RESUMEN
Preclinical as well as limited clinical studies indicate that ketamine, a non-competitive glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, may exert a quick and prolonged antidepressant effect. It has been postulated that ketamine action is due to inhibition of NMDA and stimulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Here, we sought to determine whether ketamine would exert antidepressant effects in Wistar-Kyoto (WKY) rats, a putative animal model of depression and whether this effect would be associated with changes in AMPA/NMDA receptor densities in the hippocampus. Adult female WKY rats and their control Wistar rats were subjected to acute and chronic ketamine doses and their locomotor activity (LMA) and immobility in the forced swim test (FST) were evaluated. Hippocampal AMPA and NMDA receptor densities were also measured following a chronic ketamine dose. Ketamine, both acutely (0.5-5.0 mg/kg i.p.) and chronically (0.5-2.5 mg/kg daily for 10 days) resulted in a dose-dependent and prolonged decrease in immobility in FST in WKY rats only, suggesting an antidepressant-like effect in this model. Chronic treatment with an effective dose of ketamine also resulted in an increase in AMPA/NMDA receptor density ratio in the hippocampus of WKY rats. LMA was not affected by any ketamine treatment in either strain. These results indicate a rapid and lasting antidepressant-like effect of a low ketamine dose in WKY rat model of depression. Moreover, the increase in AMPA/NMDA receptor density in the hippocampus could be a contributory factor to behavioral effects of ketamine. These findings suggest potential therapeutic benefit in simultaneous reduction of central NMDA and elevation of AMPA receptor function in treatment of depression.
Asunto(s)
Antidepresivos/administración & dosificación , Hipocampo/efectos de los fármacos , Ketamina/administración & dosificación , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Depresión/metabolismo , Modelos Animales de Enfermedad , Femenino , Hipocampo/metabolismo , Ratas , Ratas Endogámicas WKYRESUMEN
Infection with human immunodeficiency virus-1 (HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS) in humans, causes a spectrum of neuropathology that includes alterations in behavior, changes in evoked potentials, and neuronal degeneration. In the simian immunodeficiency virus (SIV) model of HIV infection, affected monkeys show clinical symptoms and neurological complications that mimic those observed in human neuro-AIDS. To investigate the relationship between morphological correlates and neurophysiological deficits, unbiased stereology was used to assess total neuron number, volume, and neuronal density for all neurons in the globus pallidus (GP) and for dopamine (DA)-containing neurons in the substantia nigra (SN) in eight macaques inoculated with macrophage-tropic, neurovirulent SIV (SIVmac R71/17E), and five control animals. There was a significant difference between rapid progressors and controls for both neuron number (P < .01) and neuronal density (P < .05) in the GP, and for neuron number (P < .05) in the SN. Neuron loss ranged from 6% to 70% in the GP and from 10% to 50% in the SN. Neuropathological analyses confirmed neuroAIDS-like changes in brain, including microglial nodules, extensive perivascular cuffing and/or the presence of multinucleated giant cells, and alterations in neuronal morphology in the majority of the rapid progressors. By comparison, slow progressors showed little, if any, neuropathology. These neuropathological changes in SIV-infected monkeys indicate that neuron death and morphological alterations in the basal ganglia may contribute to the motor impairments reported in the SIV model and, by analogy, in the subset of patients afflicted with motor impairment in human neuro-AIDS.
Asunto(s)
Encéfalo/patología , Encéfalo/virología , Degeneración Nerviosa/patología , Neuronas/patología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Animales , Ganglios Basales/patología , Ganglios Basales/virología , Recuento de Células , Progresión de la Enfermedad , Globo Pálido/patología , Globo Pálido/virología , Macaca mulatta , Masculino , Desempeño Psicomotor/fisiología , Síndrome de Inmunodeficiencia Adquirida del Simio/fisiopatología , Virus de la Inmunodeficiencia de los Simios , Sustancia Negra/patología , Sustancia Negra/virologíaRESUMEN
Hormone replacement therapy with the gonadal steroid estrogen or synthetic agents such as raloxifene, a selective estrogen receptor modulator, may affect cellular function in brains of postmenopausal women. In vitro studies suggest that 17beta estradiol and raloxifene can alter the microglial and astrocyte expression of immuno-neuronal modulators, such as cytokines, complement factors, chemokines, and other molecules involved in neuroinflammation and neurodegeneration. To directly test whether exogenous 17beta estradiol and raloxifene affect the number of glial cells in brain, C57BL/6NIA female mice aged 20-24 months received bilateral ovariectomy followed by s.c. placement of a 60-day release pellet containing 17beta estradiol (1.7 mg), raloxifene (10 mg), or placebo (cholesterol). After 60 days, numbers of microglia and astrocytes were quantified in dentate gyrus and CA1 regions of the hippocampal formation using immunocytochemistry and design-based stereology. The results show that long-term 17beta estradiol treatment in aged female mice significantly lowered the numbers of astrocytes and microglial cells in dentate gyrus and CA1 regions compared with placebo. After long-term treatment with raloxifene, a similar reduction was observed in numbers of astrocytes and microglial cells in the hippocampal formation. These findings indicate that estrogen and selective estrogen receptor modulators can influence glial-mediated inflammatory pathways and possibly protect against age- and disease-related neuropathology.
Asunto(s)
Envejecimiento/fisiología , Antagonistas de Estrógenos/farmacología , Estrógenos/farmacología , Hipocampo/citología , Neuroglía/efectos de los fármacos , Clorhidrato de Raloxifeno/farmacología , Animales , Recuento de Células , Estrógenos/administración & dosificación , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Antígeno de Macrófago-1/metabolismo , Ratones , Ratones Endogámicos C57BL , Neuroglía/citología , Ovariectomía/métodos , Técnicas EstereotáxicasRESUMEN
The vesicular monoamine transporter in the brain can sequester the neurotoxin 1-methyl-4-phenylpyridinium into synaptic vesicles and protect catecholamine-containing neurons from degeneration. Mouse nigrostriatal dopaminergic neurons, and to a lesser extent locus coeruleus noradrenergic neurons, are vulnerable to toxicity produced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The present study sought to determine whether pharmacological inactivation of the vesicular monoamine transporter in the brain would enhance the degeneration of substantia nigra dopaminergic neurons and locus coeruleus noradrenergic neurons in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-treated animals. Mice were treated subacutely with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine alone, or in combination with vesicular monoamine transporter inhibitors (tetrabenazine or Ro4-1284), and 10-24 days later striatal dopamine and cortical norepinephrine levels were measured using chromatographic methods. In the same animals, substantia nigra and locus coeruleus catecholaminergic neurons were counted using tyrosine hydroxylase immunohistochemical staining with computer imaging techniques. Mice in which pharmacological blockage of the vesicular monoamine transporter enhanced the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in the depletion of striatal dopamine concentrations also exhibited enhanced degeneration of substantia nigra dopaminergic neurons. In the same animals, however, vesicular monoamine transporter blockade did not enhance the effects of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine in the locus coeruleus noradrenergic system. These data are consistent with the hypothesis that the vesicular monoamine transporter can protect catecholamine-containing neurons from 1-methyl-4-phenylpyridinium-induced degeneration by sequestration of the toxin within brain vesicular monoamine transporter-containing synaptic vesicles. Since the amount of vesicular monoamine transporter in locus coeruleus neurons is more than in substantia nigra neurons, and because 1-methyl-4-phenylpyridinium is sequestered within locus coeruleus neurons to a far greater extent than within substantia nigra neurons, it may be that a greater amount of vesicular monoamine transporter inhibition is required for 1-methyl-4-phenylpyridinium to be toxic to locus coeruleus neurons than to substantia nigra dopaminergic neurons.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Glicoproteínas de Membrana/antagonistas & inhibidores , Proteínas de Transporte de Membrana , Mesencéfalo/fisiopatología , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/fisiopatología , Neuronas/fisiología , Neuropéptidos , 2-etil-1,3,4,6,7,11b-hexahidro-3-isobutil-9,10-dimetoxi-2H-benzo(a)quinolizin-2-ol/farmacología , Animales , Recuento de Células , Sinergismo Farmacológico , Locus Coeruleus/fisiología , Masculino , Mesencéfalo/patología , Ratones , Degeneración Nerviosa/patología , Neuronas/patología , Norepinefrina/fisiología , Tetrabenazina/farmacología , Proteínas de Transporte Vesicular de Aminas Biógenas , Proteínas de Transporte Vesicular de MonoaminasRESUMEN
BACKGROUND: The thalamus is a brain region of interest in the study of schizophrenia because it provides critical input to brain regions such as the prefrontal, cingulate, and temporal cortices, where abnormalities have been repeatedly observed in patients with schizophrenia. Postmortem anatomic studies have rarely investigated the thalamus in this population. METHODS: Postmortem tissue was obtained from the left hemisphere of eight male schizophrenic patients and eight male age-matched control subjects. The optical dissector stereologic procedure was used to count neurons in the mediodorsal (MD) and anteroventral/anteromedial (AV/AM) nuclei of the thalamus. RESULTS: The number of neurons and volume of the MD were significantly reduced by 35% and 24%, respectively. The MD cell number reduction was a consistent finding; every control subject had more and every schizophrenic subject had fewer than 3.5 million neurons. Neuron number was also significantly reduced (16%) in the AV/AM nuclei. CONCLUSIONS: The present data indicate that schizophrenia is associated with robust reductions in nerve cell numbers in nuclei that communicate with the prefrontal cortex and limbic system. These thalamic anatomic deficits may be responsible, in part, for previous reports of such prefrontal cortical abnormalities as reduced synaptic density, reduced volume, and metabolic hypofunction.
Asunto(s)
Núcleos Talámicos Anteriores/patología , Núcleo Talámico Mediodorsal/patología , Red Nerviosa/patología , Neuronas/patología , Esquizofrenia/patología , Anciano , Anciano de 80 o más Años , Núcleos Talámicos Anteriores/ultraestructura , Encéfalo/patología , Estudios de Casos y Controles , Recuento de Células , Humanos , Masculino , Núcleo Talámico Mediodorsal/ultraestructura , Persona de Mediana Edad , Neuronas/ultraestructura , Núcleos Talámicos Ventrales/patología , Núcleos Talámicos Ventrales/ultraestructuraRESUMEN
Mesopontine cholinergic neurons influence midbrain dopaminergic neurons, and thalamic and cerebellar structures which have been implicated in the neuroanatomy of schizophrenia. It has been reported that there are approximately twice as many mesopontine cholinergic neurons in schizophrenics than in normals, using nicotinomide adenosine dinucleotide phosphatediaphorase histochemistry to identify the cholinergic neurons. The present study sought to replicate this finding by analysing mesopontine cholinergic neurons using an antibody against choline acetyltransferase. The mesopontine cholinergic neurons are located in the pars compacta and pars dissipata of the pedunculopontine nucleus, and in the laterodorsal tegmental nucleus. Quantitative computer imaging techniques were used to map the distribution of mesopontine cholinergic neurons. In addition, all medium-sized and large neurons in a region of interest containing the middle portion of the pedunculopontine nucleus pars compacta were counted in Nissl-stained sections. There was no difference between schizophrenic and normal brains in terms of: (i) the rostral-caudal length of the cholinergic cell complex, approximately 10 mm; (ii) the estimated total number of cholinergic neurons in the combined pedunculopontine nucleus and laterodorsal tegmental nucleus, approximately 20,000 cells unilaterally; and (iii) the combined number of cholinergic and non-cholinergic Nissl-stained neurons in the middle portion of the pedunculopontine nucleus. The present data do not support the previous observation of increased numbers of mesopontine cholinergic neurons in schizophrenia.
Asunto(s)
Fibras Colinérgicas/patología , Neuronas/química , Puente/patología , Esquizofrenia/patología , Tegmento Mesencefálico/patología , Acetilcolina/fisiología , Acetilcolinesterasa/análisis , Acetilcolinesterasa/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos , Química Encefálica , Recuento de Células , Fibras Colinérgicas/enzimología , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Neuronas/enzimología , Neuronas/ultraestructura , Esquizofrenia/metabolismoRESUMEN
The pars compacta and pars dissipata of the pedunculopontine nucleus contain cholinergic cell group Ch5, and the laterodorsal tegmental nucleus contains cholinergic cell group Ch6. The pedunculopontine nucleus has been implicated in a variety of functions, including mediation of rapid eye movement sleep and in extrapyramidal motor function, although the role of cholinergic and non-cholinergic neurons is unclear. Quantitative neuroanatomical techniques were used to map the distribution of cholinergic neurons in the mesopontine nuclei of the adult human brain. In addition, the number and distribution of comparably sized non-cholinergic neurons at selected anatomical levels were compared. An antibody raised against human choline acetyltransferase was used to stain immunohistochemically the mesopontine neurons in six brains, ranging in age from 28 to 60 years. The rostrocaudal length of the Cb5/Ch6 cell complex was approximately 10 mm. The estimated total number of cells was similar for all brains, and varied by less than 7%. The estimated average number of cholinergic cells in the combined pedunculopontine and laterodorsal tegmental nuclei was approximately 20,000, with 30% of the cells in the pedunculopontine nucleus pars compacta, 57% in the pedunculopontine nucleus pars dissipata and 13% in the laterodorsal tegmental nucleus. There was no correlation between cell number and age. Within areas of mesopontine tegmentum occupied by the Ch5 cholinergic neurons, there were often more noncholinergic neurons than comparably sized cholinergic neurons. The present study provides detailed maps of the distribution and number of mesopontine cholinergic neurons in the normal human brain. Many non-cholinergic neurons are intermixed with the cholinergic pedunculopontine neurons. One region of the pedunculopontine nucleus pars dissipata containing few cholinergic neurons, located adjacent to the ventral border of the pedunculopontine nucleus pars compacta, may correspond to the midbrain-extrapyramidal area as defined previously in rodent and in non-human primate. These data will be useful for quantitative neuropathological studies concerning the role of both cholinergic and non-cholinergic mesopontine neurons in diseases proposed to affect these neurons, including Parkinson's disease, schizophrenia and progressive supranuclear palsy.
Asunto(s)
Acetilcolina/fisiología , Neuronas/citología , Puente/citología , Adulto , Recuento de Células , Colina O-Acetiltransferasa/análisis , Fibras Colinérgicas/enzimología , Fibras Colinérgicas/ultraestructura , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Trastornos Mentales/patología , Persona de Mediana Edad , Proteínas del Tejido Nervioso/análisis , Enfermedades del Sistema Nervioso/patología , Neuronas/enzimologíaRESUMEN
Quantitative neuroanatomical techniques were used to determine whether with aging there is random or systematic loss of locus coeruleus (LC) neurons in the human brain. The cells were identified by immunohistochemical staining for the catecholaminergic enzyme tyrosine hydroxylase and/or by neuromelanin pigment content. Cell locations were mapped, using computer imaging procedures, in horizontal sections spaced 0.5 to 0.8 mm throughout the rostrocaudal extent of the nucleus in 17 cases, from 1 to 104 years of age. Neuromelanin pigment accumulated within the neurons with aging. In brains less than 25 years of age there were many fewer pigment-containing neurons than tyrosine hydroxylase-containing neurons; however, by the fifth decade the number of cells identified by the two markers was comparable. From the first to the tenth decade of life there is over a 50% loss of LC neurons: in four cases from "young" individuals (1-28 years of age) there were 21,084 +/- 653 tyrosine hydroxylase immunostained cells (mean +/- standard error of the mean) on one side of the brain; in seven cases from "old" individuals (60-82 years of age) there were 16,502 +/- 921 pigment-containing cells; and in the three cases from the "oldest" individuals (103-104 years of age) there were 9,493 +/- 1,236 pigment-containing neurons. In both the "old" and "oldest" groups, compared to the "young," there was significantly greater loss of rostral cells than caudal cells. These data indicate a systematic loss of cells such that the rostral, forebrain-projecting neurons decrease in number with aging to a greater extent than do the caudal, spinal cord-projecting neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Locus Coeruleus/citología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Biomarcadores , Senescencia Celular/fisiología , Niño , Preescolar , Femenino , Humanos , Inmunohistoquímica , Lactante , Locus Coeruleus/química , Masculino , Melaninas/análisis , Persona de Mediana Edad , Distribución Aleatoria , Tirosina 3-Monooxigenasa/análisisRESUMEN
The dopamine transporter (DAT) is the site at which the neurotoxic metabolite of MPTP gains access to midbrain dopaminergic (DA) neurons. However, not all midbrain DA neurons degenerate following MPTP treatment. The midbrain DA neurons that contain the calcium-binding protein, calbindin-D28k (CALB), are relatively invulnerable to MPTP toxicity, compared with DA neurons that lack CALB. Using in situ hybridization and immunocytochemical staining techniques in the rat and mouse, we now report that there is as much as 10 fold less DAT mRNA in regions where DA neurons contain CALB compared with regions where DA neurons lack CALB. These data suggest that specific midbrain DA neurons are invulnerable to MPTP toxicity not only because they contain CALB, but also because they have relatively low DAT activity.
Asunto(s)
Proteínas Portadoras/biosíntesis , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Mesencéfalo/metabolismo , Proteínas del Tejido Nervioso , ARN Mensajero/biosíntesis , Proteína G de Unión al Calcio S100/metabolismo , Animales , Calbindina 1 , Calbindinas , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Expresión Génica , Humanos , Inmunohistoquímica , Hibridación in Situ , Masculino , Mesencéfalo/anatomía & histología , Ratones , Ratones Endogámicos C57BL , Ratas , Radioisótopos de Azufre , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The dopaminergic neurons in the midbrain of the rat are located in three cell groups: nucleus A8 cells in the retrorubral field, nucleus A9 cells in the substantia nigra, and nucleus A10 cells in the ventral tegmental area and related nuclei. The purpose of the present study was to map and quantify the midbrain dopaminergic neurons in two and three dimensions in the rat brain, using immunohistochemical staining and computer imaging techniques. The cells were identified with an antibody against tyrosine hydroxylase, and counted in six midbrain nuclei: the retrorubral field, substantia nigra pars compacta, substantia nigra pars reticulata, central linear nucleus, ventral tegmental area, and interfascicular nucleus. Outlines were traced around the perimeters of the coronal tissue sections, and the locations of all immunoreactive ventral midbrain cells were mapped. On one side of the brain there are approximately 1,300 nucleus A8 cells, 10,500 nucleus A9 cells, and 10,200 nucleus A10 cells. The 2- and 3-dimensional reconstructions illustrate the region-specific density of dopaminergic neurons throughout the midbrain cell complex, and provide a visual appreciation of the location and distribution of the three dopaminergic cell groups in relation to their position in the midbrain. Information about the number and location of midbrain dopaminergic neurons will be useful in conjunction with future studies that characterize these cells more specifically, for example, in terms of their co-transmitters, and afferent and efferent projections.
Asunto(s)
Mapeo Encefálico/métodos , Dopamina/análisis , Procesamiento de Imagen Asistido por Computador , Mesencéfalo/fisiología , Neuronas/química , Animales , Masculino , Mesencéfalo/citología , RatasRESUMEN
Opiates and opioid peptides are known to influence the dopaminergic (DA) neurons in the midbrain. The purpose of this study was to map and quantify the density of kappa and delta opioid receptor subtypes in the retrorubral field, substantia nigra, and ventral tegmental area and related nuclei, which contain DA nuclei A8, A9, and A10, respectively. Sections through the rostral-caudal extent of the rat midbrain were stained with an antibody against tyrosine hydroxylase, as a DA cell marker, and comparable sections were processed for in vitro receptor autoradiography using the kappa-selective ligand, U-69593, and the delta-selective ligand, D-Pen2, D-Pen5-enkephalin. In general, both kappa and delta ligands exhibited low levels of specific binding in regions occupied by the midbrain DA neurons. Kappa binding (4-8 fmol/mg tissue) was high throughout the rostral-caudal extent of the substantia nigra, in rostral portions of the ventral tegmental area, and in the nucleus paranigralis; low binding occurred in the retrorubral field and central linear nucleus raphe. Delta binding (6-18 fmol/mg tissue) was high in the caudal portion of the substantia nigra pars reticulata, and in the medial terminal nucleus of the accessory optic system (a region previously shown to contain DA dendrites). The kappa and delta receptor binding is heterogeneously distributed in regions occupied by midbrain dopaminergic neurons, and several fold lower than the binding of mu opioid receptors in the same brain regions.
Asunto(s)
Bencenoacetamidas , Dopamina , Encefalinas , Mesencéfalo/química , Pirrolidinas , Receptores Opioides delta/análisis , Receptores Opioides kappa/análisis , Animales , Autorradiografía , Densitometría , Encefalina D-Penicilamina (2,5) , Procesamiento de Imagen Asistido por Computador , Masculino , Mesencéfalo/citología , Neuronas/química , Ratas , Ratas Sprague-Dawley , Sustancia Negra/química , Tegmento Mesencefálico/químicaRESUMEN
Several lines of evidence indicate that an interaction exists between opioid peptides and midbrain dopaminergic neurons. The purpose of this study was to map and quantify the density of the mu opioid receptor subtype relative to the location of the dopaminergic (DA) neurons in the retrorubral field (nucleus A8), substantia nigra (nucleus A9), and ventral tegmental area and related nuclei (nucleus A10) in the rat. Sections through the rostral-caudal extent of the midbrain were stained with an antibody against tyrosine hydroxylase, as a DA cell marker, and comparable sections were processed for in vitro receptor autoradiography using the mu-selective ligand, 3H-Tyr-D-Ala-N-MePhe-Gyl-ol enkephalin. In the nucleus A8 region, there were low levels of mu binding. In the rostral portion of nucleus A9, there was prominent mu binding both in the ventral pars compacta, which contains numerous DA neurons, and in regions that correspond to the location of the DA dendrites which project ventrally into the underlying substantia nigra pars reticulata. In the caudal portion of nucleus A9, mu binding was greatest in the substantia nigra pars reticulata, but also in the same region that contains DA neurons. In nucleus A10, mu receptor densities differed depending upon the nucleus A10 subdivision, and the rostral-caudal position in the nucleus. Low receptor densities were observed in rostral portions of the ventral tegmental area and interfascicular nucleus, and there was negligible binding in the parabrachial pigmented nucleus and paranigral nucleus at the level of the interpeduncular nucleus; all regions where there are high densities of DA somata. Mu binding was relatively high in the central linear nucleus, and in the dorsal and medial divisions of the medial terminal nucleus of the accessory optic system, which has been shown to contain DA dendrites. These data indicate that mu opioid receptors are located in certain regions occupied by all three midbrain DA nuclei, but in a highly heterogeneous fashion.
Asunto(s)
Dopamina , Encefalinas , Mesencéfalo/química , Receptores Opioides mu/análisis , Animales , Autorradiografía , Densitometría , Encefalina Ala(2)-MeFe(4)-Gli(5) , Procesamiento de Imagen Asistido por Computador , Masculino , Mesencéfalo/citología , Neuronas/química , Ratas , Ratas Sprague-Dawley , Sustancia Negra/química , Tegmento Mesencefálico/químicaRESUMEN
Computer visualization techniques were used to map and to quantitatively reconstruct the entire locus coeruleus, including the nucleus subcoeruleus, to compare the topographic patterns of cell loss in postmortem brains from patients with Parkinson's disease, Alzheimer's disease, and Down syndrome. There was comparable cell loss in all three diseases (approximately 60%) compared with aged normal subjects, and there was a significant loss of nucleus subcoeruleus cells specifically in patients with Parkinson's disease (63%). There was a significant positive correlation between the magnitude of locus coeruleus cell loss and the duration of Alzheimer's disease, but no such correlation was found for Parkinson's disease. In patients with Parkinson's disease, there was comparable cell loss throughout the rostral-caudal extent of the nucleus; however, in patients with Alzheimer's disease and Down syndrome, the greatest cell loss always occurred within the rostral portion of the nucleus, with a relative sparing of caudal cells. These data are consistent with the hypothesis that cell loss in Parkinson's disease is the result of a pathological process that attacks the catecholaminergic cells of the locus coeruleus and the subcoeruleus in general; in Alzheimer's disease and Down syndrome, however, the pathological process only affects the rostral, cortical-projecting locus coeruleus cells and spares the caudal, noncortical-projecting cells.
Asunto(s)
Enfermedad de Alzheimer/patología , Mapeo Encefálico , Síndrome de Down/patología , Locus Coeruleus/patología , Enfermedad de Parkinson/patología , Anciano , Inteligencia Artificial , Diagnóstico por Computador , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana EdadRESUMEN
Computer imaging and immunohistochemical staining techniques were used to determine which midbrain dopaminergic (DA) cells are spared in Parkinson's disease (PD), and in animals treated with the DA neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and whether the spared cells contain the calcium-binding protein, calbindin-D28k (CaBP). The PD patients had more than 55% fewer midbrain DA neurons than age-matched normal subjects. The cell loss occurred within the combined substantia nigra and retrorubral area (greater than 61%; DA nuclei A9 and A8, respectively), and the ventral tegmental area (greater than 42%; DA nucleus A10). The cell loss was greatest within the ventral portion of the nucleus A9. A similar pattern of DA cell loss was observed in MPTP-treated Macaca fascicularis monkeys. The CaBP-containing cells were located specifically in the cell regions spared by PD and by MPTP-treatment in both monkeys and C57BL/6 mice. These data suggest that PD and MPTP both destroy the same population of midbrain DA neurons within nuclei A8, A9, and A10, and that perhaps CaBP protects the DA neurons from cell death caused by both PD and MPTP.
Asunto(s)
Dopamina/metabolismo , Intoxicación por MPTP , Mesencéfalo/metabolismo , Enfermedad de Parkinson Secundaria/metabolismo , Enfermedad de Parkinson/metabolismo , Proteína G de Unión al Calcio S100/metabolismo , Anciano , Animales , Calbindina 1 , Calbindinas , Muerte Celular , Femenino , Humanos , Macaca fascicularis , Masculino , Mesencéfalo/efectos de los fármacos , Mesencéfalo/patología , Persona de Mediana Edad , Enfermedad de Parkinson/patología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/patología , Tirosina 3-Monooxigenasa/análisis , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
A major portion of the midbrain dopamine (DA)-containing neurons project to the striatum and make up the mesostriatal DA system. The purpose of the present experiment was to map the location and quantify the density of mesostriatal neurons within two inbred mouse strains (BALB/c and CBA) known to possess different numbers of midbrain DA neurons. Computer-assisted reconstructions were made of both the wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) striatal injection site and the retrogradely labeled midbrain cells. There was no strain differences in the major source or topographical pattern of innervation of the striatum from the midbrain cellular regions. Even following small striatal injections, the labeled midbrain cells were found throughout most of the rostrocaudal extent of the midbrain DA nuclei; some labeled cells were found within the substantia nigra, the ventral tegmental area and the adjacent retrorubral field. Although the BALB/c strain has 20-25% more midbrain DA neurons than the CBA, given comparable striatal injection volumes, there was no significant difference in the number of HRP-filled mesostriatal neurons between the two mouse strains. These data suggest that the mesostriatal neurons give rise to comparable axonal branching within the striatum in the two mouse strains.
Asunto(s)
Cuerpo Estriado/citología , Dopamina/fisiología , Mesencéfalo/citología , Ratones Endogámicos BALB C/anatomía & histología , Ratones Endogámicos CBA/anatomía & histología , Tirosina 3-Monooxigenasa/metabolismo , Animales , Mapeo Encefálico , Recuento de Células , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiología , Peroxidasa de Rábano Silvestre , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Mesencéfalo/metabolismo , Mesencéfalo/fisiología , Ratones , Especificidad de la Especie , Aglutinina del Germen de Trigo-Peroxidasa de Rábano Silvestre Conjugada , Aglutininas del Germen de TrigoRESUMEN
The neurotoxic effects of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP), a substituted analog of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, were studied in BALB/cJ mice. Moderate doses of 2'CH3-MPTP produced a greater depletion of dopamine (DA) in the striatum (45%) than in the nucleus accumbens (23%), and in these same animals, there was a 35% loss of midbrain DA neurons. The greatest loss of DA cells occurred within the substantia nigra (43%), and there was also a significant loss of cells within the ventral tegmental area (28%). Higher doses of 2'CH3-MPTP decreased levels of DA more in the axon terminal/forebrain region (72%) than in the cell body/midbrain region (25%). Similar forebrain/midbrain DA depletion ratios were also found in mice that received an electrolytic lesion of the midbrain DA neurons; there was a greater Da depletion in the forebrain (29%) than in the midbrain (8%). In both 2'CH3-MPTP and electrolytically lesioned animals there was a significant increase in DA turnover in the forebrain region, as measured by the homovanillic acid/DA ratio. These data indicate that 2'CH3-MPTP: (1) destroys DA neurons within two midbrain regions containing cells which project to the striatum (i.e. mesostriatal DA neurons), rather than just nigrostriatal DA neurons; (2) produces a greater loss of DA in the axon terminal region than in the cell body region; and (3) influences the mesostriatal DA neurons in the same way as does a lesion to the cell bodies. These data are discussed with regard to the pathophysiology of 2'CH3-MPTP.