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André Parent

Publications and source records attributed to André Parent.

At least 19 recordsLinked to original sources
PubMed2006

The fate of striatal dopaminergic neurons in Parkinson's disease and Huntington's chorea.

The striatum harbours a population of dopaminergic neurons that is thought to act as a local source of dopamine (DA). This neuronal population increases in size in animal models of Parkinson's disease, where striatal DA levels are low, but its fate in idiopathic Parkinson's disease and Huntington's chorea is poorly known. In this study, we used antibodies raised against the enzyme tyrosine hydroxylase (TH), a faithful marker of dopaminergic neurons, to compare, by means of stereological counting methods, the number of striatal TH+ neurons on post-mortem brain sections from Parkinson's disease patients, Huntington's disease patients and age-matched controls. Propidium iodide nuclear staining was also performed to avoid counting short TH+ axonal segments that bear a large swollen varicosity and resemble small bipolar neurons. In normal subjects, TH+ neurons were scattered throughout the striatum, but they abounded preferentially in the ventral portion of the structure and were more numerous in the putamen than in the caudate nucleus. They displayed a multipolar cell body of medium size (10-20 mum in diameter) that emitted 3-5 smooth dendrites, a typical characteristic of striatal interneurons. These TH+ cells were rarely found in the small TH-poor striosomes, most of them being embedded in the large TH-rich extrastriosomal matrix. The number of striatal TH+ neurons was also found to vary according to an inverse relation with the age of the subjects. In pathological brains, the morphological characteristics of the striatal TH+ neurons were relatively unaltered, but the number of such neurons was markedly reduced compared with controls. The striatum of Parkinson's disease patients was found to contain six times less TH+ neurons than that of controls, whereas the striatum of Huntington's disease patients was largely devoid of such neurons. These findings are at odds with the results obtained in rodent and monkey models of Parkinson's disease, in which the number of striatal TH+ neurons is reported to increase markedly following DA denervation. Since Parkinson's disease patients examined in this study were all treated with l-3,4-dihydroxyphenylalanine to compensate for the loss of striatal DA and that levels of striatal DA are reportedly higher in the striatum of Huntington's disease patients compared with controls, we hypothesize that local DA concentrations exert a negative feedback on the expression of TH phenotype by striatal interneurons. A better knowledge of factors governing the in vivo state of this ectopic neuronal population could open new therapeutic avenues for the treatment of Parkinson's disease and Huntington's chorea.

Adult↗
PubMed2006

Neurokinin-1 and neurokinin-3 receptors in primate substantia nigra.

Striatonigral axons co-release GABA and substance P (SP) at their target sites, but little is known about the action of SP at nigral level. Therefore, we studied immunohistochemically the cellular and subcellular localization of SP and its high affinity receptors neurokinin-1 (NK-1R) and neurokinin-3 (NK-3R) at nigral level in squirrel monkeys. Immunofluorescent studies revealed that, although SP+ fibers arborised more densely in the pars reticulata (SNr) than in the pars compacta (SNc), the two nigral divisions harbored numerous neurons expressing NK-1R and NK-3R. Confocal microscopic analyses showed that numerous SNr neurons and virtually all SNc dopaminergic neurons contained both NK-1R and NK-3R. At the electron microscope level, NK-1R and NK-3R were mainly associated with intracellular sites or located at extrasynaptic position on plasma membrane. A small proportion of SP+ boutons also showed NK-3R immunoreactivity. The distribution of NK-1R and NK-3R in SNr and SNc suggests that SP exerts its effect through postsynaptic receptors, as well as via presynaptic autoreceptors and heteroreceptors. These findings indicate that the excitatory peptide SP can modulate the inhibitory action of GABA at nigral level and suggest that the co-release of these two neuroactive substances should be taken into account when considering the functional organization of the basal ganglia.

Animals↗
PubMed2006

The somatodendritic domain of substantia nigra pars reticulata projection neurons in the rat.

We have examined the morphology of the somatodendritic domain of projection neurons located in different sectors of rat substantia nigra pars reticulata (SNr) or having distinct axonal arborizations. Forty-three neurons - 23 located in the dorsal half and 20 in the ventral half of SNr - were injected with biotinylated dextran amine and their somatodendritic domain was reconstructed from serial sagittal sections with a camera lucida. The axonal arborization of 14 neurons was also reconstructed. Dorsally located SNr neurons had a larger perikaryon, a higher number of primary dendrites and a more extensive dendritic arbor than the ventrally located ones. However, irrespective of their location in the SNr, the somatodendritic domain was always longer along the rostrocaudal axis than along the dorsoventral and mediolateral axes. Specific correlations between somatodendritic morphology and axonal arborization could be established for some SNr neurons, but among SNr neurons with similar efferent projections, those lying dorsally always exhibited a larger perikaryon and a more widespread dendritic arbor than those located ventrally. These results indicate that the morphology of the somatodendritic domain of SNr projection neurons is related to the location of their perikaryon within the structure rather than to the pattern of their axonal projections.

Analysis of Variance↗
PubMed2006

Single-axon tracing study of corticostriatal projections arising from primary motor cortex in primates.

The axonal projections arising from the forelimb area of the primary motor cortex (M1) in cynomolgus monkeys (Macaca fascicularis) were studied following microiontophoretic injections of biotinylated dextran amine under electrophysiological guidance. The microinjections were centered on layer V, and 42 anterogradely labeled corticofugal axons were reconstructed from serial frontal or sagittal sections with a camera lucida. Our investigation shows that the primate striatum receives both direct and indirect projections from M1. The direct corticostriatal projection is formed by axons that remain uniformly thin and unbranched throughout their sinuous trajectory to the ipsilateral striatum. They divide as they enter the dorsolateral sector of the post-commissural putamen, the so-called sensorimotor striatal territory. The indirect corticostriatal projection derives from a thin collateral emitted within the corona radiata by thick, long-range fibers that descend toward the brainstem. The collateral enters the putamen dorsomedially and remains unbranched until it reaches the dorsolateral sector of the putamen, where it breaks out into two to four axonal branches displaying small and equally spaced varicosities. Both direct and indirect corticostriatal axons branch moderately but occupy vast rostrocaudal striatal territories, where they appear to contact en passant several widely distributed striatal neurons. These findings reveal that, in contrast to current beliefs, the primate motor corticostriatal system is not exclusively formed by axons dedicated solely to the striatum. It also comprises collaterals from long-range corticofugal axons, which can thus provide to the striatum a copy of the neural information that is being conveyed to the brainstem and/or spinal cord.

Afferent Pathways↗
PubMed2006

Cellular and subcellular localization of neurokinin-1 and neurokinin-3 receptors in primate globus pallidus.

The primate globus pallidus receives massive innervations from GABAergic striatal neurons that co-release the neuropeptide substance P (SP). To expand our knowledge regarding SP interaction at pallidal level, we used single and double antigen retrieval methods to study the cellular and subcellular localization of SP and its high-affinity receptors neurokinin-1 (NK-1R) and neurokinin-3 (NK-3R) in the globus pallidus of the squirrel monkey (Saimiri sciureus). At the light microscopic level, a large number of neurons and fibers located in both the external (GPe) and internal (GPi) segments of the globus pallidus expressed NK-1R or NK-3R immunoreactivity. At the electron microscopic level, both NK-1R and NK-3R were mainly associated with intracellular sites or located at extrasynaptic positions on the plasma membrane. Presynaptic axon terminals forming symmetric and asymmetric synapses occasionally contained NK-1R and NK-3R. Neurokinin receptors were also observed in a proportion of SP-immunoreactive axon terminals, but these terminals preferentially expressed NK-3R. The pattern of distribution of NK-1R and NK-3R in GPe and GPi indicates that SP effects at pallidal level are mediated through postsynaptic receptor as well as presynaptic autoreceptors and heteroreceptors. These morphological data suggest that, either alone or in conjunction with GABA, SP could have a wide range of effects at pallidal level. This neuroactive peptide may influence in a significant manner the integration and treatment of neural information that flows through the basal ganglia.

Animals↗
PubMed2005

Chemical characterization of newly generated neurons in the striatum of adult primates.

We recently demonstrated the existence of neurogenesis in the striatum of adult monkeys, but the number of striatal neurons generated under normal conditions was too small to establish their chemical phenotype. We therefore used brain-derived neurotrophic factor (BDNF), which promotes neuronal differentiation and survival and induces striatal neurogenesis in rodents, in an attempt to increase the number of newborn neurons in monkey striatum and facilitate their chemical characterization. An adenoviral vector (AdBDNF), encoding the human BDNF cDNA under the control of a strong promoter, was injected into the lateral ventricles (LVs) of adult squirrel monkeys, which were then treated with bromodeoxyuridine (BrdU). Two weeks after viral injection, numerous BrdU-positive cells were found within the striatum and many expressed microtubule-associated protein 2 (MAP-2) and neuronal nuclear protein (NeuN), two markers of mature neurons. Newborn neurons also expressed glutamic acid decarboxylase (GAD(65/67)), calbindin (CB) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), three markers of striatal projection neurons. We found no BrdU-positive neurons displaying the phenotype of striatal interneurons. Numerous BrdU-positive cells located near the subventricular zone (SVZ) coexpressed the migrating neuroblast markers polysialylated neural cell adhesion (PSA-NCAM) and doublecortin (DCX), suggesting that precursor cells could migrate from LVs to striatal parenchyma and develop a neuronal phenotype once they reach the striatum. However, many pairs of BrdU-positive nuclei were observed in the striatal parenchyma, suggesting that newborn neurons could also arise from resident progenitor cells. The present study demonstrates that a single injection of AdBDNF increases the number of newborn neurons into adult primate striatum and that newborn striatal neurons exhibit the chemical phenotype of medium-spiny projection neurons, which are specifically targeted in Huntington's disease.

Animals↗
PubMed2005

Patterns of axonal branching of neurons of the substantia nigra pars reticulata and pars lateralis in the rat.

Axons from neurons of the rat substantia nigra pars reticulata (SNr) and pars lateralis (SNl) were traced after injecting their cell body with biotinylated dextran amine. Thirty-two single axons were reconstructed from serial sagittal sections with a camera lucida, whereas four other SNr axons were reconstructed in the coronal plane to determine whether they innervate the contralateral hemisphere. Four distinct types of SNr projection neurons were identified based on their main axonal targets: type I neurons that project to the thalamus; type II neurons that target the thalamus, the superior colliculus (SC), and the pedunculopontine tegmental nucleus (PPTg); type III neurons that project to the periaqueductal gray matter and the thalamus; and type IV neurons that target the deep mesencephalic nucleus (DpMe) and the SC. The axons of the SNl showed the same branching patterns as SNr axons of types I, II, and IV. The coronal reconstructions demonstrated that SNr neurons innervate the thalamus, the SC, and the DpMe bilaterally. At the thalamic level, SNr and SNl axons targeted preferentially the ventral medial, ventral lateral, paracentral, parafascicular, and mediodorsal nuclei. Axons reaching the SC arborized selectively within the deep layers of this structure. Our results reveal that the SNr and SNl harbor several subtypes of projection neurons endowed with a highly patterned set of axon collaterals. This organization allows single neurons of these output structures of the basal ganglia to exert a multifaceted influence on a wide variety of diencephalic and midbrain structures.

Animals↗
PubMed2005

The striatofugal fiber system in primates: a reevaluation of its organization based on single-axon tracing studies.

The current model of basal ganglia rests on the idea that the striatofugal system is composed of two separate (direct and indirect) pathways originating from distinct cell populations in the striatum. The striatum itself is divided into two major compartments, the striosomes and the matrix, which differ by their neurochemical makeup and input/output connections. Here, neurons located in either striosomes or the extrastriosomal matrix in squirrel monkeys were injected with biotin dextran amine, and their labeled axons were entirely reconstructed with a camera lucida. Twenty-four of 27 reconstructed axons arborized into the three main striatal targets (external pallidum, globus pallidus, and substantia nigra pars reticulata), a finding that is at odds with the concept of a dual striatofugal system. Axons of striosomal neurons formed several columnar terminal fields in the substantia nigra pars reticulata. These data indicate that the substantia nigra pars compacta is neither the only nor the main target of striosomal neurons, a finding that calls for a reevaluation of the organization of the striatonigral projection system.

Animals↗
PubMed2005

Single-axon tracing and three-dimensional reconstruction of centre median-parafascicular thalamic neurons in primates.

The axonal projections from the centre median (CM)/parafascicular (Pf) thalamic complex in squirrel monkeys were studied after microiontophoretic injections of biotinylated dextran amine under electrophysiological guidance. A total of 29 axons connected to their parent cell body were entirely reconstructed from serial sections with a camera lucida. Our investigation shows that the CM and Pf nuclei in primates comprise three types of projection neurons: (1) neurons that innervate densely and focally the striatum; (2) neurons that arborize diffusely in the cerebral cortex; and (3) neurons that innervate both striatum and cerebral cortex. Striatal innervation of CM origin consists of dense clusters of axon terminals exhibiting pedunculated varicosities and forming oblique bands in the dorsolateral sector of putamen (sensorimotor striatal territory). The same type of striatal innervation occurs in the head of caudate nucleus (associative striatal territory) in cases of Pf-labeled neurons. The CM neurons that target cerebral cortex arborize principally in motor and premotor areas, whereas Pf neurons innervate chiefly prefrontal areas. Cortical innervation from both nuclei is much more profuse in layers V and VI than in layer I. Our three-dimensional reconstruction studies show that dendritic and axonal arborizations of CM neurons extend essentially along the sagittal plane. These results revealed that, in contrast to rodents where virtually all Pf neurons project to both striatum and cortex, the primate CM/Pf complex harbors several types of highly patterned projection neurons. As such, this complex might be considered as an integral part of the widely distributed basal ganglia neuronal system.

Animals↗
PubMed2005

GABAergic interneurons in human subthalamic nucleus.

The subthalamic nucleus (STN) is considered a homogeneous structure composed essentially of projection neurons that exert a profound glutamate-mediated excitatory influence upon the main output structures of the basal ganglia. It is currently the most efficient target for deep brain stimulations designed to alleviate symptoms of Parkinson's disease. STN neurons were analyzed by applying stereological methods and single/double-immunostaining procedures to postmortem material obtained from normal individuals. Besides a multitude of closely packed projection neurons ( approximately 24.7 mum in diameter), the human STN (mean volume, 174.5 +/- 20.4 mm3; total neuronal density, 239.5 +/- 31.9 x 10(3)) contained smaller neurons (approximately 12.2 microm), which displayed glutamic acid decarboxylase (GAD)(65/67) immunoreactivity and shared the morphological features of interneurons described in Golgi studies of primate STN. These putative gamma-aminobutyric acid (GABA)ergic interneurons accounted for 7.5% of the total neuronal population of the STN. Although present throughout the nucleus, they were significantly more numerous in its posterior-ventral-medial sector, which belongs to the limbic/associative functional territory. Many projection neurons located dorsolaterally in the STN showed parvalbumin immunoreactivity and others lying ventromedially displayed calretinin immunostaining, but none of the GAD-positive interneurons expressed these calcium-binding proteins. Although less abundant than projection neurons, GABAergic interneurons might play a important role in the intrinsic organization of the STN. The morphological and chemical heterogeneity of the human STN reported here might have important implications in the functional organization of the basal ganglia.

Adult↗
PubMed2005

Morphology and distribution of dopaminergic neurons intrinsic to the human striatum.

The putative dopaminergic (DA) neurons intrinsic to the human striatum were studied by applying immunofluorescence and quantitative methods to postmortem tissue from seven normal individuals. Stringent morphological and chemical criteria were used to identify striatal DA neurons, including immunostaining for tyrosine hydroxylase, DA transporter and neuronal nuclear protein. The DA neurons were scattered throughout the striatum, but abounded particularly in its ventral portion. Frequency distribution of surface areas of DA cell bodies reveals that the most frequent DA neurons (x =58.0%, S.D.=12.8%) had a medium-sized (approximately 200+/-15 microm2) perikaryon with 3-5 varicose dendrites, whereas others (x =35.5%, S.D.=14.0%) had a smaller (approximately 140+/-15 microm2) perikaryon with 3-4 varicose dendrites. There was a small number (x =6.5%, S.D.=8.5%) of larger DA neurons (209-584 microm2) with spiny dendrites and a few TH-immunoreactive cells displaying mixed neuron-glia morphology. Despite significant inter-individual variations in neuron density, the human striatum (mean volume of 8.76 cm3) harbored a mean of 331.9 DA neurons (S.D.=199.2). A prolific zone, containing about 3000 cells, occurred in the ventral striatum in two brains. The addition of these cells would increase by about 10 times the total number of striatal DA neurons, which should not be confounded with segments of nigrostriatal DA fibers that displayed large (8-12 microm) varicosities and looked like small bipolar neurons. The function of striatal DA neurons is unknown but the fact that their number increases markedly following lesion of nigral DA input or administration of various growth factors, opens up new therapeutic avenues for treatment of Parkinson's disease.

Adult↗
PubMed2005

Neurochemical characterization of dopaminergic neurons in human striatum.

We examined the neurochemical phenotype of striatal neurons expressing tyrosine hydroxylase (TH) mRNA to determine if they form a distinct class of neurons within the human striatum. Double in situ hybridization (ISH) and immunohistochemical (IHC) procedures were used to know if TH mRNA-positive striatal neurons express molecular markers of mature neurons (MAP2 and NeuN), dopaminergic neurons (DAT and Nurr1) or immature neurons (TuJ1). All TH mRNA-labeled neurons were found to express NeuN, DAT and Nurr1, whereas about 80% of them exhibited MAP2, confirming their neuronal and dopaminergic nature. Only about 30% of TH mRNA-labeled neurons expressed TuJ1, suggesting that this ectopic dopaminergic neuronal population is principally composed of mature neurons. The same double ISH/IHC approach was then used to know if these dopamine neurons display markers of well-established classes of striatal projection neurons (GAD65 and calbindin) or local circuit neurons (GAD65, calretinin, somatostatin and parvalbumin). Virtually all TH-labeled neurons expressed GAD65 mRNA, about 30% of them exhibited calretinin, but none stained for the other striatal neuron markers. These results suggest that the majority of TH-positive neurons intrinsic to the human striatum belong to a distinct subpopulation of striatal interneurons characterized by their ability to produce dopamine and GABA.

Adolescent↗
PubMed2005

Duchenne De Boulogne: a pioneer in neurology and medical photography.

Guillaume-Benjamin-Amand Duchenne was born 200 years ago in Boulogne-sur-Mer (Pas-de-Calais, France). He studied medicine in Paris and became a physician in 1831. He practiced general medicine in his native town for about 11 years and then returned to Paris to initiate pioneering studies on electrical stimulation of muscles. Duchenne used electricity not only as a therapeutic agent, as it was commonly the case earlier in the 19th century, but chiefly as a physiological investigation tool to study the anatomy of the living body. Without formal appointment he visited hospital wards across Paris searching for rare cases of neuromuscular disorders. He built a portable electrical device that he used to functionally map all bodily muscles and to study their coordinating action in health and disease. He gave accurate descriptions of many neuromuscular disorders, including pseudohypertrophic muscular dystrophy to which his name is still attached (Duchenne muscular dystrophy). He also invented a needle system (Duchenne's histological harpoon) for percutaneous sampling of muscular tissue without anesthesia, a forerunner of today's biopsy. Duchenne summarized his work in two major treatises entitled De l'électrisation localisée (1855) and Physiologie des mouvements (1867). Duchenne's iconographic work stands at the crossroads of three major discoveries of the 19th century: electricity, physiology and photography. This is best exemplified by his investigation of the mechanisms of human physiognomy in which he used localized faradic stimulation to reproduce various forms of human facial expression. The album that complements his book on this issue is considered a true incunabulum of photography. Duchenne de Boulogne, a shy but hard-working, acute and ingenious observer, became one of most original clinicians of the 19th century. He died in Paris in 1875.

Electrophysiology↗
PubMed2004

Evidence of newly generated neurons in the human olfactory bulb.

The subventricular zone (SVZ) is known to be the major source of neural stem cells in the adult brain. In rodents and nonhuman primates, many neuroblasts generated in the SVZ migrate in chains along the rostral migratory stream (RMS) to populate the olfactory bulb (OB) with new granular and periglomerular interneurons. In order to know if such a phenomenon exists in the adult human brain, we applied single and double immunostaining procedures to olfactory bulbs obtained following brain necropsy in normal adult human subjects. Double immunofluorescence labelling with a confocal microscope served to visualize cells that express markers of proliferation and immature neuronal state as well as markers that are specific to olfactory interneurons. Newborn cells that express cell cycle proteins [Ki-67, proliferating cell nuclear antigen (PCNA)] were detected in the granular and glomerular layers (GLs) of the human olfactory bulb; these cells coexpressed markers of immature neuronal state, such as Doublecortin (DCX), NeuroD and Nestin. Numerous differentiating cells expressed molecular markers of early committed neurons [beta-tubulin class III (TuJ1)] and were also immunoreactive for glutamic acid decarboxylase (GAD), a marker of GABAergic neurons, or tyrosine hydroxylase (TH), a marker of dopaminergic neurons. Other early committed neurons expressed the calcium-binding proteins calretinin (CR) or parvalbumin (PV). These results provide strong evidence for the existence of adult neurogenesis in the human olfactory system. Despite its relatively small size compared to that in rodents and nonhuman primates, the olfactory bulb in humans appears to be populated, throughout life, by new granular and periglomerular neurons that express a wide variety of chemical phenotypes.

Adult↗
PubMed2004

Striosomes are enriched in glutamic acid decarboxylase in primates.

The compartmental distribution of glutamic acid decarboxylase (GAD) in the striatum was investigated in squirrel monkeys and rats with antibodies raised against the two isoforms of this enzyme (GAD65 and GAD67) and with calbindin D-28k (CB) and/or micro-opiate receptor (MOR) as striosomal markers. In primates, immunostaining for both GAD65 and GAD67 was much more intense in striosomes than in the surrounding matrix. A thin immunoreactive strip of GAD labeling was also present in the dorsolateral part of both caudate nucleus and putamen. This narrow band appears to correspond to the so-called subcallosal streak (SS) found in rodent striatum. Although the immunostaining intensity for the two enzymes was similar at pallidal level, that for GAD65 was more intense than that for GAD67 at the striatal level. The GAD immunostaining was more uniformly distributed in the rat striatum, which did not display GAD-rich patches that corresponded to MOR-positive striosomes. Moreover, in contrast to the findings obtained in monkeys, the subcallosal streak in rats was less intensely stained for GAD than for the remaining regions of the striatum. These results reveal that GAD65 and GAD67 are faithful markers of striosomes in primates but not in rodents. They suggest the existence of a significant species difference between rodents and primates in respect to the chemical organization of the striatum, a difference that should be taken into account when using rodents as animal models to study the functional organization of the basal ganglia and the pathogenesis of neurodegenerative diseases that affect the striatum.

Animals↗
PubMed2004

The pallidofugal motor fiber system in primates.

The organization of the pallidofugal fiber system originating from the internal segment of the globus pallidus (GPi) in cynomolgus monkeys (Macaca fascicularis) was studied by means of a single-axon tracing method. The primate GPi is composed of a majority of neurons endowed with a highly collateralized axon that projects to the premotor neurons located in the ventral tier thalamic nuclei, the center-médian/parafascicular thalamic complex and the brainstem pedunculopontine nucleus. These axons often follow a long and tortuous course within the GPi and then emerge either through the ansa lenticularis (AL) or the lenticular fasciculus (LF), irrespective of the location of their parent cell body in the GPi. Other pallidofugal axons exit through the medial pole of the GPi, at various distances between the AL ventrally and the LF dorsally. Virtually all pallidofugal axons course through Forel's field H, on their way to the thalamus and brainstem. They emit numerous short collaterals and boutons en passant in this sector of the subthalamic region, which stands out as a major target of GPi axons. Our results indicate that AL and LF do not form separate anatomical entities, each carrying axons originating from distinct functional pallidal territories, as commonly believed. Instead, these two fascicles form the ventral and dorsal borders of a morphological continuum that harbors a multitude of pallidofugal axons arising from all sectors of the GPi. This type of information should be taken into account when interpreting data from deep brain stimulation applied to pallidal and subthalamic regions in Parkinson's disease.

Animals↗