Neuroscience
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Spexin (SPX) is a novel satiety factor that putatively binds the galanin receptors R2 and R3 (GalR2/R3). SPX reduces body weight, and circulating SPX is decreased in obesity. It is unknown how SPX and its receptors are regulated in the hypothalamus, critical for energy homeostasis. ⋯ We also describe the presence of OCT-1 and C/EBP-β response elements in the 5' regulatory region of Spx and demonstrate that SNP increases binding of C/EBP-β to this region, but not Oct-1 mRNA nor OCT-1 binding. Our findings suggest an acute modulation of anorexigenic SPX signaling by palmitate and NO. Furthermore, ER stress and C/EBP-β appear to mediate the changes in Spx, GalR2 and GalR3 in hypothalamic neurons.
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Angelman syndrome is a neurodevelopmental disorder presenting with severe deficits in motor, speech, and cognitive abilities. The primary genetic cause of Angelman syndrome is a maternally transmitted mutation in the Ube3a gene, which has been successfully modeled in Ube3a mutant mice. Phenotypes have been extensively reported in young adult Ube3a mice. ⋯ Reduced general exploratory locomotion at this age prevented the interpretation of an anxiety-like phenotype, and likely impacted social tasks. Robust phenotypes in middle-aged Ube3a mice appear to result from continued motor decline. Motor deficits may provide the best outcome measures for preclinical testing of pharmacological targets, towards reductions of symptoms in adults with Angelman syndrome.
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Microglia activation plays a key role in regulating inflammatory and immune reaction during cerebral ischemia and it exerts pro-inflammatory or anti-inflammatory effect depending on M1/M2 polarization phenotype. Cysteinyl leukotriene 2 receptor (CysLT2R) is a potent inflammatory mediator receptor, and involved in cerebral ischemic injury, but the mechanism of CysLT2R regulating inflammation and neuron damage remains unclear. Here, we found that LPS and CysLT2R agonist NMLTC4 significantly increased microglia proliferation and phagocytosis, up-regulated the mRNA expression of M1 polarization markers (IL-1β, TNF-α, IFN-γ, CD86 and iNOS), down-regulated the expression of M2 polarization markers (Arg-1, CD206, TGF-β, IL-10, Ym-1) and increased the release of IL-1β and TNF-α. ⋯ The conditional medium of BV-2 cells contained HAMI3379 could inhibit SH-SY5Y cells apoptosis induced by LPS and NMLTC4. These results were further confirmed in primary microglia. The findings indicate that CysLT2R was involved in inflammation and neuronal damage by inducing the activation of microglia M1 polarization and NF-κB pathway, inhibiting microglia M1 polarization and promoting microglia polarization toward M2 phenotype which may exerts neuroprotective effects, and targeting CysLT2R may be a new therapeutic strategy against cerebral ischemia stroke.
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Excessive dietary fat intake is considered a great risk factor for metabolic disorders as well as cognitive dysfunction. However, the potential mechanisms underlying the effects of a high-fat diet (HFD) on the brain remain rather obscure. The purpose of this study was to address how early exposure to HFD induces biochemical changes in different brain regions and affects short- and long-term memory. ⋯ The effect of HFD on the brain was also assessed by electrophysiology, which detected a gradual decrease in long-term potentiation in the CA1 region of the hippocampus. The abnormal expression of proteins associated with synaptic function, e.g. synaptophysin, CaMKII, CaMKIV, calcineurin A, ERK and c-fos, was observed in the hippocampus in response to HFD. These results indicate that HFD elicits rapid biochemical and neurological abnormalities in the hippocampus that contribute to cognitive defects and are potentially connected to the HFD-induced suppression of brain activity.
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Thermosensitive transient receptor potential vanilloid (TRPV) channels are widely expressed in the brain and known to profoundly influence Ca2+-signaling, neurotransmitter release and behavior. While these channels are expressed in the cerebellum, neuronal firing and hyperactivity/reflexes seem associated with cerebellar temperature modulation. However, the distribution and functional significance of TRPV-equipped elements in the cerebellum has remained unexplored. ⋯ Compared to controls, rats injected with TRPV3 inhibitor significantly reduced the stride length (P < 0.001), locomotor activity (P < 0.001), and rotarod retention time (P < 0.001), but increased footprints length (P < 0.01) and escape latency (P < 0001). TRPV3-agonist treatment, however, had no effect on these behaviors. We suggest that TRPV3 in Purkinje neurons may serve as novel molecular component for Ca2+-signaling and motor coordination function of the cerebellum.