Neuroscience
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Differential screening-selected gene aberrative in neuroblastoma (DAN) belongs to a novel gene family that includes the Xenopus head-inducing factor, Cerberus and the dorsalizing factor, Gremlin. It has been suggested that members of this family control diverse processes in growth, development and the cell cycle. ⋯ The amount of mRNA for DAN in dorsal root ganglion neurons and of its expressed protein in the spinal dorsal horn were both increased in inflammatory models. Together, these data suggest that the DAN protein may be a novel neuromodulator in primary nociceptive nerve fibers.
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In the present study we localized glial cell line-derived neurotrophic factor (GDNF), and the high affinity receptor for GDNF (GFRalpha-1) in the rat retina. We also examined the effects of neurturin on the survival of axotomized retinal ganglion cells (RGCs) and compared neurturin-mediated RGC rescue to GDNF and brain-derived neurotrophic factor (BDNF) neuroprotection. We administered combined injections of neurturin with BDNF or GDNF in order to determine if these factors rescue RGCs by different mechanisms. ⋯ These results suggest that neurturin, GDNF, and BDNF act independently to rescue injured RGCs. Our results also suggest that RGCs and retinal Müller cells may be responsive to GDNF because they both express GFRalpha-1. The present findings have implications for the rescue of injured retinal ganglion cells, as well as other CNS neurons that are responsive to neurturin, GDNF, and BDNF, including midbrain dopaminergic neurons and motor neurons.
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We examined the effects of 4-aminopyridine (4-AP) on isolated horizontal (superficial, middle and deep) rat neocortical slices in order to study laminar synchronous network behavior directly. Application of 4-AP induced spontaneous synchronized activity in all of these types of slices. In middle and deep layer slices the activities were similar to those of coronal slices, consisting of periodic short- and long-duration discharges. ⋯ By contrast, conventional coronal slices showed robust spontaneous epileptiform discharges under these circumstances. In intact coronal slices focal 4-AP application in superficial layers induced spontaneous inhibitory GABAergic events, while delivery into deep layers led to epileptiform discharges. From these results we conclude that: (1) 4-AP-induced population discharges are driven by glutamatergic transmission in middle and deep layer horizontal slices, and by GABAergic transmission in superficial layers; (2) only superficial layers are capable of supporting synchronized GABAergic activity independent of excitatory amino acid transmission; (3) superficial layers do not sustain epileptiform activity in the absence of deep layer neurons; and (4) synchronized superficial networks can inhibit deep layer neuronal activity.
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In transgenic mice carrying the G93A human mutation of Cu/Zn superoxide dismutase (SOD1), which provide a model of familial amyotrophic lateral sclerosis, we investigated, before the onset of symptoms, two parameters of the response of facial motoneurons to nerve transection, i.e. nitric oxide synthase induction and motoneuron loss. Axotomy elicited after 2 and 3 weeks high nitric oxide synthase expression in facial motoneurons of wild-type mice, whereas the induction was very weak or absent in transgenic mice. ⋯ Thus, SOD1 mutation interferes with the oxidative cascade elicited by axonal injury in cranial motoneurons. The results also indicate that the adverse gain of function of the mutant SOD1 enhances the vulnerability of motoneurons to peripheral stressful conditions.
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Enhanced expression of proinflammatory cytokines and chemokines has long been linked to neuronal and glial responses to brain injury. Indeed, inflammation in the brain has been associated with damage that stems from conditions as diverse as infection, multiple sclerosis, trauma, and excitotoxicity. In many of these brain injuries, disruption of the blood-brain barrier (BBB) may allow entry of blood-borne factors that contribute to, or serve as the basis of, brain inflammatory responses. ⋯ The mRNA levels for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6, cytokines normally expressed during the earliest stage of inflammation, were not increased up to 21 days post dosing. Lipopolysaccharide, used as a positive control, caused large inductions of cytokine mRNA in liver, as well as an increase in IL-1beta in hippocampus, but it did not result in the induction of astrogliosis. The data suggest that enhanced expression of the proinflammatory cytokines, TNF-alpha, IL-1beta and IL-6, is not required for neuronal and glial responses to injury and that MCP-1 may serve a signaling function in the damaged CNS that is distinct from its role in proinflammatory events.