The Journal of neuroscience : the official journal of the Society for Neuroscience
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Diabetic neuropathic pain imposes a huge burden on individuals and society, and represents a major public health problem. Despite aggressive efforts, diabetic neuropathic pain is generally refractory to available clinical treatments. A structure-function link between maladaptive dendritic spine plasticity and pain has been demonstrated previously in CNS and PNS injury models of neuropathic pain. ⋯ At 1 week after STZ injection, animals with hyperglycemia with no evidence of pain had few or no changes in spine morphology. These results demonstrate that diabetes-induced maladaptive dendritic spine remodeling has a mechanistic role in neuropathic pain. Molecular pathways that control spine morphogenesis and plasticity may be promising future targets for treatment.
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Painful peripheral neuropathy is a dose-limiting complication of chemotherapy. Cisplatin produces a cumulative toxic effect on peripheral nerves, and 30-40% of cancer patients receiving this agent experience pain. By modeling cisplatin-induced hyperalgesia in mice with daily injections of cisplatin (1 mg/kg, i.p.) for 7 d, we investigated the anti-hyperalgesic effects of anandamide (AEA) and cyclohexylcarbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597), an inhibitor of AEA hydrolysis. ⋯ Incubation of DRG neurons with cisplatin (4 μg/ml) for 24 h decreased the total length of neurites. URB597 (100 nM) attenuated these changes through activation of CB₁ receptors. Collectively, these results suggest that pharmacological facilitation of AEA signaling is a promising strategy for attenuating cisplatin-associated sensory neuropathy.
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Comparative Study
Fibroblast growth factor receptor signaling in oligodendrocytes regulates myelin sheath thickness.
Formation of the CNS white matter is developmentally tightly regulated, but the molecules and mechanisms of myelination control in the postnatal CNS are poorly understood. Here, we show that myelin growth is controlled by fibroblast growth factor (FGF) signaling, originally identified as a proliferative signal for oligodendrocyte precursor cells (OPCs) in vitro. We created two lines of mice lacking both FGF receptor 1 (Fgfr1) and Fgfr2 in oligodendrocyte-lineage cells but found that in these mice OPC proliferation and differentiation were unaffected. ⋯ This FGF receptor-mediated stimulation of mature oligodendrocytes could also be modeled in vitro, demonstrating that enhanced expansion of oligodendroglial processes requires signaling by extracellular signal regulated kinase-1 and -2 (Erk1/2), downstream mediators of mitogen-activated protein kinase (MAPK). In vivo, Erk1/2-MAPK activity was reduced in the hypomyelinated CNS of Fgfr1/Fgfr2 mutant mice. These studies reveal a previously unrecognized function of FGF receptor signaling in oligodendrocytes that contributes to the regulation of myelin sheath thickness and that uncouples the initiation of ensheathment from the later phase of continued myelin growth.
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We used retrograde transneuronal transport of rabies virus from the rat kidney to identify the areas of the cerebral cortex that are potential sources of central commands for the neural regulation of this organ. Our results indicate that multiple motor and nonmotor areas of the cerebral cortex contain output neurons that indirectly influence kidney function. These cortical areas include the primary motor cortex (M1), the rostromedial motor area (M2), the primary somatosensory cortex, the insula and other regions surrounding the rhinal fissure, and the medial prefrontal cortex. ⋯ The output from M1 could add precision and organ-specific regulation to descending visceromotor commands, whereas the output from M2 could add anticipatory processing which is essential for allostatic regulation. We also found that the output from M1 and M2 to the kidney originates predominantly from the trunk representations of these two cortical areas. Thus, a map of visceromotor representation appears to be embedded within the classic somatotopic map of skeletomotor representation.
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Comparative Study
Electrophysiological abnormalities in both axotomized and nonaxotomized pyramidal neurons following mild traumatic brain injury.
Mild traumatic brain injury (mTBI) often produces lasting detrimental effects on cognitive processes. The mechanisms underlying neurological abnormalities have not been fully identified, in part due to the diffuse pathology underlying mTBI. Here we employ a mouse model of mTBI that allows for identification of both axotomized and intact neurons in the living cortical slice via neuronal expression of yellow fluorescent protein. ⋯ The rheobase is significantly increased in axotomized neurons at 1 d postinjury. The slope of the plot of AP frequency versus injected current is larger for intact neurons at 2 d postinjury. Together, these results demonstrate that intact and axotomized neurons are both affected by mTBI, resulting in different changes in neuronal excitability that may contribute to network dysfunction following TBI.