the basal ganglia system.
Outputs of the basal ganglia system
Many connections of the basal ganglia are between elements of the basal ganglia. There are few output external targets. One is the superior colliculus, from the nigra lateralis. The two other major output subsystems are in the direction to the thalamus and from there to the cortex. Starting from cercopidae, the ending from the two sources of the basal ganglia are located without mixture in front of the cerebellar territory (VIm or VL) (see thalamus). From there, there is also a complete separation of medial pallidal elements from nigral. Pallidal and nigral terminal arborisations do not mix. The development of the medial pallidum creates the appearance of a new distinctive pallidal nucleus, the nucleus ventralis oralis VO, lateral to the nigral VA. This distinction is of major importance (see thalamus).
Nigra lateralis to superior colliculus
The nigra lateralis made up of the same cell type than the pars reticulata differs by its targets. The now well established connection to the tectum in macaques is not given its full value. The superior colliculus indeed sends axons to the thalamic VImM, VA, Cpf, with links with the oculomotor cortex. In addition, through a thalamic relay, the nigra lateralis sends information to the premotor and also to the frontal cortex.
Medial pallidum to thalamic VO and from there to cortex
Axons from the pallidum to the thalamus form the ansa lenticularis and the fasciculus lenticularis, making in fact a single entity. The axons arrive at the medial face of the pallidum; from there, they cross the internal capsule where they form the comb system ("Kamm system"). The axons arrives at the lateral border of the subthalamic nucleus. Passing above it they constitute the field H2 of Forel (1877). From there, they curve down towards the hypothalamus. At field H, they turn abruptly. This has been the cause of historical mistakes as it was thought that the bundle had to pursue its ventral course. In fact the bundle goes up in a dorsolateral direction (forming the H1 field) and reach in this manner the ventral border of the thalamus. Pallidal axons have their own thalamic territory in the lateral region of the thalamus; everywhere separated from the cerebellar and from the nigral territories. The VO nucleus remains everywhere lateral in macaques and humans. It stained for calbindin and acetylcholinesterase. The axons ascend in the nucleus where they emit branches that widespreadly distribute "bunches" of axonal branches. The distribution is such that if any somatotopical organisation exists, it may be only poor. The thalamocortical neurons of VO go preferentially to the supplementary motor cortex (SMA), to preSMA and to a lesser extent to the motor cortex. The pallidothalamic neurons also give branches to the pars media of the central complex (see above), which sends axons to the premotor and accessory motor cortex.
Nigra reticulata to thalamic VA and from there to cortex
Nigral axons go up dorsally without forming a clear distinctive bundle. They reach the inferomedial border of the thalamus. The nigral target thalamic territory (VA) is medial to the pallidal (VO). It is crossed by the mammillothalamic bundle. In the monkey, the nucleus is usually divided into a magnocellular part, medial and close to the mammillothalamic bundle, and a mediocellular part. In the human brain, the majority of the nucleus is composed of the magnocellular component. In any case, in macaques, the afferences from the nigra do not care about these cytoarchitectonic subdivisions. In addition to the nigral afference, VA receives axons from the tectum (superior colliculus) and from the amygdala (basal complex), which makes a singular set of afferences. Thalamocortical projections from VA travel to their own distinctive cortical territory made up of the frontal (premotor), the anterior cingulate cortex (ACC) and the oculomotor cortex (FEF and SEF), without significant connection to the motor cortex of the precentral gyrus. This set of thalamocortical outputs is different and distinct from that of the thalamic VO to which the medial pallidum connects.
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