Neuroscience
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Sites and mechanisms by which trigeminal nerve stimulation (TNS) exerts beneficial effects on symptoms of drug-resistant epilepsy and depression are still unknown. Effects of short-term TNS on brain regions involved in the physiopathology of these disorders were investigated in this study. Forty male rats were assigned to three groups: TNS (undergoing electrical stimulation of the left infraorbitary nerve via surgically implanted cuff electrodes); Sham (undergoing surgical procedure but without a stimulation); Naïve rats. ⋯ In the TNS group the number of BrdU-positive cells in the dentate gyrus was significantly greater with respect to both Naïve and Sham groups. Data show that acute TNS effectively counteracted PTZ-induced seizures and boosted hippocampal cell proliferation in rats. TNS increased c-Fos-like immunoreactivity in brainstem and forebrain structures which play a pivotal role in the physiopathology of epilepsy and depression.
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Whether the CD38/cyclic ADP-ribose (cADPR) pathway plays a protective or detrimental role in neuroinflammation remains controversial. This study aimed to determine the role of CD38 in neuroinflammation using lipopolysaccharide (LPS)-stimulated BV2 microglial cells and co-cultured Neuro-2a (N2a) cells. In monoculture experiments, BV2 cells were divided into control, CD38 interference (CD38Ri), negative control (NC), LPS, CD38Ri+LPS, NC+LPS and 8-Br-cADPR+LPS groups. ⋯ Co-culture with CD38 knockdown or 8-Br-cADPR-treated BV2 cells did not influence apoptosis or iNOS expression in N2a cells. In conclusion, our results indicate that blocking the CD38/cADPR pathway reduces intracellular Ca2+, NO and the secretion of proinflammatory cytokines. CD38 knockdown exerted a detrimental effect in apoptosis and NO production in normal microglia, but played a protective role in apoptosis and NO production in LPS-stimulated microglia.
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Adolescence has been identified as a vulnerable developmental time period during which exposure to drugs can have long-lasting, detrimental effects. Although adolescent binge-like ethanol (EtOH) exposure leads to a significant reduction in forebrain cholinergic neurons, EtOH's functional effect on acetylcholine (ACh) release during behavior has yet to be examined. Using an adolescent intermittent ethanol exposure model (AIE), rats were exposed to binge-like levels of EtOH from postnatal days (PD) 25 to 55. ⋯ In contrast, AIE rats were impaired during the first attentional set shift on an operant set-shifting task, indicative of an EtOH-mediated deficit in cognitive flexibility. A unique pattern of cholinergic cell loss was observed in the basal forebrain following AIE: Within the medial septum/diagonal band there was a selective loss (30%) of choline acetyltransferase (ChAT)-positive neurons that were nestin negative (ChAT+/nestin-); whereas in the Nucleus basalis of Meynert (NbM) there was a selective reduction (50%) in ChAT+/nestin+. These results indicate that early adolescent binge EtOH exposure leads to a long-lasting frontocortical functional cholinergic deficit, driven by a loss of ChAT+/nestin+ neurons in the NbM, which was associated with impaired cognitive flexibility during adulthood.
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RNA binding motif 5 (RBM5) is a nuclear protein that modulates gene transcription and mRNA splicing in cancer cells. The brain is among the highest RBM5-expressing organ in the body but its mRNA target(s) or functions in the CNS have not been elucidated. Here we knocked down (KO) RBM5 in primary rat cortical neurons and analyzed total RNA extracts by gene microarray vs. neurons transduced with lentivirus to deliver control (non-targeting) shRNA. The mRNA levels of Sec23A (involved in ER-Golgi transport) and the small GTPase Rab4a (involved in endocytosis/protein trafficking) were increased in RBM5 KO neurons relative to controls. At the protein level, only Rab4a was significantly increased in RBM5 KO extracts. Also, elevated Rab4a levels in KO neurons were associated with decreased membrane levels of oligomeric serotonin transporters (SERT). Finally, RBM5 KO was associated with increased uptake of membrane-derived monomeric SERT. ⋯ Rab4a is involved in the regulation of endocytosis and protein trafficking in cells. In the CNS it regulates diverse neurobiological functions including (but not limited to) trafficking of transmembrane proteins involved in neurotransmission (e.g. SERT), maintaining dendritic spine size, promoting axonal growth, and modulating cognition. Our findings suggest that RBM5 regulates Rab4a in rat neurons.
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Alzheimer's disease (AD) is the most common late onset neurodegenerative disorder with indications that women are disproportionately affected. Mitochondrial dysfunction has been one of the most discussed hypotheses associated with the early onset and progression of AD, and it has been attributed to intraneuronal accumulation of amyloid β (Aβ). It was suggested that one of the possible mediators for Aβ-impaired mitochondrial function is the nuclear factor kappa B (NF-κB) signaling pathway. ⋯ The pattern of changes in NF-κB signaling was the same in both brain structures, but was sex specific. Whereas in females there was an increase in all three subunits of NF-κB, in males we observed increase in p65 and p105, but no changes in p50 levels. These results demonstrate that mitochondrial function and inflammatory signaling in the AD-like brain is region- and sex-specific, which is an important consideration for therapeutic strategies.