Combatting malaria disease among gold miners: a qualitative research within the Malakit project.

Malaria is endemic in French Guiana, in particular, where illegal gold mining activities take place. Gold miners travel from Brazil to remote camps in the Guiana forest to carry out mining activities, exposing themselves to the presumed contamination area. This article presents the results of a qualitative case study of the Malakit project, an intervention where health facilitators offer appropriate training and distribution of self-diagnosis and self-treatment kits to manage an episode of malaria at resting sites on the French Guiana borders. The objectives were: (i) Determine the contextual elements influencing the use of Malakit; (ii) Understand the way gold miners perceive Malakit; (iii) Identify the elements that are favorable and unfavorable to the use of Malakit; (iv4) Identify what can be improved in the project. The data were collected using three methods: on-site observation, semi-structured individual interviews (n = 26), and group interviews (n = 2). The results indicate that Malakit responds to the need for treatment and facilitates access to care. Gold miners say they trust the facilitators and receive accurate explanations, the kit is easy to use and carry, and explanations given are sufficient. Nonetheless, the results lead us to believe that contextual elements influence exposure to numerous risk factors and that malaria among gold miners working illegally in French Guiana is a question of social inequalities in health. Thus, malaria intervention practices such as Malakit cannot be carried out without considering the complexity generated by social inequalities in health.

The highly selective mGlu2 receptor positive allosteric modulator LY-487,379 alleviates l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease.

l-3,4-Dihydroxyphenylalanine (l-DOPA) is the most effective treatment for Parkinson's disease (PD), but its use over a long period is marred by motors complications such as dyskinesia. We previously demonstrated that selective metabotropic glutamate 2/3 (mGlu2/3 ) receptor activation with LY-354,740 alleviates dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset and the 6-hydroxydopamine (6-OHDA)-lesioned rat. Here, we sought to determine the role played by selective mGlu2 activation in the anti-dyskinetic effect of mGlu2/3 stimulation and have investigated the effect of the highly selective mGlu2 positive allosteric modulator LY-487,379 at alleviating established, and preventing the development of, l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat. First, dyskinetic 6-OHDA-lesioned rats were administered l-DOPA in combination with LY-487,379 (0.1, 1 and 10 mg/kg) or vehicle, and the severity of dyskinesia was determined. Second, 6-OHDA-lesioned rats were administered LY-487,379 (0.1 or 1 mg/kg), started concurrently with l-DOPA, once daily for 22 days, and dyskinesia severity was evaluated weekly for four consecutive weeks. We also assessed the effect of LY-487,379 on l-DOPA anti-parkinsonian effect. We found that acute challenges of LY-487,379 0.1 mg/kg in combination with l-DOPA, significantly diminished dyskinesia severity, by ≈54% (p < .01), when compared to vehicle. Moreover, animals treated with l-DOPA/LY-487,379 0.1 and 1 mg/kg during the dyskinesia induction phase exhibited milder dyskinesia, by ≈74% and ≈61%, respectively (both p < .01), when compared to l-DOPA/vehicle. LY-487,379 did not impair l-DOPA anti-parkinsonian activity. These results suggest that mGlu2 activation may be an effective and promising therapeutic strategy to alleviate the severity and prevent the development of dyskinesia.

A Tribute to James Parkinson.

Exactly 200 years ago, the London surgeon-apothecary James Parkinson (1755-1824) published a 66-page-long booklet entitled An Essay on the Shaking Palsy, which contains the first clear clinical description of the shaking palsy or paralysis agitans, which we now refer to as Parkinson's disease. However, the value of this essay was not fully recognized during Parkinson's lifetime, which spanned the American Revolution, the French Revolution, and the Napoleonic Wars. James Parkinson was one of the most singular figures of his time and place. He was successively or concomitantly a virulent political activist, a popular medical writer, a scholarly medical contributor, a highly appreciated parish doctor, a prominent amateur chemist, a devoted madhouse doctor, and a renowned paleontologist. It is that branch of geology that brought Parkinson fame during his lifetime. He was an insatiable collector of fossils, minerals, and shells that came to form the core of the museum that he set out at his home in Shoreditch, England. These specimens are beautifully illustrated in his Organic Remains of a Former World (1804-1811), a three-volume treatise that rapidly became a standard paleontology textbook. Parkinson was a founding member of the Geological Society of London, and in recognition of his contribution to the nascent field of paleontology his name was given to many fossils, particularly ammonites (e.g. Nautilus parkinsoni). Hence, we owe much to Mr. Parkinson, the Paleontologist, as he used to be referred to after his death, for such a vast and multifaceted contribution to natural science and medicine.

Impacts of online and group perinatal education: a mixed methods study protocol for the optimization of perinatal health services.

BACKGROUND: Prenatal education is a core component of perinatal care and services provided by health institutions. Whereas group prenatal education is the most common educational model, some health institutions have opted to implement online prenatal education to address accessibility issues as well as the evolving needs of future parents. Various studies have shown that prenatal education can be effective in acquisition of knowledge on labour and delivery, reducing psychological distress and maximising father's involvement. However, these results may depend on educational material, organization, format and content. Furthermore, the effectiveness of online prenatal education compared to group prenatal education remains unclear in the literature. This project aims to evaluate the impacts of group prenatal education and online prenatal education on health determinants and users' health status, as well as on networks of perinatal educational services maintained with community-based partners. METHODS: This multipronged mixed methods study uses a collaborative research approach to integrate and mobilize knowledge throughout the process. It consists of: 1) a prospective cohort study with quantitative data collection and qualitative interviews with future and new parents; and 2) a multiple case study integrating documentary sources and interviews with stakeholders involved in the implementation of perinatal information service networks and collaborations with community partners. Perinatal health indicators and determinants will be compared between prenatal education groups (group prenatal education and online prenatal education) and standard care without these prenatal education services (control group). DISCUSSION: This study will provide knowledge about the impact of online prenatal education as a new technological service delivery model compared to traditional group prenatal education. Indicators related to the complementarity of these interventions and those available in community settings will refine our understanding of regional perinatal services networks. Results will assist decision-making regarding service organization and delivery models of prenatal education services. PROTOCOL VERSION: Version 1 (February 9 2018).

A dense cluster of D1 + cells in the mouse nucleus accumbens.

The striatum is known to be largely composed of intermingled medium-sized projection neurons expressing either the D1 or the D2 dopamine receptors. In the present study, we took advantage of the double BAC Drd1a-TdTomato/Drd2-GFP (D1 /D2 ) transgenic mice to reveal the presence of a peculiar cluster of densely-packed D1 + cells located in the shell compartment of the nucleus accumbens. This spherical cluster has a diameter of 110 µm and is exclusively composed by D1 + cells, which are all immunoreactive for the neuronal nuclear marker (NeuN). However, in contrast to other D1 + or D2 + striatal cells, those that form the accumbens cluster are devoid of calbindin (CB) and DARPP-32, two faithful markers for striatal projection neurons. Using GAD-GFP transgenic mice, we confirm the GABAergic nature of the D1 + clustered neurons. Intracellular injections from fixed brain slices indicate that these neurons are endowed with distinctive morphological features, including a small (5-6 µm), round cell body giving rise to a single primary dendrite that branches into two secondary processes. Single-neuronal injections combined to electron microscopy reveal the existence of GAP junctions linking these D1 + cells. Based on their location, morphological characteristics and neurochemical phenotype, we conclude that the D1 + accumbens cluster form a highly compact group of small neurons distinct from the larger and more diffusely distributed D1 + or D2 + striatal projection neurons that surround it. This remarkable nucleus might play a crucial role in the limbic function of the murine striatum.

The number of striatal cholinergic interneurons expressing calretinin is increased in parkinsonian monkeys.

The most abundant interneurons in the primate striatum are those expressing the calcium-binding protein calretinin (CR). The present immunohistochemical study provides detailed assessments of their morphological traits, number, and topographical distribution in normal monkeys (Macaca fascicularis) and in monkeys rendered parkinsonian (PD) by MPTP intoxication. In primates, the CR+ striatal interneurons comprise small (8-12µm), medium (12-20µm) and large-sized (20-45µm) neurons, each with distinctive morphologies. The small CR+ neurons were 2-3 times more abundant than the medium-sized CR+ neurons, which were 20-40 times more numerous than the large CR+ neurons. In normal and PD monkeys, the density of small and medium-sized CR+ neurons was twice as high in the caudate nucleus than in the putamen, whereas the inverse occurred for the large CR+ neurons. Double immunostaining experiments revealed that only the large-sized CR+ neurons expressed choline acetyltransferase (ChAT). The number of large CR+ neurons was found to increase markedly (4-12 times) along the entire anteroposterior extent of both the caudate nucleus and putamen of PD monkeys compared to controls. Comparison of the number of large CR-/ChAT+ and CR+/ChAT+ neurons together with experiments involving the use of bromo-deoxyuridine (BrdU) as a marker of newly generated cells showed that it is the expression of CR by the large ChAT+ striatal interneurons, and not their absolute number, that is increased in the dopamine-depleted striatum. These findings reveal the modulatory role of dopamine in the phenotypic expression of the large cholinergic striatal neurons, which are known to play a crucial role in PD pathophysiology.

Franciscus Sylvius on Clinical Teaching, Iatrochemistry and Brain Anatomy.

Born in Hanau, Germany, in 1614, Franciscus (Dele Boë) Sylvius received his medical doctor diploma from Basel University in 1637 and became Professor of Practical Medicine at Leiden University in 1658. One of the founders of medical biochemistry, Sylvius was also an outstanding anatomopathologist, with contributions ranging from the first description of the pulmonary tubercles to that of the lateral fissure of the brain. Thanks to Sylvius, a gifted teacher and one of the greatest physicians of his time, Leiden became a major European medical training center. He died in 1772 after having served as Rector Magnificus at Leiden University.

Cholinergic and Nadph-δ neurons in the pedunculopontine and laterodorsal tegmental nuclei of human and nonhuman primates.

The brainstem pedunculopontine (PPN) and laterodorsal tegmental (LDTg) nuclei are involved in multifarious activities, including motor control. Yet, their exact cytoarchitectural boundaries are still uncertain. We therefore initiated a comparative study of the topographical and neurochemical organization of the PPN and LDTg in cynomolgus monkeys (Macaca fascicularis) and humans. The distribution and morphological characteristics of neurons expressing choline acetyltransferase (ChAT) and/or nicotinamide adenine dinucleotide phosphate diaphorase (Nadph-δ) were documented. The number and density of the labeled neurons were obtained by stringent stereological methods, whereas their topographical distribution was reported upon corresponding magnetic resonance imaging (MRI) planes. In both human and nonhuman primates, the PPN and LDTg are populated by three neurochemically distinct types of neurons (ChAT-/Nadph-δ+, ChAT+/Nadph-δ-, and ChAT+/Nadph-δ+), which are distributed according to a complex spatial interplay. Three-dimensional reconstructions reveal that ChAT+ neurons in the PPN and LDTg form a continuum with some overlaps with pigmented neurons of the locus coeruleus, dorsally, and of the substantia nigra (SN) complex, ventrally. The ChAT+ neurons in the PPN and LDTg are -two to three times more numerous in humans than in monkeys but their density is -three to five times higher in monkeys than in humans. Neurons expressing both ChAT and Nadph-δ have a larger cell body and a longer primary dendritic arbor than singly labeled neurons. Stereological quantification reveals that 25.6% of ChAT+ neurons in the monkey PPN are devoid of Nadph-δ staining, a finding that questions the reliability of Nadph-δ as a marker for cholinergic neurons in primate brainstem.

Quantitative and ultrastructural study of serotonin innervation of the globus pallidus in squirrel monkeys.

The present immunohistochemical study was aimed at characterizing the serotonin (5-HT) innervation of the internal (GPi) and external (GPe) pallidal segments in the squirrel monkey (Saimiri sciureus) with an antibody against the 5-HT transporter (SERT). At the light microscopic level, unbiased counts of SERT+ axon varicosities showed that the density of innervation is similar in the GPi (0.57 ± 0.03 × 10(6)  varicosities/mm(3) of tissue) and the GPe (0.60 ± 0.04 × 10(6) ), with the anterior half of both segments being more densely innervated than the posterior half. Dorsoventral and mediolateral decreasing gradients of SERT varicosities occur in both pallidal segments, but are statistically significant only in the GPi. The neuronal density being significantly greater in the GPe (3.41 ± 0.23 × 10(3)  neurons/mm(3) ) than in the GPi (2.90 ± 0.11 × 103), the number of 5-HT axon varicosities per pallidal neuron was found to be superior in the GPi (201 ± 27) than in the GPe (156 ± 26). At the electron microscopic level, SERT+ axon varicosities are comparable in size and vesicular content in GPi and GPe, where they establish mainly asynaptic contacts with unlabeled profiles. Less than 25% of SERT+ varicosities display a synaptic specialization, which is of the symmetrical or asymmetrical type and occurs exclusively on pallidal dendrites. No SERT+ axo-axonic synapses are present, suggesting that 5-HT exerts its well-established modulatory action upon various pallidal afferents mainly through diffuse transmission, whereas its direct control of pallidal neurons results from both volumic and synaptic release of the transmitter.

Niels Stensen: a 17th century scientist with a modern view of brain organization.

In 1665 the Danish scholar Niels Stensen (1638-1686) reached Paris, where he pronounced a discourse on brain anatomy that was to orient neuroscientists for years to come. In his lecture, Stensen rejected ancient speculations about animal spirits and criticized René Descartes and his followers who, despite a poor knowledge of brain anatomy, elaborated complex models to explain the multifaceted function of what he considered the principal organ of the human mind. He advocated the need for studying the brain through a comparative, developmental and pathological convergent approach and called for appropriate dissection methods and accurate illustrations. His own careful anatomical studies permitted him to precisely depict many brain structures. After pioneering works in paleontology and geology, he devoted himself to theology. In 1677 Stensen converted from Lutheranism to Catholicism and, while working relentlessly as a bishop and apostolic vicar in Northern Europe, he died in self-imposed poverty at age 48.

A Topographic Atlas of the Human Brainstem in the Ponto-Mesencephalic Junction Plane.

The human brainstem harbors neuronal aggregates that ensure the maintenance of several vital functions. It also acts as a major relay structure for the neuronal information that travels between the cerebral cortex, the cerebellum and the spinal cord. As such, this relatively small portion of the human brain houses a multitude of ascending and descending fibers that course among numerous nuclei whose exact boundaries are still uncertain. Such a large number of nuclei and fiber tracts confined to a relatively small and compact brain region imposes upon the brainstem a highly complex cytoarchitectonic organization that still needs to be deciphered. The present work provides a topographic atlas of the human brainstem composed of 45 anatomical plates, each containing a pair of adjacent sections stained with Cresyl Violet and Luxol Fast Blue to help delineating brainstem nuclei and fiber tracts, respectively. The plates, which cover the entire midbrain, pons and medulla oblongata, are composed of equally-spaced sections referenced and aligned parallel to the ponto-mesencephalic junction rather than the fastigium or the obex. This topographic landmark is particularly suitable for neurosurgical interventions aiming at specific nuclei of the mesencephalic tegmentum. In complement, we provide 8 anatomical plates containing adjacent sections stained for choline acetyltransferase and Luxol Fast Blue, taken through the midbrain and the pons. This open access atlas of the human brainstem is intended to assist neuroanatomists, neurosurgeons and neuropathologists in their work.

Vasculature guides migrating neuronal precursors in the adult mammalian forebrain via brain-derived neurotrophic factor signaling.

Adult neuronal precursors retain the remarkable capacity to migrate long distances from the posterior (subventricular zone) to the most anterior [olfactory bulb (OB)] parts of the brain. The knowledge about the mechanisms that keep neuronal precursors in the migratory stream and organize this long-distance migration is incomplete. Here we show that blood vessels precisely outline the migratory stream for new neurons in the adult mammalian forebrain. Real-time video imaging of cell migration in the acute slices demonstrate that neuronal precursors are retained in the migratory stream and guided into the OB by blood vessels that serve as a physical substrate for migrating neuroblasts. Our data suggest that endothelial cells of blood vessels synthesize brain-derived neurotrophic factor (BDNF) that fosters neuronal migration via p75NTR expressed on neuroblasts. Interestingly, GABA released from neuroblasts induces Ca(2+)-dependent insertion of high-affinity TrkB receptors on the plasma membrane of astrocytes that trap extracellular BDNF. We hypothesize that this renders BDNF unavailable for p75NTR-expressing migrating cells and leads to their entrance into the stationary period. Our findings provide new insights into the functional organization of substrates that facilitate the long-distance journey of adult neuronal precursors.

Morphological changes in serotoninergic neurites in the striatum and globus pallidus in levodopa primed MPTP treated common marmosets with dyskinesia.

Hyperinnervation of the striatum by serotoninergic (5-HT) terminals occurs after destruction of the dopaminergic nigro-striatal pathway. Recent studies have suggested that non-physiological release of dopamine (DA) formed from levodopa in these serotoninergic terminals underlies abnormal involuntary movement (AIMs) induction in 6-OHDA lesioned rats. In the present study, we used tryptophan hydroxylase (TPH) immunohistochemistry to determine whether 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treatment and the induction of dyskinesia by levodopa alter the morphology of 5-HT fibres in the striatum of common marmosets. The caudate-putamen of normal monkeys contained numerous fine and smooth TPH positive fibres and numerous varicose fibres, but a marked hyperinnervation of TPH positive fibres characterised by a significant increase in the number and diameter of TPH positive axon varicosities was noted in the dorsal caudate and putamen of MPTP-intoxicated monkeys but not the globus pallidus. In MPTP-intoxicated marmosets that had received chronic levodopa treatment to induce dyskinesia, a further increase in the number and enlargement of TPH positive axonal varicosities in both caudate nucleus and putamen was evident. Following LID induction, a similar pattern of increase was also observed in the external segment of the globus pallidus, but only a significant varicosity enlargement was seen in the internal pallidal segment. These results confirm that striatal 5-HT hyperinnervation follows nigro-striatal pathway loss and provide the first evidence in primates that chronic levodopa treatment and the onset of dyskinesia are associated with a marked hypertrophy of striatal 5-HT axonal varicosities. These findings support the concept that altered 5-HT function may contribute to the genesis or expression of LID.

Substantia nigra and Parkinson's disease: a brief history of their long and intimate relationship.

The substantia nigra was discovered in 1786 by Félix Vicq d'Azyr, but it took more than a century before Paul Blocq and Georges Marinesco alluded to a possible link between this structure and Parkinson's disease. The insight came from the study of a tuberculosis patient admitted in Charcot's neurology ward at la Salpêtrière because he was suffering from unilateral parkinsonian tremor. At autopsy, Blocq and Marinesco discovered an encapsulated tumor confined to the substantia nigra, contralateral to the affected side, and concluded that tremor in that particular case resulted from a midbrain lesion. This pioneering work, published in 1893, led Edouard Brissaud to formulate, in 1895, the hypothesis that the substantia nigra is the major pathological site in Parkinson's disease. Brissaud's hypothesis was validated in 1919 by Constantin Trétiakoff in a remarkable thesis summarizing a post-mortem study of the substantia nigra conducted in Marinesco's laboratory. Despite highly convincing evidence of nigral cell losses in idiopathic and post-encephalitic Parkinsonism, Trétiakoff's work raised considerable doubts among his colleagues, who believed that the striatum and pallidum were the preferential targets of parkinsonian degeneration. Trétiakoff's results were nevertheless confirmed by detailed neuropathological studies undertaken in the 1930s and by the discovery, in the 1960s, of the dopaminergic nature of the nigrostriatal neurons that degenerate in Parkinson's disease. These findings have strengthened the link between the substantia nigra and Parkinson's disease, but modern research has uncovered the multifaceted nature of this neurodegenerative disorder by identifying other brain structures and chemospecifc systems involved in its pathogenesis.

Berengario da Carpi and the Renaissance of Brain Anatomy.

Berengario da Carpi (Jacopo Barigazzi) was born around 1460 in the small Italian town of Carpi near Modena. Berengario's father, Faustino, was a reputable barber-surgeon who initiated his son early into the art of anatomy and surgery. After his graduation from the University of Bologna in 1489, Berengario rapidly acquired an enviable reputation as a physician and surgeon following the successful treatment of several dignitaries, including Lorenzo de' Medici, Duke of Urbino who suffered a severe head injury in 1517. While professor of anatomy and surgery at the University of Bologna, Berengario published in 1518 his De fractura cranei, a landmark work on cranio-cerebral surgery. Berengario's masterpiece, however, is undoubtedly his detailed Commentaria on the famous medieval anatomy treatise of Mondino de' Liuzzi (ca. 1270-1326) that he published in 1521. A shorter version entitled Isagogae Breves appeared a year later. Besides a facsimile of Mondino's work, Berengario's Commentaria contains a wealth of new information, including observations that challenged Galenic physiology. Galen taught that the rete mirabile-a vascular plexus believed to occur at the basis of the human brain-is the locus where the vital spirit is transformed into the more sophisticated animal spirit that is stored in the brain ventricles to be later released at the periphery through a journey within hollow nerves. Courageously, Berengario wrote that despite many attempts he was unable to detect the famous rete mirabile in humans. He also noted that the nerves linked to the brain are solid structures, not hollow tubes, as advocated by Galen. His conclusions were based on a systematic dissection method that he called anatomia sensibilis, a term that emphasizes the sensory over textual versions of the truth. Berengario contributed significantly to human brain anatomy, with a detailed description of the meninges and cranial nerves and the first comprehensive view of the ventricular system, including choroid plexuses, interventricular foramen, infundibulum, pituitary stalk and gland. Berengario, who died around 1530 in Ferrara, should be remembered for his catalyzing role in the transmutation of medieval morphological knowledge into a modern anatomical science based upon direct observation and experimental demonstration.

Deep Brain Stimulation of the Pedunculopontine Nucleus Area in Parkinson Disease: MRI-Based Anatomoclinical Correlations and Optimal Target.

BACKGROUND: Experimental studies led to testing of deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) as a new therapy to treat freezing of gait (FOG) in Parkinson disease (PD). Despite promising initial results fueling a growing interest toward that approach, several clinical studies reported heterogeneity in patient responses. Variation in the position of electrode contacts within the rostral brainstem likely contributes to such heterogeneity. OBJECTIVE: To provide anatomoclinical correlations of the effect of DBS of the caudal mesencephalic reticular formation (cMRF) including the PPN to treat FOG by comparing the normalized positions of the active contacts among a series of 11 patients at 1- and 2-yr follow-up and to provide an optimal target through an open-label study. METHODS: We defined a brainstem normalized coordinate system in relation to the pontomesencephalic junction. Clinical evaluations were based on a composite score using objective motor measurements and questionnaires allowing classification of patients as "bad responders" (2 patients), "mild responders" (1 patient) and "good responders" (6 patients). Two patients, whose long-term evaluation could not be completed, were excluded from the analysis. RESULTS: Most effective DBS electrode contacts to treat FOG in PD patients were located in the posterior part of the cMRF (encompassing the posterior PPN and cuneiform nucleus) at the level of the pontomesencephalic junction. CONCLUSION: In the present exploratory study, we performed an anatomoclinical analysis using a new coordinate system adapted to the brainstem in 9 patients who underwent PPN area DBS. We propose an optimal DBS target that allows a safe and efficient electrode implantation in the cMRF.

L-Dopa treatment abolishes the numerical increase in striatal dopaminergic neurons in parkinsonian monkeys.

The striatum harbors a population of dopaminergic interneurons that increases in number in animal models of Parkinson's disease (PD), presumably to compensate for dopamine (DA) depletion. The purpose of the present study was to determine the fate of striatal dopaminergic neurons in parkinsonian monkeys in which striatal DA depletion had been alleviated by systemic administration of l-dopa. The number of striatal dopaminergic neurons, visualized with tyrosine hydroxylase (TH) immunohistochemistry, was measured in three groups of cynomolgus (Macaca fascicularis) monkeys: (1) normal untreated monkeys; (2) monkeys rendered parkinsonian following systemic injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), but otherwise untreated; and (3) MPTP-intoxicated monkeys that received oral l-dopa on a chronic basis. In agreement with previous studies, the number of striatal TH-positive (TH+) neurons in l-dopa-free parkinsonian monkeys was significantly higher (p<0.05) than in normal (non-parkinsonian) monkeys. However, this increase was abolished in parkinsonian monkeys that received l-dopa treatment. In fact, the number of striatal TH+ neurons in l-dopa-treated parkinsonian monkeys was not significantly different (p>0.05) from values obtained in normal monkeys. These findings suggest that the DA concentration regulates the numerical density of this ectopic neuronal population, a phenomenon that is more likely the result of a shift in the phenotype of preexistent striatal interneurons rather than the recruitment of newborn neurons that would eventually develop a DA phenotype. Our data also reinforce the hypothesis that striatal TH+ neurons act as local DA source and, as such, are part of a compensatory mechanism that could be artificially enhanced to alleviate or delay PD symptoms.

The fate of the large striatal interneurons expressing calretinin in Huntington's disease.

Huntington's disease (HD) is characterized by the atrophy of the striatum due to losses of projection neurons, while interneurons are relatively spared. However, little is known about the fate of the large interneurons that express calretinin (Cr) in HD. We addressed this issue by applying a double immunofluorescent labeling technique to postmortem striatum from HD patients and controls. We compared the distribution and density of Cr-positive (+) interneurons and their degree of choline acetyltransferase (ChAT) coexpression in normal and HD cases. Large interneurons containing only Cr, ChAT, or both occurred in the normal human striatum and a twofold decrease in the density of Cr+/ChAT+ and Cr-/ChAT+ neurons was recorded in HD striatum compared to controls. However, studies undertaken with neurokinin-1 receptor as a marker of large Cr+ and ChAT+ neurons revealed that these neurons are selectively spared in HD. Hence, the apparent decrease in the number of Cr+/ChAT+ and Cr-/ChAT+ neurons in HD is better explained by a diminution in the expression of Cr and ChAT than by the degeneration of these cells. Altogether, our data suggest that neurodegenerative processes at play in HD affect the expression of Cr and ChAT in the large striatal interneurons without causing their death.

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.