The neurological basis of developmental coordination disorder (DCD) is thought to be deficits in the internal model and mirror-neuron system (MNS) in the parietal lobe and cerebellum. However, it is not clear if the visuo-motor temporal integration in the internal model and automatic-imitation function in the MNS differs between children with DCD and those with typical development (TD). The current study aimed to investigate these differences. Using the manual dexterity test of the Movement Assessment Battery for Children (second edition), the participants were either assigned to the probable DCD (pDCD) group or TD group. The former was comprised of 29 children with clumsy manual dexterity, while the latter consisted of 42 children with normal manual dexterity. Visuo-motor temporal integration ability and automatic-imitation function were measured using the delayed visual feedback detection task and motor interference task, respectively. Further, the current study investigated whether autism-spectrum disorder (ASD) traits, attention-deficit hyperactivity disorder (ADHD) traits, and depressive symptoms differed among the two groups, since these symptoms are frequent comorbidities of DCD. In addition, correlation and multiple regression analyses were performed to extract factors affecting clumsy manual dexterity. In the results, the delay-detection threshold (DDT) and steepness of the delay-detection probability curve, which indicated visuo-motor temporal integration ability, were significantly prolonged and decreased, respectively, in children with pDCD. The interference effect, which indicated automatic-imitation function, was also significantly reduced in this group. These results highlighted that children with clumsy manual dexterity have deficits in visuo-motor temporal integration and automatic-imitation function. There was a significant correlation between manual dexterity, and measures of visuo-motor temporal integration, and ASD traits and ADHD traits and ASD. Multiple regression analysis revealed that the DDT, which indicated visuo-motor temporal integration, was the greatest predictor of poor manual dexterity. The current results supported and provided further evidence for the internal model deficit hypothesis. Further, they suggested a neurorehabilitation technique that improved visuo-motor temporal integration could be therapeutically effective for children with DCD.
Inhibitors of the mammalian target of rapamycin (mTOR) have been shown to protect against neuronal injury, but the mechanisms underlying this effect are not fully understood. The present study aimed to examine the effects of rapamycin, an inhibitor of the mTOR pathway, on inflammation and capillary degeneration in a rat model of N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity. Inflammation and capillary degeneration were evaluated by counting the numbers of CD45-positive leukocytes and Iba1-positive microglia, and by measuring the length of empty basement membrane sleeves, respectively. Marked increases in the numbers of leukocytes and microglia were observed 1 d after intravitreal injection of NMDA (200 nmol), and significant capillary degeneration was observed after 7 d. These NMDA-induced changes were significantly reduced by the simultaneous injection of rapamycin (20 nmol) with NMDA. These results suggest that rapamycin has preventive effects on inflammation and capillary degeneration during retinal injury.Key words endothelial cell; excitotoxicity; leukocyte; mammalian target of rapamycin; microglia Glutamate is a major excitatory neurotransmitter, and excessive extracellular levels of glutamate cause neuronal cell death. The neurotoxicity induced by elevated glutamate levels is implicated in some ocular diseases, including diabetic retinopathy and glaucoma. 1,2) In many cases, glutamate-induced neurotoxicity has been predominantly attributed to overstimulation of N-methyl-D-aspartate (NMDA) receptors. 3,4) In addition to direct effects on neurons, indirect effects, such as upregulation of pro-inflammatory cytokines and recruitment of leukocytes into the retina, are involved in NMDA-induced retinal neuronal damage. 5,6) Recent studies have shown that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), exerts neuroprotective and axon growth-promoting effects during neuronal injury. 7,8) The mTOR is a serine/threonine kinase that regulates a wide array of cellular functions, including cell proliferation and cell-cycle control. 9) There are two distinct functional mTOR complexes, mTOR complex 1 and 2 (mTORC1 and mTORC2). Rapamycin inhibits mTORC1, which prevents phosphorylation of at least 2 well-characterized effectors: the p70S6 kinases (S6K1 and S6K2) and eIF4E-binding proteins (4E-BP1). 10) Inactivation of mTORC1 can cause autophagy, which has an important role in cellular homeostasis. 11) A role for autophagy has been suggested as a neuroprotective mechanism, whereby it enhances the clearance of harmful protein aggregates. 12,13) In addition, rapamycin could prevent inflammatory responses during brain injury, including activation of microglia. 14) Thus, multiple mechanisms might be involved in the neuroprotective effects of rapamycin.In the present study, we examined the effects of rapamycin on inflammation and capillary degeneration in a rat model of retinal neurotoxicity induced by overstimulation of NMDA receptors. MATERIALS AND METHODSAnimals Male Sprague-Dawley rats weighi...
Lesions to brain regions such as the temporoparietal junction (TPJ) and inferior frontal cortex (IFC) are thought to cause autism-spectrum disorder (ASD). Previous studies indicated that transcranial direct current stimulation (tDCS) of the right TPJ improves social cognitive functions such as imitation-inhibition and perspective-taking. Although previous work shows that tDCS of the right IFC improves imitation-inhibition, its effects on perspective-taking have yet to be determined. In addition, the role of the TPJ and IFC in determining the Autism-Spectrum Quotient (AQ), which is a measure of autism spectrum traits, is still unclear. Thus, the current study performed tDCS on the right TPJ and the right IFC of healthy adults, and examined its effects on imitation-inhibition, perspective-taking and AQ scores. Based on previous studies, we hypothesized that anodal tDCS of the right IFC and right TPJ would improve imitation-inhibition, perspective-taking and the AQ score. Anodal tDCS of the right TPJ or IFC significantly decreased the interference effect in an imitation-inhibition task and the cost of perspective-taking in a perspective-taking task, in comparison to the sham stimulation control. These findings indicated that both the TPJ and the IFC play a role in imitation-inhibition and perspective-taking, i.e., control of self and other representations. However, anodal stimulation of the right TPJ and the right IFC did not alter participants’ AQ. This finding conflicts with results from previous brain imaging studies, which could be attributed to methodological differences such as variation in sex, age and ASD. Therefore, further research is necessary to determine the relationship between the TPJ and IFC, and the AQ.
We previously demonstrated that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), protects against N-methyl-D-aspartic acid (NMDA)-induced retinal neurotoxicity, but the mechanism underlying this protection is not fully understood. The present study aimed to examine the effects of everolimus, another inhibitor of mTOR, on neuronal cell loss and inflammation in a rat model of NMDAinduced retinal neurotoxicity, and to determine whether the extracellular signal-regulated kinase (ERK) pathway contributes to the protective effect of everolimus. Intravitreal injection of NMDA (200 nmol) resulted in (1) cell loss in the ganglion cell layer, (2) increase in the numbers of CD45-positive leukocytes and Iba1-positive microglia, and (3) phosphorylation of ribosomal protein S6 (pS6), a downstream indicator of mTOR activity. Simultaneous injection of everolimus with NMDA significantly attenuated these NMDA-induced responses. The neuroprotective effect of everolimus was almost completely prevented by the mitogen-activated protein kinase/ERK kinase inhibitor U0126 (1 nmol). NMDA increased the level of phosphorylated ERK (pERK) in Müller cells, and increase in pERK levels was also observed after co-injection of NMDA and everolimus. These results suggest that everolimus has a neuroprotective effect against NMDA-induced retinal neurotoxicity, an effect that seems to be mediated partly by activation of the ERK pathway in Müller cells.
The interactions between neuronal, glial, and vascular cells play a key role in regulating blood flow in the retina. In the present study, we examined the role of the interactions between neuronal and glial cells in regulating the retinal vascular tone in rats upon stimulation of retinal neuronal cells by intravitreal injection of N-methyl-d-aspartic acid (NMDA). The retinal vascular response was assessed by measuring the diameter of the retinal arterioles in the in vivo fundus images. Intravitreal injection of NMDA produced retinal vasodilation that was significantly diminished following the pharmacological inhibition of nitric oxide (NO) synthase (nNOS), loss of inner retinal neurons, or intravitreal injection of glial toxins. Immunohistochemistry revealed the expression of nNOS in ganglion and calretinin-positive amacrine cells. Moreover, glial toxins significantly prevented the retinal vasodilator response induced by intravitreal injection of NOR3, an NO donor. Mechanistic analysis revealed that NO enhanced the production of vasodilatory prostanoids and epoxyeicosatrienoic acids in glial cells in a ryanodine receptor type 1-dependent manner, subsequently inducing the retinal vasodilator response. These results suggest that the NO released from stimulated neuronal cells acts as a key messenger in neuron–glia signaling, thereby causing neuronal activity-dependent and glial cell-mediated vasodilation in the retina.
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