Neuroscience
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The role of the common neurotrophin receptor p75 (p75NTR) in neuronal survival and cell death remains controversial. On the one hand, p75NTR provides a positive modulatory influence on nerve growth factor (NGF) signaling through the high affinity neurotrophin receptor TrkA, and hence increases NGF survival signaling. However, p75NTR may also signal independently of TrkA, causing cell death or cell survival, depending on the cell type and stage of development. ⋯ P75NTR signaling independent of TrkA, such as increased neutral sphingomyelinase (NSMase) activity causing enhanced levels of ceramide, were not detected after exposure of hippocampal neurons to NGF. Interestingly, inhibition of sphingosine-kinase blocked the neuroprotective effect of NGF, suggesting that sphingosine-1-phosphate was also involved in NGF-mediated survival in our cultured hippocampal neurons. Overall, our results indicate an essential role for p75NTR in supporting NGF-triggered TrkA signaling pathways mediating neuronal survival in hippocampal neurons.
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The role of the dorsal columns in neuropathic behavior: evidence for plasticity and non-specificity.
Despite conflicting clinical and experimental evidence, textbook description of somatic sensations continues to follow a rigid dichotomy based on the concept that pain sensation is transmitted cephalad primarily through anterolateral pathways, while touch is mediated through the dorsal column pathway. This study provides an example of the dynamic rerouting in the transmission of the nociceptive signals following injuries to the peripheral and central processes of sensory neurons. In two rat models for mononeuropathy, the chronic constriction injury model [Bennett, G. ⋯ Furthermore, these results shade doubts on the validity of the concept of segregation of pathways involved in the transmission of neuropathic manifestations. Therefore, principles governing acute pain transmission are not necessarily applicable to chronic pain situations. The latter conditions seem to engage other available pathways to reestablish the pain signaling system.
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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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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.