Neuroscience
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Huntingtin-associated protein 1 (HAP1) is a neuronal interactor with causatively polyglutamine (polyQ)-expanded huntingtin in Huntington's disease and also associated with pathologically polyQ-expanded androgen receptor (AR) in spinobulbar muscular atrophy (SBMA), being considered as a protective factor against neurodegenerative apoptosis. In normal brains, it is abundantly expressed particularly in the limbic-hypothalamic regions that tend to be spared from neurodegeneration, whereas the areas with little HAP1 expression, including the striatum, thalamus, cerebral neocortex and cerebellum, are targets in several neurodegenerative diseases. While the spinal cord is another major neurodegenerative target, HAP1-immunoreactive structures have yet to be determined there. ⋯ Double-immunostaining for HAP1 and AR demonstrated that more than 80% of neurons expressed both in the same areas. In contrast, HAP1 was specifically lacking in the lamina IX motoneurons with or without AR expression. The present study first demonstrated that HAP1 is abundantly expressed in spinal neurons of the somatosensory, viscerosensory, and autonomic regions but absent in somatomotor neurons, suggesting that the spinal motoneurons are, due to lack of putative HAP1 protectivity, more vulnerable to stresses in neurodegenerative diseases than other HAP1-expressing neurons probably involved in spinal sensory and autonomic functions.
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Hydrogen sulfide (H2S) is an endogenous gasotransmitter with neuroprotective properties that participates in the regulation of transmitter release and neuronal excitability in various brain structures. The role of H2S in the growth and maturation of neural networks however remains unclear. The aim of the present study is to reveal the effects of H2S on neuronal spontaneous activity relevant to neuronal maturation in hippocampal slices of neonatal rats. ⋯ The subsequent decrease in the neuronal activity by H2S appears to be due to the rightward shift of activation and inactivation of voltage-gated Na(+) currents, thus preventing network activity. NaHS also reduced NMDA-mediated currents, without essential effect on AMPA/kainate or GABAA-mediated currents Finally, H2S abolished the interictal-like events induced by bicuculline. In summary, our results suggest that through the inhibitory action on voltage-gated Na(+) channels and NMDA receptors, H2S prevents the enhanced neuronal excitability typical to early hippocampal networks.
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Glutaryl-CoA dehydrogenase (GCDH) is a mitochondrial enzyme that is involved in the degradation of tryptophan, lysine and hydroxylysine. Deficient enzyme activity leads to glutaric aciduria type-I (GA-I). This neurometabolic disease usually manifests with acute encephalopathic crises and striatal neuronal death in early childhood leading to an irreversible dystonic-dyskinetic movement disorder. ⋯ GCDH was found widely expressed in embryonic and adult rat tissues. In rat embryos GCDH is predominantly expressed in brain implying an important role for brain development. Interestingly, GCDH was found to be significantly expressed in different other organs (e.g. kidney, gut) in adult rats probably explaining the evolving phenotype in GA-I patients.
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The recent development of organoid techniques, in which embryonic brain-like tissue can be grown from human or mouse stem cells in vitro offers the potential to transform the way in which brain development is studied. In this review, we summarize key aspects of the embryonic development of mammalian forebrains, focussing in particular on the cerebral cortex and highlight significant differences between mouse and primates, including human. We discuss recent work using cerebral organoids that has revealed key similarities and differences between their development and that of the brain in vivo. Finally, we outline the ways in which cerebral organoids can be used in combination with CRISPR/Cas9 genome editing to unravel genetic mechanisms that control embryonic development of the cerebral cortex, how this can help us understand the causes of neurodevelopmental disorders and some of the key challenges which will have to be resolved before organoids can become a mainstream tool to study brain development.
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Review
Parieto-frontal gradients and domains underlying eye and hand operations in the action space.
In monkeys, motor intention in its different forms emerges from a parietal-frontal gradient of visual, eye and hand signals, containing discrete dominant domains. These are formed by areas sharing cortical connections and functional properties. Within this gradient, the combination of different inputs determines the tuning properties of neurons, while local and long cortico-cortical connections shape the structure and temporal delays of the network. ⋯ This eye-hand matrix provides a framework to address, within a unitary frame, not only basic forms of motor behavior, such as reaching and grasping, but also actions of increasing complexity, such as interception of moving targets, tool use, construction of complex objects, maze analysis and solution, among others. The organization of the cerebral cortex into functional gradients and domains, beyond frontal and parietal cortices, is common to other brain regions, such as prefrontal cortex and hippocampus, and does not support views of the parieto-frontal operations based on specific and strictly segregated eye and hand modules. These can only be found at the eye and hand motor output domains in the frontal cortex, that is in the frontal eye fields and in the primary motor cortex, respectively.