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The basal ganglia system is a pair and symmetrical major cerebral system that has only recently been recognized. In the past, part of it was presented as "motor" or "extrapyramidal", complementary to the corticospinal (pyramidal) system. Contrary to what was thought, the basal ganglia system has no direct output to the spinal cord. As already known by Charcot, the motor effects are exerted through the "pyramidal" cortex and the pyramidal fascicle. The unilateral effects are thus contralateral. The basal ganglia system participates in much more than motor functions. As it is highly evolutive, it appears opportune to consider the primate system apart. Major changes have occurred in recent years that drastically modify the subject, which thus deserves to be examined in detail.
The first anatomical identification of distinct subcortical structures, at the "base" of the brain, was published by Willis in 1664. For many years (see Percheron et al. 1994), the term "corpus striatum" was used (e.g.Vieussens, 1685) to describe a large group of subcortical elements, some of which were later discovered to be functionally unrelated. For a long period, the putamen and the caudate nucleus were not linked together. Conversely, the putamen was associated with the pallidum in what was called the "nucleus lenticularis" or "lentiformis" (concepts and terms that should no more be used). Pioneering work by Cécile and Oskar Vogt (1941) greatly simplified the description of the basal ganglia in proposing to link under a single term elements made up of same neuronal elements. The term striatum unites together the caudate nucleus, the putamen and the mass linking them ventrally, the fundus. The striatum got its name from the striated appearance created by dense radiating bundles of striato -pallidonigral axons, described by Kinnier Wilson (1912) as "pencils". The anatomical link of the striatum with its primary targets, the pallidum and the substantia nigra, was discovered later. The name of globus pallidus, according to Déjerine would be attributable to Burdach (1822). Here again the Vogts proposed the simpler term of pallidum. The name "locus niger" used for a long period is due to Vicq d'Azyr (tache noire) (1786) anteceding that of substantia nigra (Sömmering,1788). The similarity between the structure of the substantia nigra and that of the "globus pallidus" was noted very early by Mirto (1896). The regrouping of the two as a well characterised ensemble (the pallidonigral set) is still accepted with difficulty in spite of a solid body of arguments. The striato-pallidonigral ensemble represents the core of the basal ganglia. The striato-pallidonigral bundle passes through the pallidum, crosses the internal capsule as the "comb bundle" of Edinger, then finally reaches the substantia nigra. Additional structures later became associated with the basal ganglia such as the "body of Luys" (1865, Forel 1877) or subthalamic nucleus, the lesion of which was known to produce hemiballism. More recently, other areas such as the central complex (centre médian-parafascicular) of Luys and the pedunculopontine complex have been considered as parts of the system. This is finally made up of a restricted number of elements but linked with strong interrelations, which give its strength to the system.
Definition and content
The basal ganglia system, as recently identified, met problems even in its naming. The term basal comes from the fact that most of its elements are located in the "basal" part of the brain (the basal nucleus of Meynert is however not a part of the system). The term ganglion has never been adequate for central nervous elements. Terminologia anatomica (1998), the international authority for anatomical naming, retained "nuclei basales", which is not used. The International Basal Ganglia Society (IBAGS), (unformally) considers as basal ganglia, the striatum, the pallidum (with two nuclei), the substantia nigra (with its two distincts parts) and the subthalamic nucleus. To this is added today the central region (centre median-parafascicular) (Percheron et al. 1991, Parent and Parent, 2005) and for some, the pedunculopontine complex (Mena-Segovia et al. 2004). The basal ganglia system may be defined as the set of subcortical nuclear elements commencing from the striatum, in interaction together and with connected parts of the thalamus and cortex. This ensemble must not be seen as a collection of elements but as a complete system. Given that the major inputs to the striatum include most of the overlying cerebral cortex (see below) and the basal ganglia outputs from the medial nucleus of the pallidum and the reticulate part of the substantia nigra send axons to regions of the lateral mass of the thalamus that, in turn, connect back to specific regions of the cortex, the basal ganglia has been seen as a major subcortical system of cortical re-entrance. The significance of re-entrant systems has been postulated by Gerald Edelman to be the basis for the emergence of primary consciousness(a theoretically based hypothesis). Recent results, indeed, insist on autonomous oscillators inside the basal ganglia and thus limit the importance of cortico subcortico-cortical loops.
The whole system starts as a major output of the cortex, about the same size as the corticopontine system opening the cerebellar system. The cortico-striatal 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 (Parent and Parent, 2006). 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 (Goldman-Rakic and Nauta, 1977, Selemon and Goldman-Rakic, 1985). The cortico-stiatal 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"(Flaherty and Graybiel, 1991).
The corticostriate connection is the first in a chain of strong reduction in numbers between emitter and receiver neurons (Percheron et al. 1987), i.e. a numerical convergence. The effect of this is that if each striatocortical neurons has its own message, this will be mixed or compressed, leading to lesser definition of the input map.
The striatum is the main element of the basal ganglia system. It consists in a huge neuronal telencephalic subcortical mass. It has a toric topology but is a single closed space.
In primates, the striatum has four neuronal genera: 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 (Czubayko and Plenz, 2002). 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 (Kimura et al. 2003). The microneurons are local circuit neurons similar to those found in the thalamus for instance. They are GABAergic, and some may be dopaminergic (Cossette et al.2005).
The spontaneous activity of striatal neurons of awake monkeys is surprisingly "low or absent" (DeLong, 1980). 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, caudate and fundus. In fact, 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 (Künzle 1975 and several other papers), accessory motor and anterior parietal, constitute a sensorimotor territory (or for short sensorimotor striatum) essentially putaminal, but which does not cover the total extent of the putamen. Conversely it 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. To this is opposed 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 (Brauer et al. 2000) 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 (Graybiel and Ragsdale, 1978). 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) (Eblen and Graybiel,1995). 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 no to be actually true.
Basal ganglia core
The basal ganglia core includes the striatum and its direct targets, reached through the striato-pallidonigral bundle: the two nuclei of the pallidum and the substantia nigra.
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 macaque (Levesque and Parent et al. 2005)(following another one in 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. Since Haber and Elde (1981), it is known that 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 (François et al. (1994) 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 (Kitano et al.1998)
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, Cecile and Oskar Vogt (1941) simplified the case by selecting the term pallidum, also offered 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 (Yelnik et al. 1987). 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 (Yelnik et al. 1984). Their principal plane is parallel one to the others and all parallel to the lateral border of the pallidum; thus perpendicular to the axis of the afferences (Percheron et al. 1984). 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 (Fox et al. 1974). 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 (Di Figlia et al. 1982 ). 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 (di Figlia et al. 1982, François et al. 1984) that could act as elements of local circuitry, there are weak or no functional interrelations between pallidal neurons (Bar-Gad et al 2003).
Lateral pallidum (lateral nucleus of the pallidum, external "segment" of the globus pallidus(GPe, )
The lateral pallidum 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 (Percheron et al. 1984). 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" (DeLong, 1971). 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" (Tremblay and Filion 1989). 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 striatopllidal inhibitory signal and, spatially to focus and contrast it into a restricted number of pallidal neurons" (Tremblay and Filion 1989). This should be compared to morphological datas. 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 Sato et al. (2000), 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).
Medial pallidum (internal "segment"of the globus pallidus(GPi, Pallidum mediale)
The medial pallidum, 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 (Mink and Thach, 1991), 70 to 80 for Fillion and Tremblay (1991). In opposition to that of the lateral pallidum, the activity is continuous devoid of long intervals of silence (DeLong, 1971). 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 (Percheron et al., 1996) and to the retrorubral area (Parent and Parent (2004). 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" (Soemering,1891); yet not 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" (Olszewski and Baxter 1954), the nigrum (the Vogts, 1941) 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 simililarity 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 (Yelnik, et al. 1987). The difference between pallidal and nigral neurons is only in the three-dimensional extension of their dendritic arborizations (François et al. 1987). 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 to day very difficult to convince the 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 (Beckstead et al. 1981). "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 (Beckstead and Franckfurter, 1982, François et al. 1984). 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" (Hikosaka and Wurtz, 1989). 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 (Lesvesque and Parent, 2005). 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 (Beckstead and Frankfurter, 1982) and to the parafascicular part of the central complex. The substantia nigra reticulata is another "fast-spiking pacemaker" (Surmeier et al. 2005). 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" (Wicheman and Kliem, 2004) 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 pallidonigral pacemaker
One of the most important recent discovery is that the basal ganglia machinery is not simply set in motion from the outside (from afferent information). It has indeed several "autonomous pacemakers", defined as sets of "neurons capable of periodic spiking in the absence of synaptic input" (Surmeier et al. 2005) i.e. able of producing an own activity. Among autonomous pacemakers, the pallidonigral ensemble belongs to the "fast-spiking pacemakers" "capable of discharges rates in excess of 200 Hz for sustained periods" (Surmeier et al., 2005). The regularity and frequency of the pacemaker is linked to cyclic nucleotide-gated channels (HCN2 and HCN1, Chan et al. 2004) present on the dendrites of pallidal neurons. Pacemakers are oscillatory systems, that meet today a considerable interest, biologically and theoretically (Mikhailov, 1992). They are indeed chaotic oscillators. In the so evolutive basal ganglia system it is important to specify that the majority of what is known about the production and regulation of the pallidonigral pacemaker comes from work on slices in rodents. These having no true medial pallidum, the data deal with the external, which belongs to a particular subsystem. In a recent paper in humans, (Rasouli et al. 2006) wrote that "robust fractal dynamics (could be) observed in single neurons...the neuronal dynamics of the internal segment of the globus pallidus are essentially a nonlinear and nonequilibrium process". As well as for the atrial pacemaker there is a double need: regularity and adaptability. The pallidonigral pacemaker is modulated by striato-pallidonigral inputs. This topic is expected to become a rich field of research in the near future.
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 (see Percheron et al. 1984, 1987). 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 given by Percheron et al. (1987, 1989) indicate that, for 31 million striatal spiny neurons in macaques, there are only 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). Another 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, unfrequent, 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 (Mouchet and Yelnik, 2004). Physiological analyses have shown a central inhibition/peripheral excitation pattern (Tremblay and Filion, 1989), 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 (Filion et al, 1988 and Tremblay et al. 1989) . Focusing is not a propery 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 (Fox et al.,1974, Di Figlia et al. 1982). 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", Percheron 1991). 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 (Hoover and Strick 1994 and Middleton and Strick, 1994). 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 (Middleton and Strick, 2002).
Substantia nigra compacta (SNc) and nearby dopaminergic elements
In the srict sens, 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 blak place) and then ('substantia nigra', Soemering ) 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 (François et al. 1999). 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 (Percheron et al. 1989). They end intensively but inhomogeneously in the striatum, rather in the matrix of the anterior part and rather in the striosomes dorsalwards (Prensa et al.2000). 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" (Surmeier et al. 2005), 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 (Tretiakoff, 1919), 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 (Yelnik and Percheron,1979).The subthalamic neurons are "fast-spiking pacemakers" (Surmeier et al. 2005) spiking at 80 to 90 Hz. There are also about 7,5% of GABA microneurons participating in the local circuitry (Levesque and Parent 2005). 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 (Nambu et al. 2000). 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 (Sato et al. 2000). 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. Chronic stereotactic stimulation of the nucleus suppress most of the symptoms of the Parkinson' syndrome, particularly dyskinesia induced by dopatherapy.
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 (Surmeier et al.2005). Together they constitute the "central pacemaker of the basal ganglia" (Plenz and Kitai,1999) 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 is 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 (Percheron et al. 1991). 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 (Fenelon et al. 1994). From there, two opposed interpretations were proposed concerning the belonging of the intermediate part: either to the centre médian (the Vogts, 1941) or to the parafascicular nucleus (Niimi et al. 1960). This is undecidable. 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 (François et al. 1991). 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, Olszewski and Baxter 1954) is not a primary part of the basal ganglia. It is a part of the reticulate formation (Mesulam et al. 1989) 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) (Mesulam et al. 1989). 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 (Lavoie and Parent, 1994). 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 (Percheron et al. 1998) (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 (Matsumura, Watanabe and Ohye (1997). 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 (Percheron et al. 1998). 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 (Percheron, 2003). 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 establihed connection to the tectum in macaques (Jayaraman et al.1977, François et al.1984) 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 (Middleton and Strick, 2002).
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" of Edinger, 1900). 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 (Arrrechi-Bouchhiouia et al.1996,1997). 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.
Subsystems and models
Classical and current models
System representations very frequently use the "box-and-arrow model", in which boxes are elements (often reduced to their name) and arrows are connections. In very poor theoretical appparatus, many contributions, boxes were presumed to be clearly distinct one from the other, homogeneous and closed. In ordinary models, the cortex is reduced to one box and the (motor) thalamus to an undifferentiate single "VA/VL complex". Connections in these models have no topology and no numeral weight. Several models have been proposed at about the same time. Anatomical work has demonstrated that there is a strong compression of numbers of neurons meaning a numerical convergence (Yelnik et al.1984, Percheron et al. 1984). This objective "funneling" has been attacked in the opposed model of Alexander et al.(1986), Alexander and Crutcher (1990), presented in several other forms. These authors proposed distinct chains of anatomical connections that would escape funneling and preserve 5 to 6 "basal ganglia-thalamocortical circuits": motor, oculomotor, prefrontal (dorsolateral prefrontal and lateral orbitofrontal) and limbic (or anterior cingulate), which through the basal ganglia and the thalamus would return to the initial point of the cortex. This "parallelist" view does not fit with the observable anatomy. As repeatedly proven, the corticostriate connection does not follow the Kemp and Powell model (1970). In addition to compression there is an intricacy of subsystems (e.g.the oculomotor component intricate with the frontal one). The thalamo-cortical connection does not follow simple rules and usually has several cortical targets (see corticostriate connection). Another model, that of Albin et al.(1989) (later admitted to have been too simplistic) selected two criteria: the inhibitory/excitatory character of connections and the mediator involved. More recent models place the subthalamic nucleus in a privileged position due to the fact that it is excitatory when the striatum, the pallidum and the nigra have inhibitory mediators. To a "direct pathway" (cortex-striatum-medialpallidonigro-thalamo-cortical)(5-circuit) was opposed an "indirect pathway"(cortex-striatum-lateral pallidum-subthalamic nucleus-medialpallidonigral-thalamo-cortical) (6-circuit). The particularly complex system of the basal ganglia incites to more refined systemic analyses, with systems and subsystems. The distinction between output subsystems and regulator subsystems does not correspond exactly with that made above between the core and the regulators. One part of the core, the lateral pallidum, is indeed a part of the core and a regulator. It does not send axons to the thalamus and from there to the cortex. All its efferent axons instead return inside the basal ganglia system. With its main target the subthalamic nucleus they constitute together a particular subsystem, with two high frequency autonomous pacemakers, one inhibitory (GABA) and one excitatory (glutamate). The subthalamic nucleus sends axons to another regulator: the pedunculo-pontine complex (also excitatory, glutamatergic). This and the central complex are elements of other basal ganglia regulating subsystems. There are many arguments against treating in the same manner the "indirect circuit" involving a regulator circuit and the output circuits. These, do not send axons (hence no regulatory messages) to the striatum, lateral pallidum or subthalamic nucleus. In addition, there is not one "direct" but two output subsystems in primates. Starting from the striatum, each forms a 3-path to the cortex. The first output path from the striatum has its first relay in the medial pallidum (GABAegic, inhibitory). This sends axons (again GABAergic and inhibitory) to a particular part of the thalamus, the nucleus ventralis oralis VO (see 'human thalamus). VO sends its axons to the accessory motor, dorsal premotor and motor cortex (with glutamate as the mediator). The second output subsystem follows exactly the same pattern, but, this time, starts from the nigra reticulata. Nigral axon go to the nucleus ventralis anterior VA. This VA (not exactly corresponding to the popular nucleus) sends axons to the frontal cortex and the oculomotor areas (glutamatergic). The separation of the two subsystems corresponding to a differentiated cortical distribution should be always distinguished. The new data concerning the morphology and physiology of the basal ganglia system raise problems. The fact that the pallidonigral set (as defined above) is a high-frequency pacemaker (1) emitting inhibitory signals (2) receiving at low frequency, but in possibly large numbers, messages from the striatum that are also inhibitory should modify the way of reasoning. The so-called "indirect circuit" in fact grab a part of the regulator set essentially the lateropallidal-subthalamic system. Some axons from the lateral pallidum go to the striatum (Sato et al.2000). Above all, many of them go to other basal ganglia elements: the medial pallidum, the nigra reticulata and the subthalamic nucleus. The activity of the medial pallidum is thus influenced by afferences from the lateral pallidum and from the subthalamic nucleus (Smith, Y., Wichmann, T.,DeLong, M.R. 1994). The same holds true for the nigra reticulata (Smith, Y., Hazrati, L-N, Parent, A. 1990). Among other ways of looking to the basal ganglia system, that indicated by morphology and physiology raises problems. The pallidonigral set (as defined above) is a high-frequency pacemaker (1) emitting inhibitory signals (2) receiving at low frequency but in possibly large numbers messages from the striatum that are also inhibitory. Adaquate striatal patterns thus might carve, by desinhibition, an appropriate pattern of signals (a message) to the thalamus and from there to the cortex.
Theoretical tools that are not all recent allow objective systemic analysis relying on graph theoretical and systemic concepts These may be found in fundamental neuromorphology. Only one point will be considered. In directed graphs or digraphs, connection, the graph theoretical link (arc) or segment between two elements (the "boxes") is oriented in a single direction (1-path). Two connections are necessary to constitute to a 2-circuit, which, in system theory usually corresponds to one connection with a regulating feed-back.
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