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1.
Neurosci Res ; 170: 350-359, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33333087

RESUMO

We quantitatively investigated temporal changes of macrophages and microglia (MΦ/MG) after focal infarction of the internal capsule using a macaque model we recently established. Immunoreactivity for Iba1, a general marker for MΦ/MG, in the periinfarct core gradually increased from 0 days to 2-3 weeks after infarction, and the increased immunoreactivity continued at least until 6 months; no study in rodents has reported increased Iba1-immunoreactive cells for so long. Retrograde atrophy or degeneration of neurons in layer V of the primary motor cortex, where the descending motor tract originates, was seen as secondary damage. Here we found that Iba1-positive MΦ/MG transiently increased in layer V during several weeks after the infarction. Therefore, the time course of MΦ/MG activation differs between the perilesional area and the remote brain area where secondary damage occurs to tissue initially preserved after the infarct. Detailed analyses using the functional phenotype markers CD68, CD86, and CD206, as well as cytokines released by cells with each phenotype, suggest an anti-inflammatory role for activated MΦ/MG both in the periinfarct core during the chronic phase and in the primary motor cortex.


Assuntos
Cápsula Interna , Microglia , Animais , Modelos Animais de Doenças , Infarto , Macaca , Macrófagos
2.
Sci Rep ; 8(1): 11941, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30093721

RESUMO

We developed an fNIRS system for monitoring macaque cerebral motor activity during voluntary movements without head fixation. fNIRS data at 27 channels in 7.5 mm spatial interval were calibrated by simulating light propagation through the macaque cranial tissues. The subject was instructed to repeatedly (75 times) retrieve a food pellet with alternating left or right hands from a food well for each session. We detected significant increases in oxygenated hemoglobin (Hb) and decrease in deoxygenated Hb in the primary motor area (M1) contralateral to the hand used. In more rostral and ventral regions in both hemispheres, the hemodynamic similarly changed regardless of used hand. Direct feeding to the mouth eliminated activity in the hand M1 whereas that at bilateral ventral regions (mouth M1 area) remained. Statistical analyses for the hemodynamics between left/right-hand use revealed the location of each hand M1 in either hemisphere. In these regions, the maximum amplitude and time of the maximum amplitude in the hemodynamic response evoked by food retrieval were highly correlated with the time associated with food retrieval. We could assign each channel to an appropriate functional motor area, providing proof of principle for future studies involving brain damage models in freely moving macaque monkeys.


Assuntos
Movimentos da Cabeça/fisiologia , Atividade Motora/fisiologia , Córtex Motor/fisiologia , Movimento/fisiologia , Músculo Esquelético/fisiologia , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Animais , Mapeamento Encefálico , Feminino , Lateralidade Funcional , Hemodinâmica , Hemoglobinas/metabolismo , Macaca , Imageamento por Ressonância Magnética , Córtex Motor/metabolismo , Oxiemoglobinas/metabolismo
3.
Pain Res Manag ; 2018: 1630709, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29854035

RESUMO

The antineoplastic agent oxaliplatin induces an acute hypersensitivity evoked by cold that has been suggested to be due to sensitized central and peripheral neurons. Rodent-based preclinical studies have suggested numerous treatments for the alleviation of oxaliplatin-induced neuropathic pain, but few have demonstrated robust clinical efficacy. One issue is that current understanding of the pathophysiology of oxaliplatin-induced neuropathic pain is primarily based on rodent models, which might not entirely recapitulate the clinical pathophysiology. In addition, there is currently no objective physiological marker for pain that could be utilized to objectively indicate treatment efficacy. Nonhuman primates are phylogenetically and neuroanatomically similar to humans; thus, disease mechanism in nonhuman primates could reflect that of clinical oxaliplatin-induced neuropathy. Cold-activated pain-related brain areas in oxaliplatin-treated macaques were attenuated with duloxetine, the only drug that has demonstrated clinical efficacy for chemotherapy-induced neuropathic pain. By contrast, drugs that have not demonstrated clinical efficacy in oxaliplatin-induced neuropathic pain did not reduce brain activation. Thus, a nonhuman primate model could greatly enhance understanding of clinical pathophysiology beyond what has been obtained with rodent models and, furthermore, brain activation could serve as an objective marker of pain and therapeutic efficacy.


Assuntos
Antineoplásicos/toxicidade , Modelos Animais de Doenças , Neuralgia/induzido quimicamente , Compostos Organoplatínicos/toxicidade , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Cloridrato de Duloxetina/uso terapêutico , Humanos , Neuralgia/patologia , Neuralgia/terapia , Oxaliplatina , Primatas
4.
Sci Rep ; 7(1): 4305, 2017 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-28655928

RESUMO

The antineoplastic agent oxaliplatin induces a painful peripheral neuropathy characterized by an acute cold hypersensitivity. There is a lack of effective treatments to manage oxaliplatin-induced cold hypersensitivity which is due, in part, to a lack of understanding of the pathophysiology of oxaliplatin-induced cold hypersensitivity. Thus, brain activity in oxaliplatin-treated macaques was examined using functional magnetic resonance imaging (fMRI). Oxaliplatin treatment reduced tail withdrawal latency to a cold (10 °C) stimulus, indicating cold hypersensitivity and increased activation in the secondary somatosensory cortex (SII) and the anterior insular cortex (Ins) was observed. By contrast, no activation was observed in these areas following cold stimulation in untreated macaques. Systemic treatment with an antinociceptive dose of the serotonergic-noradrenergic reuptake inhibitor duloxetine decreased SII and Ins activity. Pharmacological inactivation of SII and Ins activity by microinjection of the GABAA receptor agonist muscimol increased tail withdrawal latency. The current findings indicate that SII/Ins activity is a potential mediator of oxaliplatin-induced cold hypersensitivity.


Assuntos
Antineoplásicos/efeitos adversos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Síndromes Periódicas Associadas à Criopirina/etiologia , Síndromes Periódicas Associadas à Criopirina/fisiopatologia , Oxaliplatina/efeitos adversos , Animais , Mapeamento Encefálico , Modelos Animais de Doenças , Macaca , Imageamento por Ressonância Magnética , Masculino , Córtex Somatossensorial/efeitos dos fármacos , Córtex Somatossensorial/fisiopatologia , Fatores de Tempo
5.
PLoS One ; 5(5): e10483, 2010 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-20463958

RESUMO

The neuronal mechanisms for ordering sensory signals in time still need to be clarified despite a long history of research. To address this issue, we recently developed a behavioral task of temporal order judgment in mice. In the present study, we examined the expression of c-Fos, a marker of neural activation, in mice just after they carried out the temporal order judgment task. The expression of c-Fos was examined in C57BL/6N mice (male, n = 5) that were trained to judge the order of two air-puff stimuli delivered bilaterally to the right and left whiskers with stimulation intervals of 50-750 ms. The mice were rewarded with a food pellet when they responded by orienting their head toward the first stimulus (n = 2) or toward the second stimulus (n = 3) after a visual "go" signal. c-Fos-stained cell densities of these mice (test group) were compared with those of two control groups in coronal brain sections prepared at bregma -2, -1, 0, +1, and +2 mm by applying statistical parametric mapping to the c-Fos immuno-stained sections. The expression of c-Fos was significantly higher in the test group than in the other groups in the bilateral barrel fields of the primary somatosensory cortex, the left secondary somatosensory cortex, the dorsal part of the right secondary auditory cortex. Laminar analyses in the primary somatosensory cortex revealed that c-Fos expression in the test group was most evident in layers II and III, where callosal fibers project. The results suggest that temporal order judgment involves processing bilateral somatosensory signals through the supragranular layers of the primary sensory cortex and in the multimodal sensory areas, including marginal zone between the primary somatosensory cortex and the secondary sensory cortex.


Assuntos
Julgamento/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Especificidade de Anticorpos , Comportamento Animal/fisiologia , Contagem de Células , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Somatossensorial/citologia , Córtex Somatossensorial/metabolismo , Coloração e Rotulagem , Fatores de Tempo
6.
Behav Brain Res ; 208(1): 158-62, 2010 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-19931567

RESUMO

Expression of immediate early genes, such as c-fos, has been extensively used as a marker of neural activity. However, their expression in the brain has so far been examined by using invasive procedures. In this study, we tried to image c-fos expression in the mouse barrel cortex noninvasively by detecting bioluminescence produced by the reporter luciferase. To detect asymmetry in c-fos expression in the bilateral barrel cortices, we used ten Fos-Luc mice and removed long whiskers on one side. After 1h of exploration in a novel cage, luciferin was intraperitoneally administrated under gas anesthesia and bioluminescence was measured with a cooled CCD camera. We observed moderate but clear emission over the head that was significantly stronger on the side of removal. After regrowth of the whiskers, the same mice had the vibrissae clipped on the other side. Bioluminescence was again dominant on the side of removal. In three of the mice, c-fos expression was examined immunohistochemically. The distribution of bioluminescence generally agreed with that of the c-fos positive cells though the bioluminescence tended to distribute wider, by around 0.5mm, probably due to scattering of light through the tissues. The results show that expression of c-fos in the mouse barrel cortex can be imaged repeatedly and noninvasively in the living animal.


Assuntos
Córtex Cerebral/metabolismo , Diagnóstico por Imagem/métodos , Luciferases/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Processamento de Imagem Assistida por Computador/métodos , Luciferases/genética , Medições Luminescentes/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Estimulação Física/métodos , Proteínas Proto-Oncogênicas c-fos/genética , Vibrissas/inervação
7.
J Comp Neurol ; 516(6): 493-506, 2009 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-19672995

RESUMO

To investigate the neural basis for functional recovery of the cerebral cortex following spinal cord injury, we measured the expression of growth-associated protein 43 (GAP-43), which is involved in the process of synaptic sprouting. We determined the GAP-43 mRNA expression levels in the sensorimotor cortical areas of macaque monkeys with a unilateral lesion of the lateral corticospinal tract (l-CST) at the C4/C5 level of the cervical cord and compared them with the levels in the corresponding regions of intact monkeys. Lesioned monkeys recovered finger dexterity during the first months after surgery, and the GAP-43 mRNA levels increased in layers II-III in primary motor areas (M1), bilaterally. Double-labeling analysis of the lesioned monkeys showed that GAP-43 mRNA was expressed strongly in excitatory neurons but only rarely in inhibitory interneurons. Expression also increased in the medium-sized (area, 500-1,000 microm(2)) and large pyramidal cells (area, >1,000 microm(2)) in layer V of the bilateral M1. The increased expression of GAP-43 mRNA in the M1 contralateral to the lesion was more prominent during the early recovery stage than during the late recovery stage. In addition, GAP-43 mRNA increased in layers II-III of both the contralesional ventral premotor area and the primary somatosensory area. These results suggest that GAP-43 is involved in time-dependent and brain region-specific plastic changes after l-CST lesioning. The expression patterns imply that plastic changes occur not only in M1 but also in the broad associative cortical network, including the ventral premotor and primary sensory areas.


Assuntos
Lobo Frontal/metabolismo , Proteína GAP-43/metabolismo , Córtex Motor/metabolismo , Neurônios/metabolismo , Tratos Piramidais/lesões , Córtex Somatossensorial/metabolismo , Animais , Vértebras Cervicais , Feminino , Interneurônios/metabolismo , Macaca , Macaca mulatta , Masculino , Células Piramidais/metabolismo , RNA Mensageiro/metabolismo , Recuperação de Função Fisiológica , Fatores de Tempo
8.
J Comp Neurol ; 509(2): 180-9, 2008 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-18461604

RESUMO

By using the developing monkey brain as a model for human development, we investigated the expression pattern of the FOXP2 gene, a member of the FOX family of transcription factors in the developing monkey brain, and compared its expression pattern with transcription factors PBX3, MEIS2, and FOXP1. We observed FOXP2 mRNA expression in several brain structures, including the striatum, the islands of Calleja and other basal forebrain regions, the cerebral cortex, and the thalamus. FOXP2 mRNA was preferentially expressed in striosomal compartments during striatal development. The striosomal expression was transient and developmentally down-regulated in a topographical order. Specifically, during the perinatal state, striosomal FOXP2 expression was detected in both the caudate nucleus and the putamen, although expression was more prominent in the caudate nucleus than in the putamen. Striosomal FOXP2 expression declined during the postnatal period, first in the putamen and later in the caudate nucleus. During the same period, we also detected PBX3 mRNA in the striosomal compartment of the developing monkey striatum. FOXP2, as well as PBX3 and MEIS2, was expressed in the islands of Calleja and other cell clusters of the basal forebrain. FOXP2, in combination with PBX3 and MEIS2, may play a pivotal role in the development of striosomal neurons of the striatum and the islands of Calleja.


Assuntos
Fatores de Transcrição Forkhead/biossíntese , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/biossíntese , Macaca/genética , Proteínas do Tecido Nervoso/biossíntese , Prosencéfalo/metabolismo , Proteínas Proto-Oncogênicas/biossíntese , Animais , Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Corpo Estriado/embriologia , Corpo Estriado/crescimento & desenvolvimento , Corpo Estriado/metabolismo , Feminino , Fatores de Transcrição Forkhead/genética , Hipocampo/embriologia , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Proteínas de Homeodomínio/genética , Hibridização In Situ , Macaca/embriologia , Macaca/crescimento & desenvolvimento , Masculino , Proteínas do Tecido Nervoso/genética , Especificidade de Órgãos , Prosencéfalo/embriologia , Prosencéfalo/crescimento & desenvolvimento , Precursores de Proteínas/biossíntese , Precursores de Proteínas/genética , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Septo do Cérebro/embriologia , Septo do Cérebro/crescimento & desenvolvimento , Septo do Cérebro/metabolismo , Especificidade da Espécie , Taquicininas/biossíntese , Taquicininas/genética , Tálamo/embriologia , Tálamo/crescimento & desenvolvimento , Tálamo/metabolismo , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética
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