André Parent

Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop

This paper reviews some of the recent findings on different aspects of the anatomical organization of the basal ganglia. Attempts have been made to delineate the anatomical substrate of information processing along the cortico-basal ganglia-thalamo-cortical loop. Emphasis has been placed on data obtained with highly sensitive anterograde tract-tracing methods applied to the study of the main axis of the loop, which is composed of the striatum, the pallidum, and the substantia nigra. These findings have highlighted the complexities of the organization of the intrinsic basal ganglia circuitry, which comprises multiple modular units that are distributed according to highly ordered and repetitive patterns. Such an arrangement is well suited to convey cortical information in a highly specific manner throughout the basal ganglia. The basal ganglia circuitry is also designed so as to modulate in a precise manner the neuronal activity of several brain functional systems, which are involved in the direct control of different aspects of psychomotor behavior. Of utmost importance is the action of the basal ganglia on thalamocortical premotor neurons. It is through these neurons, which can be considered as a sort of final common pathway, that the basal ganglia ultimately influence the complex neuronal computation that goes on at cortical level.

Extrinsic connections of the basal ganglia

Recent neuroanatomical studies undertaken with various powerful neural tracing methods have radically changed our concept of the organization of the basal ganglia. This paper briefly reviews some of the findings that have led to the conclusion that the major components of the basal ganglia can no longer be considered as single undifferentiated entities. Instead, each of these structures is characterized by several distinct afferent and efferent chemospecific subsystems by which they can modulate and convey the multifarious information that flows through the basal ganglia. This paper focuses mainly on data obtained in primates, but also stresses the importance of comparison with non-primate species.

Newly generated neurons in the amygdala and adjoining cortex of adult primates

The subventricular zone remains mitotically active throughout life in rodents. Studies with tritiated thymidine, which is incorporated into the DNA of mitotic cells, have revealed that the rodent subventricular zone produces neuroblasts that migrate toward the olfactory bulb along the rostral migratory stream. A similar migratory stream has been documented in monkeys by using the thymidine analogue BrdUrd. The same approach showed that neurogenesis occurred in the dentate gyrus of adult primates, including humans. In the present study, experiments combining injections of BrdUrd and the dye 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindo-carbocyanine, with the immunostaining for molecular markers of neurogenesis (polysialylated neural cell adhesion molecule, β-tubulin-III, collapsin response mediator protein-4, neuronal nuclear protein) in New World (Saimiri sciureus) and Old World (Macaca fascicularis) monkeys have revealed that new neurons are produced in the amygdala, piriform cortex, and adjoining inferior temporal cortex in adult primates. These newborn neurons expressed the antiapoptotic protein Bcl-2 and formed a more-or-less continuous pathway that extended from the tip of the temporal ventricular horn to the deep portion of the temporal lobe. The production of newborn neurons in the amygdala, piriform cortex, and inferior temporal cortex seems to parallel the continuing addition of neurons in the olfactory bulb. These two concomitant phenomena may ensure structural stability and functional plasticity to the primate olfactory system and temporal lobe.

Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration.

This report describes the presence of reactive microglia, the accumulation of extracellular melanin, and the extensive loss of dopaminergic neurons in the substantia nigra of monkeys administered 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) 5 to 14 years before death. This evidence of chronic neuroinflammation years after MPTP exposure is similar to that previously reported in humans. The monkeys were drug free for at least 3 years before death, indicating that a brief exposure to MPTP had instituted an ongoing inflammatory process. The mechanism is unknown but could have important implications regarding the cause of Parkinsons disease and possible approaches to therapy.

Neurons of the subthalamic nucleus in primates display glutamate but not GABA immunoreactivity

Immunohistochemical studies undertaken with a highly specific antiserum raised against gamma-aminobutyric acid (GABA)-glutaraldehyde-lysyl-protein conjugate showed that cell bodies of the subthalamic nucleus in the squirrel monkey (Saimiri sciureus) were closely surrounded by several GABA-positive terminals but were not themselves immunoreactive. In contrast, after incubation with a monoclonal antibody directed against carbodiimide-fixed glutamate, virtually all cell bodies of the subthalamic nucleus displayed an intense immunoreactivity. They were surrounded by various neuronal processes that also stained for glutamate. These results suggest that the neurons of the subthalamic nucleus in primates utilize the excitatory neurotransmitter glutamate instead of the inhibitory neurotransmitter GABA.

Projections of cholinergic and non-cholinergic neurons of the brainstem core to relay and associational thalamic nuclei in the cat and macaque monkey

The projections of brainstem core neurons to relay and associational thalamic nuclei were studied in the cat and macaque monkey by combining the retrograde transport of wheat germ agglutinin conjugated with horseradish peroxidase with choline acetyltransferase immunohistochemistry. All major sensory (medial geniculate, lateral geniculate, ventrobasal), motor (ventroanterior, ventrolateral, ventromedial), associational (mediodorsal, pulvinar, lateral posterior) and limbic (anteromedial, anteroventral) thalamic nuclei of the cat were found to receive projections from cholinergic neurons located in the peribrachial area of the pedunculopontine nucleus and in the laterodorsal tegmental nucleus as well as from non-cholinergic neurons in the rostral (perirubral) part of the central tegmental mesencephalic field. Specific relay nuclei receive less than 10% of their brainstem afferents from non-cholinergic neurons located at rostral midbrain levels and receive 85-96% of their brainstem innervation from a region at midbrain-pontine junction where the cholinergic peribrachial area and laterodorsal tegmental nucleus are maximally developed. Of the total number of horseradish peroxidase-positive brainstem neurons seen after injections in various specific relay nuclei, the double-labeled (horseradish peroxidase + choline acetyltransferase) neurons represent approximately 70-85%. Three to eight times more numerous horseradish peroxidase-labeled brainstem cells were found after injections in associational (mediodorsal and pulvinar-lateral posterior complex) and diffusely cortically-projecting (ventromedial) thalamic nuclei of cat than after injections in specific relay nuclei. The striking retrograde cell labeling observed after injections in nuclei with associative functions and widespread cortical projections was due to massive afferentation from non-cholinergic parts of the midbrain and pontine reticular formation, on both ipsi- and contralateral sides. After wheat germ agglutinin-horseradish peroxidase injections in the associative pulvinar-lateral posterior complex and mediodorsal nucleus of Macaca sylvana, 45-50% of horseradish peroxidase-positive brainstem peribrachial neurons were also choline acetyltransferase-positive. While cells in the medial part of the cholinergic peribrachial area were found to project especially towards the pulvinar-lateral posterior nuclear complex in monkey, the retrograde cell labeling seen after the mediodorsal injection was mostly confined to the lateral part of both dorsal and ventral aspects of the peribrachial area.(ABSTRACT TRUNCATED AT 400 WORDS)

The striatopallidal and striatonigral projections: two distinct fiber systems in primate

The use of the fluorescence retrograde double-labeling method has revealed that striatal neurons projecting to the globus pallidus in the squirrel monkey are mainly confined to the putamen whereas those projecting to the substantia nigra occur mostly in the caudate nucleus. Only about 10% of the striatal neurons were found to be double-labeled after injections into the globus pallidus and substantia nigra. The segregation of the putaminofugal and caudatofugal projections was further confirmed by the anterograde tracing of WGA-HRP. These findings do not fit in the current unitary concept of the striatofugal fiber system. Instead, they suggest that the striatopallidal and striatonigral projections exist largely as two distinct subsystems in the primate.

Projections of brainstem core cholinergic and non-cholinergic neurons of cat to intralaminar and reticular thalamic nuclei

We combined the retrograde transport of wheat germ agglutinin conjugated with horseradish peroxidase with choline acetyltransferase immunohistochemistry to study the projections of cholinergic and non-cholinergic neurons of the upper brainstem core to rostral and caudal intralaminar thalamic nuclei, reticular thalamic complex and zona incerta in the cat. After wheat germ agglutinin-horseradish peroxidase injections in the rostral pole of the reticular thalamic nucleus, the distribution and amount of retrogradely labeled brainstem neurons were similar to those found after tracer injection in thalamic relay nuclei (see preceding paper). After wheat germ agglutinin-horseradish peroxidase injections in the caudal intralaminar centrum medianum-parafascicular complex, rostral intralaminar central lateral-paracentral wing, and zona incerta, the numbers of retrogradely labeled brainstem neurons were more than three times higher than those found after injections in thalamic relay nuclei. The larger numbers of horseradish peroxidase-positive brainstem reticular neurons after tracer injections in intralaminar or zona incerta injections results from a more substantial proportion of labeled neurons in the central tegmental field at rostral midbrain (perirubral) levels and in the ventromedial part of the pontine reticular formation, ipsi- and contralaterally to the injection site. Of all retrogradely labeled neurons in the caudal midbrain core at the level of the cholinergic peribrachial area and laterodorsal tegmental nucleus, 45-50% were also choline acetyltransferase-positive after the injections into central lateral-paracentral and reticular nuclei, while only 25% were also choline acetyltransferase-positive after the injection into the centrum medianum-parafascicular complex. These findings are discussed in the light of physiological evidence of brainstem cholinergic mechanisms involved in the blockade of synchronized oscillations and in activation processes of thalamocortical systems.

Glutamatergic inputs from the pedunculopontine nucleus to midbrain dopaminergic neurons in primates: Phaseolus vulgaris-leucoagglutinin anterograde labeling combined with postembedding glutamate and GABA immunohistochemistry.

To verify the possibility that the pedunculopontine nucleus is a source of glutamatergic terminals in contact with midbrain dopaminergic neurons in the squirrel monkey, we used the anterograde transport of Phaseolus vulgaris‐leucoagglutinin in combination with preembedding immunohistochemistry for tyrosine hydroxylase and for calbindin D‐28k and postembedding immunocytochemistry for glutamate and for γ‐aminobutyric acid. Following tracer injections in the pedunculopontine nucleus, numerous anterogradely labeled fibers emerged from the injection sites to innervate densely the pars compacta of the substantia nigra and ventral tegmental area. The major type of labeled fibers were thin with multiple collaterals and varicosities that established intimate contacts with midbrain dopaminergic neurons. At the electron microscopic level, the anterogradely labeled boutons were medium sized (maximum diameter between 0.9 μm and 2.5 μm) and contained numerous round vesicles and mitochondria. Postembedding immunocytochemistry revealed that 40–60% of anterogradely labeled terminals were enriched in glutamate and formed asymmetric synapses with dendritic shafts of substantia nigra and ventral tegmental area neurons. In triple‐immunostained sections, some of the postsynaptic targets to these terminals were found to be dopaminergic. In addition, 30–40% of the anterogradely labeled terminals in both regions displayed immunoreactivity for γ‐aminobutyric acid and, in some cases, formed symmetric synapses with dendritic shafts.

Organization of the basal ganglia: the importance of axonal collateralization

Recent neuroanatomical data obtained with single-axon or single-cell labeling procedures in both rodents and primates have revealed the presence of various types of projection neurons with profusely collateralized axons within each of the major components of the basal ganglia. Such findings call for a reappraisal of current concepts of the anatomical and functional organization of the basal ganglia,which play such a crucial role in the control of motor behavior. The basal ganglia now stand as a widely distributed neuronal network, whose elements are endowed with a highly patterned set of axon collaterals. The elucidation of this finely tuned network is needed to understand the complex spatiotemporal sequence of neural events that ensures the flow of cortical information through the basal ganglia.