Neuroscience
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Chylomicron Retention Disease (CMRD) is a rare inherited lipid malabsorption syndrome that exhibits a recessive hypocholesterolemia in infants. CMRD has been associated with genetic mutations of SAR1B-a member of the Arf GTPase family involved in the secretory pathway from the endoplasmic reticulum to the Golgi. CMRD patients suffer from multiple neurological deficits, the etiologies of which remain unclear. ⋯ At postnatal day 3, the neurons stalled in the white matter fail to develop axons across the midline of the corpus callosum, resulting in the loss of the neurons later on. hSAR1B(D137N), a CMRD-associated mutant of SAR1B, also impairs the positioning of the cortical neurons in the mouse brain, suggesting a dominant-negative effect by the human heterozygous mutant. The results indicate that SAR1B is crucial to radial migration and axon morphogenesis of the cortical neurons. Our study reveals a cell-autonomous action of Sar1b, which is unrelated to lipid absorption from the gut, on the development of the cerebral cortex.
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Cerebral small vessel disease (CSVD) is a common disease among elderly individuals and recognized as a major cause of vascular cognitive impairment. Recent studies demonstrated that CSVD is a disconnection syndrome. However, due to the covert neurological symptoms and subtle changes in clinical performance, the connection alterations during the stage of preclinical cognitive impairment (PCI) and mild cognitive impairment (MCI) are usually neglected and still largely unknown. ⋯ Moreover, in all CSVD patients, the strength of the rich-club, feeder and local connections was significantly correlated with multiple cognitive scores, especially in attention, executive, and memory domains; while in MCI patients, only the strength of the rich-club connections was significantly correlated with cognition. Furthermore, based on the network-based statistic analysis, we also identified distinct network component disruption pattern between the PCI group and the MCI group, validating the results described above. These results suggest a disruption pattern from peripheral to central connections with the change of cognitive status, shedding light on the early identification and the underlying disruption of CSVD.
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Acute itch is elicited by histamine, as well as non-histaminergic itch mediators including chloroquine, BAM8-22 and Ser-Leu-Ile-Gly-Arg-Leu (SLIGRL). When injected intradermally, histamine binds to histamine H1 and H4 receptors that activate transient receptor potential vanilloid 1 (TRPV1) to depolarize pruriceptors. Chloroquine, BAM8-22, and SLIGRL, respectively, bind to Mas-related G-protein-coupled receptors MrgprA3, MrgprC11, and MrgprC11/PAR2 that in turn activate transient receptor potential ankyrin 1 (TRPA1). ⋯ Pretreatment with the TRPV1 antagonist AMG-517 (10 or 20 μg), but not the TRPA1 antagonist HC-030031 (50 or 100 μg), significantly attenuated the magnitude and time course of thermal hyperalgesia and mechanical allodynia elicited by histamine (p < 0.001 for both), indicating that these effects are mediated by TRPV1. In contrast, pretreatment with the TRPA1 antagonist significantly reduced thermal hyperalgesia and mechanical allodynia elicited by chloroquine (p < 0.001 for both ), BAM-822 (p < 0.01, p < 0.001, respectively) and SLGRL (p < 0.05, p < 0.001, respectively), indicating that effects elicited by these non-histaminergic itch mediators require TRPA1. TRPV1 and TRPA1 channel inhibitors thus may have potential use in reducing hyperalgesia and allodynia associated with histaminergic and non-histaminergic itch, respectively.
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Low-power and high-frequency bidirectional control of spatiotemporal patterns of neural spiking is one of the major challenges in optogenetics. A detailed theoretical analysis and optimization with ChR2-NpHR, ChR2(H134R)-eNpHR3.0, Chrimson-GtACR2 and also with prospective opsin pairs namely, Chronos-Jaws, Chronos-eNpHR3.0, CheRiff-Jaws and vf-Chrimson-GtACR2 has been presented. Biophysical circuit models of bidirectional optogenetic control in above opsin pairs expressing hippocampal neurons and fast-spiking neocortical interneurons have been formulated. ⋯ Although, Chrimson-GtACR2 enables bidirectional control at very low-power, vf-Chrimson-GtACR2 provides control with reduced cross-talk. The theoretical analysis highlights the usefulness of computational methods to virtually optimize stimulation protocols for optogenetic tool combinations. The study is useful to generate neural codes with desired spatiotemporal resolution and to design optogenetic neuroprosthetic devices and circuits.
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Recently, circular RNAs (circRNAs) have been revealed to be an important non-coding element of the transcriptome. The brain contains the most abundant and widespread expression of circRNA. There are also indications that the circular transcriptome undergoes dynamic changes as a result of brain ageing. ⋯ These changes in expression were validated by RT-qPCR. We provide the first comprehensive survey of the circular transcriptome in mammalian synapses, thereby paving the way for future studies. Additionally, we present 16 genes that express solely circRNAs, without linear RNAs co-expression, exclusively in young and aged synaptosomes, suggesting a synaptic gene network that functions along canonical splicing activity.