Primate basal ganglia

The basal ganglia form a major brain system in all species of vertebrates, but in primates (including humans) there are 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, there are two pallidal subdivisions called the external globus pallidus (GPe) and internal globus pallidus (GPi). Also in primates, the dorsal striatum is divided by a large tract called the internal capsule into two masses named the caudate nucleus and the putamen—in most other species no such division exists, and only the striatum as a whole is recognized. Beyond this, there is a complex circuitry of connections between the striatum and cortex that is specific to primates. This complexity reflects the difference in functioning of different cortical areas in the primate brain. 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.

A major output from the cortex, with axons from most of the cortical regions connecting to the striatum, is called the corticostriatal connection, part of the cortico basal ganglia thalamo cortical loop. In the primate most of these axons are thin and unbranched. The striatum does not receive axons from the primary olfactory, visual or auditory cortices. The corticostriatal connection is an excitatory glutamatergic pathway. One small cortical site can project many axon branches to several parts of the striatum.

The striatum is the largest structure of the basal ganglia.

Medium spiny neurons (MSN)s, account for up to 95 per cent of the striatal neurons. There are two populations of these projection neurons, MSN1 and MSN2, both of which are inhibitory GABAergic. There are also various groups of GABAergic interneurons and a single group of cholinergic interneurons. These few types are responsible for the reception, processing, and relaying of all the cortical input. Most of the dendritic spines on the medium spiny neurons synapse with cortical afferents and their axons project numerous collaterals to other neurons. The cholinergic interneurons of the primate, are very different from those of non primates. These are said to be tonically active. The dorsal striatum and the ventral striatum have different populations of the cholinergic interneurons showing a marked difference in shape.

The striatum is one mass of grey matter that has two different parts, a ventral and a dorsal part. The dorsal striatum contains the caudate nucleus and the putamen, and the ventral striatum contains the nucleus accumbens and the olfactory tubercle. The internal capsule is seen as dividing the two parts of the dorsal striatum. Sensorimotor input is mostly to the putamen. An associative input goes to the caudate nucleus and possibly to the nucleus accumbens. There are two different components of the striatum differentiated by staining – striosomes and a matrix. Striosomes are located in the matrix of the striatum and these contain μ opioid receptors and dopamine receptor D1 binding sites. The striatopallidal fibers give a connection from the putamen to the globus pallidus and substantia nigra.

Unlike the inhibitory GABAergic neurons in the neocortex that only send local connections, in the striatum these neurons send long axons to targets in the pallidum and substantia nigra. A study in macaques showed that the medium spiny neurons have several targets. Most striatal axons first target the GPe, some of these also target the GPi and both parts of the substantia nigra. There are no single axon projections to either the GPi, or to the SN, or to both of these areas; only connecting as continuing targets via axon collaterals from the striatum to the GPe. The only difference between the axonal connectomes of the striosomes and the axons of those neurons in the matrix, is in the numbers of their branching axons. Striosomal axons cross the extent of the SN, and in macaques emit 4 to 6 vertical collaterals that form vertical columns which enter deep into the SN pars compacta (SNpc); the axons from those in the matrix are more sparsely branched. This pattern of connectivity is problematic. The main mediator of the striatopallidonigral system is GABA and there are also cotransmitters. The GPe stains for met enkephalin, the GPi stains for either substance P or dynorphin or both, and the SN stains for both. This probably means that a single axon is able to concentrate different co mediators in different subtrees, depending on the target.

A study of the percentage of striatal axons from the sensorimotor (dorsolateral putamen) and associative striatum (caudate nucleus and ventromedial putamen) to the globus pallidus found important differences. The GPe for instance receives a large input of axons from the associative areas. The GPi is strongly sensorimotor connected. The SN is at first associative. This is confirmed by the effects of striatal stimulations. All the projections from the primary somatosensory cortex to the putamen, avoid the striosomes and innervate areas within the matrix.

The pallidonigral set comprises the direct targets of the striatal axons: the two nuclei of the pallidum, and the pars compacta (SNpc) and pars reticulata (SNpr) 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). 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 SN neurons. The pallidal dendritic arborisations are very large flat and disc shaped. 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 discs are thin, they are crossed only for a short distance by striatal axons. However, since they are wide, they are crossed by many striatal axons from wide striatal parts. Since they are loose, the chances of contact are not very high. Striatal arborisations 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 not only 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. that could act as elements of local circuitry, there are weak or no functional interrelations between pallidal neurons.

The external globus pallidus (GPe) or lateral globus pallidus, is flat, curved and extended in depth and width. The branching dendritic trees are disc shaped, flat, run parallel to each other and to the pallidum border, and are perpendicular to those axons coming from the striatum. In monkeys an initial inhibition was seen in response to striatal input, followed by a regulated excitation. In the study this suggested that the excitation was used temporarily to control the magnitude of the incoming signal and to spatially focus this into a limited number of pallidal neurons. GPe neurons are often multi targeted and may respond to a number of neuron types. In macaques, axons from the GPe to the striatum account for about 15%; those to the GPi, SNpr and subthalamic nucleus are about 84%. The subthalamic nucleus was seen to be the preferred target which also sends most of its axons to the GPe.

The internal globus pallidus (GPi) or medial globus pallidus is only found in the primate brain and so is a younger portion of the globus pallidus. Like the GPe and the substantia nigra the GPi is a fast spiking pacemaker but its activity does not show the long intervals of silence seen in the others. and to the area behind the red nucleus. The evolutionary increase of the internal pallidus also brought an associated increase in the pallidothalamic tracts, and the appearance of the ventral lateral nucleus in the thalamus. The mediator is GABA.

The substantia nigra is made up of two parts, the pars compacta (SNpc) and the pars reticulata (SNpr), sometimes there is a reference to the pars lateralis but that is usually included as part of the pars reticulata. The ‘’black substance’’ that the term translates as, refers to the neuromelanin found in the dopaminergic neurons. These are found in a darker region of the SNpc. The SNpr is a lighter coloured region. There are similar cells in the substantia nigra and the globus pallidus. Both parts receive input from the striatopallidal fibres.

The pars compacta is the most lateral part of the substantia nigra and sends axons to the superior colliculus. The neurons have high firing rates which make them a fast spiking pacemaker and they are involved in ocular saccades.

The border between the SNpc and SNpr 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 SNpr. The ventral dendrites of the SNpc from the reverse direction go also deeply in it. The SN also send axons to the pedunculopontine nucleus. and to the parafascicular part of the central complex. The SNpr 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 SNpr receives a dopamine innervation from the SNpc 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 ventral anterior nucleus (VA) differentiated from the ventral lateral nucleus (VL) receiving pallidal afferences. The mediator is GABA.

The striatopallidonigral 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. Physiological analyses have shown a central inhibition/peripheral excitation pattern, 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.

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 assessed 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.

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", 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.

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" 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 feed axons to the other elements of the core of the basal ganglia. 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.

The centromedian nucleus is in the central region of the thalamus. In upper primates it has three parts instead of two, with their own types of neuron. Output from here goes to the subthalamic nucleus and the putamen. Its input includes fibers from the cortex and globus pallidus.

The pedunculopontine nucleus is a part of the reticular formation in the brainstem and a main component of the reticular activating system, and gives a major input to the basal ganglia. As indicated by its name, it is located at the junction between the pons and the cerebral peduncle, and near the substantia nigra. The axons are either excitatory or inhibitory and mainly target the substantia nigra. Another strong input is to the subthalamic nucleus. Other targets are the GPi 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 VL. 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. It has a dual role as a regulator of, and of being regulated by the basal ganglia.

In the cortico basal ganglia thalamo cortical loop the basal ganglia are interconnected, with little output to external targets. One target is the superior colliculus, from the pars reticulata. The two other major output subsystems are to the thalamus and from there to the cortex. In the thalamus the GPimedial fibers are separated from the nigral as their terminal arborisations do not mix. Pallidal axons have their own territory in the ventral lateral nucleus (VL); separated from the cerebellar and nigral territories. The VL is stained for calbindin and acetylcholinesterase. The axons ascend in the nucleus where they branch profusely. The VL output goes preferentially to the supplementary motor cortex (SMA), to the preSMA and to a lesser extent to the motor cortex. The pallidothalamic axons give branches to the pars media of the central complex which sends axons to the premotor and accessory motor cortex.

The ventral anterior nucleus (VA) output targets the premotor cortex, the anterior cingulate cortex and the oculomotor cortex, without significant connection to the motor cortex.