Neuroscience
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Although the receptor-interacting protein 1 kinase (RIP1K)-regulated necroptosis can be evoked by cerebral ischemia, the effects of RIP1K in mediating neuronal and astrocytic cell death and the underlying mechanisms remain poorly understood. This study evaluates the contribution of RIP1K to ischemic stroke-induced neuronal and astrocytic cell death, and the activation of autophagic-lysosomal pathway. Using an in vitro oxygen and glucose deprivation (OGD) in primary cultured neurons or astrocytes and a permanent middle cerebral artery occlusion (pMCAO) model in rats or mice, we observed the role of RIP1K in the ischemic neuronal and astrocytic cell death and the underlying mechanisms by pharmacological or genetic inhibition of RIP1K. pMCAO or OGD condition led to an increase in RIP1K, RIP3K and RIP1K-RIP3K complex. ⋯ RIP1K knockdown decreased RIP1K-RIP3K complex formation, light chain 3 II (LC3II) and active cathepsin B levels and lysosomal membrane permeability (LMP). Furthermore, a combination of Nec-1 and an inhibitor of autophagy or cathepsin B produced an enhancement of protective effect on neuronal or astrocytic cell death. RIP1K-mediated necroptosis may play important roles in ischemia-induced neuronal and astrocytic cell death through the activation of autophagic-lysosomal pathway.
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Macrophages are implicated in the pathological processes and functional recovery of spinal cord injury (SCI). Macrophage activation following inflammation depends on networks of interferons and cytokines. Recent evidence indicate that IL-7 signaling can influence the release of proinflammatory factors, however, its roles in modulating macrophage phenotype and function and whether it could affect the functional recovery of SCI are poorly understood. ⋯ Furthermore, IL-7 displays strong chemotactic property for macrophages and A7R34 treatment inhibits their infiltration into injured sites in vivo. More importantly, the A7R34 treatment promotes functional recovery after SCI, indicating its therapeutic effects on spinal cord repair. Hence, our study proposes a new therapeutic strategy to treat SCI by blocking IL-7 signaling.
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The effect of cerebellar transcranial direct current stimulation (tDCS) on motor performance remains controversial. Some studies suggest that the effect of tDCS depends upon task-difficulty and individual level of task performance. Here, we investigated whether the effect of cerebellar tDCS on the motor performance depends upon the individual's level of performance. ⋯ This resulted in a significant performance improvement only for the sub-group of participants with lower performance levels as compared to that with sham-tDCS (p < 0.05). These findings suggest that the facilitation effect of cerebellar cathodal tDCS on motor skill learning of complex whole-body movements depends on the level of an individual's task performance. Thus, cerebellar tDCS would facilitate learning of a complex motor skill task only in a subset of individuals.
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Brain functional networks show high variability in short time windows but mechanisms governing these transient dynamics remain unknown. In this work, we studied the temporal evolution of functional brain networks involved in a working memory (WM) task while recording high-density electroencephalography (EEG) in human normal subjects. ⋯ Additionally, computational investigations further supported the experimental results. The brain functional organization may respond to the information processing demand of a WM task following a 2-step atomic scheme wherein segregation and integration alternately dominate the functional configurations.
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The molecular basis for onset, maintenance and propagation of excitation along neuronal networks in epilepsy is still poorly understood. Besides different neurotransmitter receptors that control signal transfer at the synapse, one key regulator involved in all of these processes is the ATPase N-ethylmaleimide-sensitive fusion protein (NSF). Therefore, we analyzed receptor subunits and NSF levels in tissues from the medial temporal gyrus (MTG) of patients with pharmaco-resistant focal temporal lobe epilepsy resected during epilepsy surgery and autopsy controls. ⋯ We detected increased levels of NSF, NMDA 1.1, 2A and GABAAγ2 receptor subunits associated with spontaneous sharp wave spiking activity. We further identified correlations between NSF, AMPA receptor subunit, metabotropic glutamate receptor and adenosine 1 receptor levels in the spontaneous sharp wave spiking tissues. Our findings suggest that NSF plays a key role in controlling spontaneous network excitation in epilepsy by two mechanisms of action: (1) directly via controlling transmitter release at the presynaptic side, and (2) indirectly via altering the function of possible receptor crosstalk and directing/integrating specific receptor compounds through/into the postsynaptic membrane.