Neuroscience
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Lithium and valproic acid (VPA) are two primary drugs used to treat bipolar disorder, and have been shown to have neuroprotective properties in vivo and in vitro. A recent study demonstrated that combined treatment with lithium and VPA elicits synergistic neuroprotective effects against glutamate excitotoxicity in cultured brain neurons, and the synergy involves potentiated inhibition of glycogen synthase kinase-3 (GSK-3) activity through enhanced GSK-3 serine phosphorylation [Leng Y, Liang MH, Ren M, Marinova Z, Leeds P, Chuang DM (2008) Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition. J Neurosci 28:2576-2588]. ⋯ Moreover, lithium in conjunction with VPA was more effective than lithium or VPA alone in enhancing the immunostaining of phospho-GSK-3beta(Ser9) in brain and lumbar spinal cord sections. To our knowledge, this is the first demonstration of enhanced neuroprotection by a combinatorial approach using mood stabilizers in a mouse ALS model. Our results suggest that clinical trials using lithium and VPA in combination for ALS patients are a rational strategy.
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Reward-seeking behavior is controlled by neuronal circuits that include the basolateral nucleus of amygdala (BLA), medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and ventral tegmental area. Using a discriminative stimulus (DS) task in which an intermittently presented cue (DS) directs rats to make an operant response for sucrose, we previously demonstrated that dopamine receptor antagonism in the NAc reduced reinforced cue responding, whereas general inactivation of the NAc increased behavioral responding in the absence of the cue. Because they send major glutamatergic projections to the NAc, the BLA and mPFC may also contribute to reward-seeking behaviors modulated by the NAc. ⋯ Dorsal medial prefrontal cortex (dmPFC) inactivation also inhibited cue-evoked reward-seeking. In contrast, ventral medial prefrontal cortex (vmPFC) inactivation disinhibited responding to unrewarded cues with less influence on reinforced cue responding. These findings demonstrate that the BLA and dmPFC facilitate cue-evoked reward-seeking, whereas, in the same task the vmPFC exerts inhibitory control over unrewarded behaviors.
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The expression of voltage-gated sodium channels is regulated at multiple levels, and in this study we addressed the potential for alternative splicing of the Na(v)1.2, Na(v)1.3, Na(v)1.6 and Na(v)1.7 mRNAs. We isolated novel mRNA isoforms of Na(v)1.2 and Na(v)1.3 from adult mouse and rat dorsal root ganglia (DRG), Na(v)1.3 and Na(v)1.7 from adult mouse brain, and Na(v)1.7 from neonatal rat brain. These alternatively spliced isoforms introduce an additional exon (Na(v)1.2 exon 17A and topologically equivalent Na(v)1.7 exon 16A) or exon pair (Na(v)1.3 exons 17A and 17B) that contain an in-frame stop codon and result in predicted two-domain, truncated proteins. ⋯ Here we show that the expression of Na(v)1.3 mRNA containing exons 17A and 17B is unchanged in mouse following peripheral nerve injury (axotomy), whereas total Na(v)1.3 mRNA expression is upregulated by 33% (P=0.003), suggesting differential regulation of the alternatively spliced transcripts. The alternatively spliced rodent exon sequences are highly conserved in both the human and chicken genomes, with 77-89% and 72-76% identities to mouse, respectively. The widespread conservation of these sequences strongly suggests an additional level of regulation in the expression of these channels, that is also tissue-specific.
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Cytidine-5-diphosphocholine (CDP-choline or citicholine) is an essential molecule that is required for biosynthesis of cell membranes. In adult humans it is used as a memory-enhancing drug for treatment of age-related dementia and cerebrovascular conditions. However the effect of CDP-choline on perinatal brain is not known. ⋯ However significant increases in neurite length, branch points and total area occupied by the neurons were observed. We conclude that exogenous supplementation of CDP-choline during development causes stable changes in neuronal morphology. Significant increase in dendritic growth and branching of pyramidal neurons from the somatosensory cortex resulted in enlarging the surface area occupied by the neurons which we speculate will augment processing of sensory information.
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There is growing evidence indicating that neurogenesis in adulthood is influenced by certain types of the central diseases such as neuroinflammation, however, its mechanism is not fully understood. This study was, therefore, designed to examine the effects of lipopolysaccharide (LPS), a bacterial endotoxin known to cause the neuroinflammation, on the neurogenesis in the dentate gyrus of adult mice using the bromodeoxyuridine (BrdU) -pulse chase method. LPS failed to affect the number of BrdU-labeled cells in the dentate gyrus 2 h after BrdU injection, indicating no effects of LPS on the proliferation of the neural stem cells (NSCs). ⋯ Furthermore, the central injection of NS398 also ameliorated LPS-induced suppression of the newborn cell survival in the dentate gyrus. The treatment with LPS increased the expression of COX-2 protein 7 h and 7 days after the injection in the dentate gyrus. These results suggest that LPS impairs the survival of newly generated cells derived from the NSCs in the dentate gyrus without affecting the differentiation fate, and these effects of LPS were mediated presumably by COX-2 expression in the dentate gyrus.