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Articles by Martin Parent in JoVE
Other articles by Martin Parent on PubMed
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Hippocampal Atrophy and Abnormal Brain Development Following a Prolonged Hyperthermic Seizure in the Immature Rat with a Focal Neocortical Lesion
Neurobiology of Disease.
Oct, 2008 |
Pubmed ID: 18678257 In rats subjected to a focal cortical lesion soon after birth, hyperthermia at P10 induces a prolonged epileptic seizure, often followed by temporal lobe epilepsy in the adult. To determine whether brain damage and notably hippocampal atrophy occur early on in this model, whole brain as well as hemispheric, cortical, subcortical and hippocampal volumes was measured in non-lesioned and lesioned rat pups, 2 days (P12) and 12 days (P22) after the hyperthermic seizure. All pups with a cortical lesion showed reductions in whole brain and in ipsilateral hemispheric, cortical and hippocampal volumes at P12, which persisted at P22 in pups having also sustained a prolonged hyperthermic seizure at P10. Limiting the duration of the seizure with Diazepam prevented the hippocampal atrophy. Thus, a prolonged hyperthermic seizure in immature brain with a subtle neocortical lesion impairs normal brain development, and the duration of the seizure appears to be a key factor in generating hippocampal atrophy.
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Acetylcholine Innervation of the Adult Rat Thalamus: Distribution and Ultrastructural Features in Dorsolateral Geniculate, Parafascicular, and Reticular Thalamic Nuclei
The Journal of Comparative Neurology.
Dec, 2008 |
Pubmed ID: 18924144 The acetylcholine (ACh) innervation of thalamus arises mainly from the brainstem pedunculopontine and laterodorsal tegmental nuclei. By using immunocytochemistry with a monoclonal antibody against whole rat choline acetyltransferase (ChAT), we quantified the distribution and characterized the ultrastructural features of these nerve terminals (axon varicosities) in the dorsolateral geniculate (DLG), parafascicular (PF), and reticular thalamic (Rt) nuclei of adult rat. The regional density of ACh innervation was the highest in PF (2.1 x 10(6) varicosities/mm(3)), followed by Rt (1.7 x 10(6)) and DLG (1.3 x 10(6)). In single thin sections, ChAT-immunostained varicosity profiles appeared comparable in shape and content in the three nuclei, but significantly larger in PF than in DLG and Rt. The number of these profiles displaying a synaptic junction was also much higher in PF than in DLG and Rt, indicating that all ChAT-immunostained varicosities in PF were synaptic, but only 39% in DLG and 33% in Rt. The hypothesis that glutamate corelease might account for the maintenance of the entirely synaptic ACh innervation in PF was refuted by the lack of colocalization of ChAT and vesicular glutamate transporter 2 (VGLUT2) in PF axon varicosities after dual immunolabeling. These data suggest that diffuse as well as synaptic transmission convey modulatory effects of the ACh input from brainstem to DLG and Rt during waking. In contrast, the entirely synaptic ACh input to PF should allow for a direct relaying of the information from brainstem, affecting basal ganglia function as well as perceptual awareness, including attention and pain perception.
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Distribution and Ultrastructural Features of the Serotonin Innervation in Rat and Squirrel Monkey Subthalamic Nucleus
The European Journal of Neuroscience.
Apr, 2010 |
Pubmed ID: 20345924 The main purpose of this light and electron microscopic immunocytochemical study was to characterize and compare the serotonin (5-HT) innervation of the subthalamic nucleus (STN) in rats and squirrel monkeys (Saimiri sciureus) following labeling with an antibody against the 5-HT transporter (SERT). Unbiased counts of SERT+ axon varicosities revealed an average density of 5-HT innervation higher in monkeys (1.52 x 10(6) varicosities/mm3) than rats (1.17 x 10(6)), particularly in the anterior half of the nucleus (1.70 x 10(6)). As measured by electron microscopy, SERT+ axon varicosity profiles in the STN of both species were smaller than unlabeled profiles. The number of SERT+ profiles displaying a synaptic junction indicated that, in both rat and monkey STN, approximately half of 5-HT axon varicosities were asynaptic. In monkeys, all synaptic junctions made by SERT+ varicosities were asymmetrical, as opposed to only 77% in rats. Despite the higher density of 5-HT innervation in the anterior half of monkey STN, the ultrastructural features of its SERT+ varicosities, including synaptic incidence, did not significantly differ from those in its posterior half. These findings suggest that, throughout the rat and monkey STN, 5-HT afferents may exert their influence via both synaptic delivery and diffusion of 5-HT, and that an ambient level of 5-HT maintained in STN by these two modes of transmission might also modulate neuronal activity and influence motor behavior. A better understanding of the factors governing the complex interplay between these signaling processes would greatly improve our knowledge of the physiopathology of the STN.
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Substantia Nigra and Parkinson's Disease: a Brief History of Their Long and Intimate Relationship
The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques.
May, 2010 |
Pubmed ID: 20481265 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.
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Jules Bernard Luys in Charcot's Penumbra
Frontiers of Neurology and Neuroscience.
2011 |
Pubmed ID: 20938152 Jules Bernard Luys (1828-1897) is a relatively unknown figure in 19th century French neuropsychiatry. Although greatly influenced by Jean-Martin Charcot (1825-1893), Luys worked in the shadow of the 'master of La Salpêtrière' for about a quarter of a century. When he arrived at this institution in 1862, he used microscopy and photomicrography to identify pathological lesions underlying locomotor ataxia and progressive muscular atrophy. He later made substantial contributions to our knowledge of normal human brain anatomy, including the elucidation of thalamic organization and the discovery of the subthalamic nucleus. Luys's name has long been attached to the latter structure (corps de Luys), which is at the center of our current thinking about the functional organization of basal ganglia and the physiopathology of Parkinson's disease. As head of the Maison de santé d'Ivry, Luys developed a highly original view of the functional organization of the normal human brain, while improving our understanding of the neuropathological and clinical aspects of mental illnesses. In 1886, Luys left La Salpêtrière and became chief physician at La Charité hospital. Following Charcot, whom he considered as the father of scientific hypnotism, Luys devoted the last part of his career to hysteria and hypnosis. However, Luys ventured too deeply into the minefield of hysteria. He initiated experiments as unconventional as the distant action of medication, and became one of the most highly caricatured examples of the fascination that hysteria exerted upon neurologists as well as laypersons at the end of the 19th century.
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Serotonin Innervation of Human Basal Ganglia
The European Journal of Neuroscience.
Apr, 2011 |
Pubmed ID: 21375599 This study aimed to provide a first detailed description of the serotonin (5-hydroxytryptamine, 5-HT) innervation of the human basal ganglia under nonpathological conditions. We applied an immunohistochemical approach to postmortem human brain material with antibodies directed against the 5-HT transporter and the 5-HT-synthesizing enzyme (tryptophane hydroxylase) to visualize 5-HT axons and cell bodies, respectively. Adjacent sections were immunostained for tyrosine hydroxylase to compare the distribution of 5-HT axons with that of dopamine axons. Human basal ganglia are innervated by 5-HT axons that emerge chiefly from the dorsal and, less abundantly, from the median raphe nuclei. These axons form thick ascending fascicles that fragment themselves as they penetrate the decussation of the superior cerebellar peduncle. They regroup within the ventral tegmental area and ascend along the medial forebrain bundle, immediately beneath the dopamine ascending fibers. At regular intervals along their course, 5-HT axons detach themselves from the medial forebrain bundle and sweep laterally to arborize within all basal ganglia components, where they display highly variable densities and patterns of innervation. The substantia nigra is the most densely innervated component of the basal ganglia, whereas the caudate nucleus is more heterogeneously innervated than the putamen and pallidum. The subthalamic nucleus harbors 5-HT-immunoreactive fibers that display a mediolateral-decreasing gradient. The fact that all components of human basal ganglia receive a dense 5-HT input indicates that, in concert with dopamine, 5-HT plays a crucial role in the functional organization of these motor-related structures, which are often targeted in neurodegenerative diseases.
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Brain 5-HT(2A) Receptors in MPTP Monkeys and Levodopa-induced Dyskinesias
The European Journal of Neuroscience.
May, 2011 |
Pubmed ID: 21501255 Levodopa-induced dyskinesias (LIDs) are abnormal involuntary movements induced by the chronic use of levodopa (l-Dopa) limiting the quality of life of Parkinson's disease (PD) patients. We evaluated changes of the serotonin 5-HT(2A) receptors in control monkeys, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys and in l-Dopa-treated MPTP monkeys, without or with adjunct treatments to inhibit the expression of LID: CI-1041, a selective NR1A/2B subunit antagonist of glutamate N-methyl-d-aspartic acid (NMDA) receptor, or Cabergoline, a long-acting dopamine D(2) receptor agonist. All treatments were administered for 1 month and animals were killed 24 h after the last dose of l-Dopa. Striatal concentrations of serotonin were decreased in all MPTP monkeys investigated, as measured by high-performance liquid chromatography. [(3) H]Ketanserin-specific binding to 5-HT(2A) receptors was measured by autoradiography. l-Dopa treatment that induced dyskinesias increased 5-HT(2A) receptor-specific binding in the caudate nucleus and the anterior cingulate gyrus (AcgG) compared with control monkeys. Moreover, [(3) H]Ketanserin-specific binding was increased in the dorsomedial caudate nucleus in l-Dopa-treated MPTP monkeys compared with saline-treated MPTP monkeys. Nondyskinetic monkeys treated with CI-1041 or Cabergoline showed low 5-HT(2A) -specific binding in the posterior dorsomedial caudate nucleus and the anterior AcgG compared with dyskinetic monkeys. No significant difference in 5-HT(2A) receptor binding was observed in any brain regions examined in saline-treated MPTP monkeys compared with control monkeys. These results confirm the involvement of serotonergic pathways and the glutamate/serotonin interactions in LID. They also support targeting 5-HT(2A) receptors as a potential treatment for LID.
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Effect of Chronic L-DOPA Treatment on 5-HT(1A) Receptors in Parkinsonian Monkey Brain
Neurochemistry International.
Dec, 2012 |
Pubmed ID: 22940695 After chronic use of l-3,4-dihydroxyphenylalanine (l-DOPA), most Parkinson's disease (PD) patients suffer from its side effects, especially motor complications called l-DOPA-induced dyskinesia (LID). 5-HT(1A) agonists were tested to treat LID but many were reported to worsen parkinsonism. In this study, we evaluated changes in concentration of serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and of 5-HT(1A) receptors in control monkeys, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys, dyskinetic MPTP monkeys treated chronically with l-DOPA, low dyskinetic MPTP monkeys treated with l-DOPA and drugs of various pharmacological activities: Ro 61-8048 (an inhibitor of kynurenine hydroxylase) or docosahexaenoic acid (DHA) and dyskinetic MPTP monkeys treated with l-DOPA+naltrexone (an opioid receptor antagonist). Striatal serotonin concentrations were reduced in MPTP monkeys compared to controls. Higher striatal 5-HIAA/serotonin concentration ratios in l-DOPA-treated monkeys compared to untreated monkeys suggest an intense activity of serotonin axon terminals but this value was similar in dyskinetic and nondyskinetic animals treated with or without adjunct treatment with l-DOPA. As measured by autoradiography with [(3)H]8-hydroxy-2-(di-n-propyl) aminotetralin (8-OH-DPAT), a decrease of 5-HT(1A) receptor specific binding was observed in the posterior/dorsal region of the anterior cingulate gyrus and posterior/ventral area of the superior frontal gyrus of MPTP monkeys compared to controls. An increase of 5-HT(1A) receptor specific binding was observed in the hippocampus of MPTP monkeys treated with l-DOPA regardless to their adjunct treatment. Cortical 5-HT(1A) receptor specific binding was increased in the l-DOPA-treated MPTP monkeys alone or with DHA or naltrexone and this increase was prevented in low dyskinetic MPTP monkeys treated with l-DOPA and Ro 61-8048. These results highlight the importance of 5-HT(1A) receptor alterations in treatment of PD with l-DOPA.
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Quantitative and Ultrastructural Study of Serotonin Innervation of the Globus Pallidus in Squirrel Monkeys
The European Journal of Neuroscience.
May, 2013 |
Pubmed ID: 23432025 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.
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Basal Ganglia Serotonin 1B Receptors in Parkinsonian Monkeys with L-DOPA-induced Dyskinesia
Biochemical Pharmacology.
Oct, 2013 |
Pubmed ID: 23954709 L-DOPA-induced dyskinesias (LID)s are abnormal involuntary movements limiting the chronic use of L-DOPA, the main pharmacological treatment of Parkinson's disease (PD). Serotonin receptors are thought to contribute to LID but serotonin 1B (5-HT1B) receptors have never been investigated in any primate models of PD and LID. Therefore, we measured 5-HT1B receptors with [(3)H]GR 125743 autoradiography in controls, MPTP-lesioned monkeys, and L-DOPA-treated MPTP monkeys, with or without Ro 61-8048 treatment, a kynurenine hydroxylase inhibitor alleviating LID. In normal condition, 5-HT1B receptor specific binding was highest in the substantia nigra pars reticulata (SNr), high in the globus pallidus (GP), nucleus accumbens and substantia innominata and lower in the caudate nucleus and putamen. 5-HT1B receptors were increased in caudate nucleus, putamen and SNr of MPTP monkeys compared to controls. L-DOPA-treated MPTP monkeys had elevated 5-HT1B receptor specific binding in caudate nucleus, putamen, SNr and internal GP. In all these brain regions, increases were prevented by co-administration of Ro 61-8048. No effect of MPTP lesion or treatment was observed for 5-HT1B specific binding in the external GP, nucleus accumbens and substantia innominata. This study is the first description in primates of altered brain 5-HT1B receptors associated with prevention of LID.
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Distribution of VGLUT3 in Highly Collateralized Axons from the Rat Dorsal Raphe Nucleus As Revealed by Single-neuron Reconstructions
PloS One.
2014 |
Pubmed ID: 24504335 This study aimed at providing the first detailed morphological description, at the single-cell level, of the rat dorsal raphe nucleus neurons, including the distribution of the VGLUT3 protein within their axons. Electrophysiological guidance procedures were used to label dorsal raphe nucleus neurons with biotinylated dextran amine. The somatodendritic and axonal arborization domains of labeled neurons were reconstructed entirely from serial sagittal sections using a computerized image analysis system. Under anaesthesia, dorsal raphe nucleus neurons display highly regular (1.72 ± 0.50 Hz) spontaneous firing patterns. They have a medium size cell body (9.8 ± 1.7 µm) with 2-4 primary dendrites mainly oriented anteroposteriorly. The ascending axons of dorsal raphe nucleus are all highly collateralized and widely distributed (total axonal length up to 18.7 cm), so that they can contact, in various combinations, forebrain structures as diverse as the striatum, the prefrontal cortex and the amygdala. Their morphological features and VGLUT3 content vary significantly according to their target sites. For example, high-resolution confocal analysis of the distribution of VGLUT3 within individually labeled-axons reveals that serotonin axon varicosities displaying VGLUT3 are larger (0.74 ± 0.03 µm) than those devoid of this protein (0.55 ± 0.03 µm). Furthermore, the percentage of axon varicosities that contain VGLUT3 is higher in the striatum (93%) than in the motor cortex (75%), suggesting that a complex trafficking mechanism of the VGLUT3 protein is at play within highly collateralized axons of the dorsal raphe nucleus neurons. Our results provide the first direct evidence that the dorsal raphe nucleus ascending projections are composed of widely distributed neuronal systems, whose capacity to co-release serotonin and glutamate varies from one forebrain locus to the other.
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The Role of Dopamine in Huntington's Disease
Progress in Brain Research.
2014 |
Pubmed ID: 24968783 Alterations in dopamine (DA) neurotransmission in Parkinson's disease are well known and widely studied. Much less is known about DA changes that accompany and underlie some of the symptoms of Huntington's disease (HD), a dominant inherited neurodegenerative disorder characterized by chorea, cognitive deficits, and psychiatric disturbances. The cause is an expansion in CAG (glutamine) repeats in the HTT gene. The principal histopathology of HD is the loss of medium-sized spiny neurons (MSNs) and, to a lesser degree, neuronal loss in cerebral cortex, thalamus, hippocampus, and hypothalamus. Neurochemical, electrophysiological, and behavioral studies in HD patients and genetic mouse models suggest biphasic changes in DA neurotransmission. In the early stages, DA neurotransmission is increased leading to hyperkinetic movements that can be alleviated by depleting DA stores. In contrast, in the late stages, DA deficits produce hypokinesia that can be treated by increasing DA function. Alterations in DA neurotransmission affect glutamate receptor modulation and could contribute to excitotoxicity. The mechanisms of DA dysfunction, in particular the increased DA tone in the early stages of the disease, are presently unknown but may include initial upregulation of DA neuron activity caused by the genetic mutation, reduced inhibition resulting from striatal MSN loss, increased excitation from cortical inputs, and DA autoreceptor dysfunction. Targeting both DA and glutamate receptor dysfunction could be the best strategy to treat HD symptoms.
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Internalization of Targeted Quantum Dots by Brain Capillary Endothelial Cells in Vivo
Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism.
Apr, 2016 |
Pubmed ID: 26661181 Receptors located on brain capillary endothelial cells forming the blood-brain barrier are the target of most brain drug delivery approaches. Yet, direct subcellular evidence of vectorized transport of nanoformulations into the brain is lacking. To resolve this question, quantum dots were conjugated to monoclonal antibodies (Ri7) targeting the murine transferrin receptor. Specific transferrin receptor-mediated endocytosis of Ri7-quantum dots was first confirmed in N2A and bEnd5 cells. After intravenous injection in mice, Ri7-quantum dots exhibited a fourfold higher volume of distribution in brain tissues, compared to controls. Immunofluorescence analysis showed that Ri7-quantum dots were sequestered throughout the cerebral vasculature 30 min, 1 h, and 4 h post injection, with a decline of signal intensity after 24 h. Transmission electron microscopic studies confirmed that Ri7-quantum dots were massively internalized by brain capillary endothelial cells, averaging 37 ± 4 Ri7-quantum dots/cell 1 h after injection. Most quantum dots within brain capillary endothelial cells were observed in small vesicles (58%), with a smaller proportion detected in tubular structures or in multivesicular bodies. Parenchymal penetration of Ri7-quantum dots was extremely low and comparable to control IgG. Our results show that systemically administered Ri7-quantum dots complexes undergo extensive endocytosis by brain capillary endothelial cells and open the door for novel therapeutic approaches based on brain endothelial cell drug delivery.
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Chemical Anatomy of Pallidal Afferents in Primates
Brain Structure & Function.
Dec, 2016 |
Pubmed ID: 27028222 Neurons of the globus pallidus receive massive inputs from the striatum and the subthalamic nucleus, but their activity, as well as those of their striatal and subthalamic inputs, are modulated by brainstem afferents. These include serotonin (5-HT) projections from the dorsal raphe nucleus, cholinergic (ACh) inputs from the pedunculopontine tegmental nucleus, and dopamine (DA) afferents from the substantia nigra pars compacta. This review summarizes our recent findings on the distribution, quantitative and ultrastructural aspects of pallidal 5-HT, ACh and DA innervations. These results have led to the elaboration of a new model of the pallidal neuron based on a precise knowledge of the hierarchy and chemical features of the various synaptic inputs. The dense 5-HT, ACh and DA innervations disclosed in the associative and limbic pallidal territories suggest that these brainstem inputs contribute principally to the planification of motor behaviors and the regulation of attention and mood. Although 5-HT, ACh and DA inputs were found to modulate pallidal neurons and their afferents mainly through asynaptic (volume) transmission, genuine synaptic contacts occur between these chemospecific axon varicosities and pallidal dendrites, revealing that these brainstem projections have a direct access to pallidal neurons, in addition to their indirect input through the striatum and subthalamic nucleus. Altogether, these findings reveal that the brainstem 5-HT, ACh and DA pallidal afferents act in concert with the more robust GABAergic inhibitory striatopallidal and glutamatergic excitatory subthalamopallidal inputs. We hypothesize that a fragile equilibrium between forebrain and brainstem pallidal afferents plays a key role in the functional organization of the primate basal ganglia, in both health and disease.
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The Number of Striatal Cholinergic Interneurons Expressing Calretinin is Increased in Parkinsonian Monkeys
Neurobiology of Disease.
Nov, 2016 |
Pubmed ID: 27388937 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.
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A Dense Cluster of D1 + Cells in the Mouse Nucleus Accumbens
Synapse (New York, N.Y.).
Jan, 2017 |
Pubmed ID: 27785835 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.
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