The Journal of neuroscience : the official journal of the Society for Neuroscience
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Wrapping of the myelin sheath around axons by oligodendrocytes is critical for the rapid conduction of electrical signals required for the normal functioning of the CNS. Myelination is a multistep process where oligodendrocytes progress through a well coordinated differentiation program regulated by multiple extracellular growth and differentiation signals. The intracellular transduction of the extracellular signals that regulate myelination is poorly understood. ⋯ Similarly, in vitro ERK1/ERK2-deficient oligodendrocytes differentiated normally but failed to form typical myelin-like membrane sheets. None of these effects were observed in single ERK1 or ERK2 mutants. These studies suggest that the predominant role of ERK1/ERK2 signaling in vivo is in promoting rapid myelin growth to increase its thickness, subsequent to oligodendrocyte differentiation and the initiation of myelination.
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Neuropathic pain is a common cause of pain after nerve injury, but its molecular basis is poorly understood. In a post-gene chip microarray effort to identify new target genes contributing to neuropathic pain development, we report here the characterization of a novel neuropathic pain contributor, thrombospondin-4 (TSP4), using a neuropathic pain model of spinal nerve ligation injury. TSP4 is mainly expressed in astrocytes and significantly upregulated in the injury side of dorsal spinal cord that correlates with the development of neuropathic pain states. ⋯ Intrathecal injection of TSP4 protein into naive rats is sufficient to enhance the frequency of EPSCs in spinal dorsal horn neurons, suggesting an increased excitatory presynaptic input, and to cause similar behavioral hypersensitivities. Together, these findings support that injury-induced spinal TSP4 may contribute to spinal presynaptic hypersensitivity and neuropathic pain states. Development of TSP4 antagonists has the therapeutic potential for target-specific neuropathic pain management.
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Vezatin is an integral membrane protein associated with cell-cell adhesion complex and actin cytoskeleton. It is expressed in the developing and mature mammalian brain, but its neuronal function is unknown. Here, we show that Vezatin localizes in spines in mature mouse hippocampal neurons and codistributes with PSD95, a major scaffolding protein of the excitatory postsynaptic density. ⋯ Accordingly, neither the amplitude nor the frequency of miniature EPSCs was affected in Vezatin-deficient hippocampal neurons. However, the AMPA/NMDA ratio of evoked EPSCs was reduced, suggesting impaired functional maturation of excitatory synapses. These results suggest a role of Vezatin in dendritic spine morphogenesis and functional synaptic maturation.
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Extensive evidence implicates the amygdala as a major station for acquisition, extinction, and consolidation of emotional memories. Most of this work relies on fear-conditioning in rodents and imaging in humans. Few studies have explored coding of value in the primate amygdala, but the circuitry that underlies extinction and overnight retention remains largely unexplored. ⋯ We suggest that these changes can serve to increase neuronal sensitivity to an upcoming event and facilitate learning mechanisms. We further show formation of aversive-bias during the acquisition of associations and during overnight retention, in the sense that neurons preferentially code for the aversive conditioned stimuli, even if they initially homogenously represent value of the reinforcer. Our findings show flexible representations in the primate amygdala during the different cycles of learning and memory, and suggest selective potentiation of aversive information.
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Functional abnormalities in the dorsal-anterior-cingulate-cortex (dACC) underlie anxiety disorders and specifically post-traumatic stress disorder (PTSD). Promising and common behavioral approaches have limited effectiveness and many subjects exhibit spontaneous recovery of fear, as also evident in animal models following extinction training. Here, we use low-frequency stimulation (LFS), a protocol shown to induce long-term depression, with the aim of affecting synaptic plasticity induced by fear acquisition and extinction. ⋯ Moreover, this decrease in neural excitability predicted the successful reduction of overnight spontaneous recovery on a day-by-day basis. Finally, we show that this effect occurs when using either visual or auditory modality as the conditioned stimulus, and that the reduction was specific to the conditioned modality. Our results suggest that the primate dACC is actively involved in maintaining the original aversive memory, and propose that a combination of LFS with behavioral therapy might significantly improve treatment in severe cases.