Neuroscience
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Both rare, high risk, loss-of-function mutations and common, low risk, genetic variants in the CUL3 gene are strongly associated with neuropsychiatric disorders. Network analyses of neuropsychiatric risk genes have shown high CUL3 expression in the prenatal human brain and an enrichment in neural precursor cells (NPCs) and cortical neurons. The role of CUL3 in human neurodevelopment however, is poorly understood. ⋯ However, both optogenetic and electrical stimulation of induced neurons revealed decreased excitability in Cullin-3 deficient cultures, while basal synaptic transmission remained unchanged. Analysis of target gene expression pointed to alterations in FGF signaling in CUL3 KO NPCs, which is required for NPC proliferation and self-renewal, while RhoA and Notch signaling appeared unaffected. Our data provide first evidence for a major role of Cullin-3 in neuronal differentiation, and for neurodevelopmental deficits underlying neuropsychiatric disorders associated with CUL3 mutations.
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Angiogenesis after intracerebral hemorrhage (ICH) injury can effectively alleviate brain damage and improve neurological function. Hypoxia-inducible factor 2α (HIF-2α) is an important angiogenic regulator and exhibits protective effects in several neurological diseases; however, its role in ICH has not yet been reported. Hence, in the present study, we explored whether HIF-2α reduces ICH injury by promoting angiogenesis. ⋯ Likewise, the HIF-2α-mediated increase in phospho-VEGFR-2, cleaved-Notch1 and Notch1 expression was reversed via a VEGFR2-specific inhibitor. Taken together, our results indicate that HIF-2α promotes angiogenesis via the VEGF/Notch pathway to attenuate ICH injury. Moreover, our findings may contribute to the development of a novel strategy for alleviating ICH injury via HIF-2α-mediated upregulation of angiogenesis.
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Understanding how the brain decodes sensory information to give rise to behaviour remains an important problem in systems neuroscience. Across various sensory modalities (e.g. auditory, visual), the time-varying contrast of natural stimuli has been shown to carry behaviourally relevant information. However, it is unclear how such information is actually decoded by the brain to evoke perception and behaviour. ⋯ Further analysis revealed that the lower detection thresholds of midbrain neurons were not due to increased sensitivity to the stimulus. Rather, these were due to the fact that midbrain neurons displayed lower variability in their firing activities in the absence of stimulation, which is due to lower firing rates. Our results suggest that midbrain neurons play an active role towards enabling the detection of weak stimulus contrasts, which in turn leads to perception and behavioral responses.
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Ghrelin administration increases food intake, body weight (BW), adiposity, and blood glucose. In contrast, although mouse models lacking ghrelin or its receptor (Growth Hormone Secretagogue Receptor (GHSR)) exhibit life-threatening hypoglycemia in starvation-like states, they do not exhibit appreciable reductions in food intake, BW, adiposity, blood glucose, or survival when food availability is unrestricted. This suggests the existence of a parallel neuromodulatory system that can compensate for disruptions in the ghrelin system in certain settings. ⋯ We conclude that CB1R is not responsible for the normal BW, adiposity, food intake, and blood glucose observed in GHSR-null mice in the setting of unrestricted food availability. Nor is CB1R required for plasma acyl-ghrelin secretion in that setting. However, GHSR may be protective against exaggerated mortality associated with CB1R deletion.