Neuroscience
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DYT1 dystonia is caused by a GAG deletion in TOR1A, the gene which encodes torsinA. Gene expression studies in rodents and functional imaging studies in humans suggest that DYT1 dystonia may be a network disorder of neurodevelopmental origin. ⋯ The hMT1 mice showed increased CO activity in the IOM and Purkinje cell layer of cerebellar cortex, and decreased CO activity in the caudal caudate-putamen, substantia nigra reticulata and MGP. These findings suggest that (1) the DYT1 carrier state increases energy demand in the olivocerebellar network and (2) the IO may be a pivotal node for abnormal basal ganglia-cerebellar interactions in dystonia.
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Increasing evidence indicates that both the ATP P2X receptors and adrenergic systems play a very important role in the development of nociception. However, there is little information concerning the interactions between these two systems in the dorsal root ganglia (DRG). In the present study, we examined the effects of noradrenaline (NA) on the P2X3 receptor expression in the DRG of Sprague-Dawley rats. ⋯ In electrophysiological experiments, perfusion of neuronal cultures with the P2X3 agonist (αβ-methylene ATP) increased neuronal firing rate by 139% and 273% in neurons treated with either PBS (control) or NA, respectively, indicating that chronic NA treatment significantly enhanced the neuronal response to P2X3 activation. In behavior studies, combination of NA (2 or 20 nmol) with αβ-methylene ATP (10 nmol) produced a significant and long lasting augmentation of thermal hyperalgesia. These results indicate that NA stimulates P2X3 expression in DRG neurons, and this could contribute to the development of pain sensitization.
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Previous studies have demonstrated that pioglitazone (Piog), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, inhibits ischemia-induced brain injury. Piog has also been shown to exert anti-inflammatory effects by attenuation of nuclear factor-κB (NF-κB) activation after myocardial ischemia/reperfusion injury. Because NF-κB is known to play a major role in the pathophysiology of brain ischemia, the present study was undertaken to elucidate whether pioglitazone attenuates ischemic neuronal damage through PPARγ-mediated suppression of NF-κB apoptotic signaling pathway. ⋯ Pre-treatment with GW9662 blocked Piog-elicited reduction in infarction volume, the increase in protein levels of IκBα and p-ERK, the reduction in the nuclear translocation of NF-κB subunit p65 and the repression of p53 mRNA expression. In addition, Piog attenuated the OGD-induced neuronal damage and inhibited the OGD-induced increases in p- NF-κB p65 in neurons. The present findings suggest that Piog's neuroprotection appears to be associated with PPARγ-mediated suppression of NF-κB signaling pathway.
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Painful peripheral neuropathies produced by nerve trauma are accompanied by substantial axonal degeneration and by a response in spinal cord microglia that is characterized by hypertrophy and increased expression of several intracellular and cell-surface markers, including ionizing calcium-binding adapter molecule 1 (Iba1) and Cd11b (a complement receptor 3 antigen recognized by the OX42 antibody). The microglia response has been hypothesized to be essential for the pathogenesis of the neuropathic pain state. In contrast, the painful peripheral neuropathies produced by low doses of cancer chemotherapeutics do not produce degeneration of axons in the peripheral nerve, although they do cause partial degeneration of the sensory axons' distal-most tips, that is the intraepidermal nerve fibers that form the axons' terminal receptor arbors. ⋯ As expected, microglia hypertrophy and increased expression of Iba1 were pronounced in the nerve transection and CCI animals. However, there was no microglia hypertrophy or increased Iba1 staining in the animals treated with paclitaxel, vincristine, oxaliplatin, or ddC. These results suggest that the mechanisms that produce neuropathic pain after exposure to chemotherapeutics may be fundamentally different than those operating after nerve trauma.
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The lateral part of intermediate layer of superior colliculus (SCl) is a critical substrate for successful predation by rats. Hunting-evoked expression of the activity marker Fos is concentrated in SCl while prey capture in rats with NMDA lesions in SCl is impaired. Particularly affected are rapid orienting and stereotyped sequences of actions associated with predation of fast moving prey. ⋯ The predatory behaviour of rats with re-grown whiskers returned to normal. In parallel, Fos expression in SCl induced by predation was significantly reduced in whiskerless animals. We conclude that whiskers contribute to the efficiency of rat prey capture and that the loss of vibrissal input to SCl, as reflected by reduced Fos expression, could play a critical role in predatory deficits of whiskerless rats.