Neuroscience
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Amyloid plaque is a prominent pathologic hallmark in the brains of patients with Alzheimer's disease (AD), and it has been shown to be associated with endoplasmic reticulum (ER) stress response. However the precise regulation mechanism of amyloid-beta (Aβ) toxicity remains unclear. Here, we found that dauricine could activate X-box binding protein 1 (XBP-1; active form XBP-1S) and eukaryotic translation initiation factor eIF2α and thus delay the progression of AD in the Aβ1-42-transgenic Caenorhabditis elegans CL2120. ⋯ Our study reveals that dauricine activates the ire-1/xbp-1 and perk/eIF2α pathways of the unfolded protein response, attenuates translation, and enhances ER-associated degradation, which reduces Aβ expression and attenuates Aβ-associated toxicity. On the contrary, xbp-1 depletion counteracts the effects of dauricine on Aβ-associated toxicity. These results underscore the functional relevance of XBP-1 in Aβ toxicity and degradation, and highlight the potentially pharmacodynamic value of dauricine in preventing the progression of AD.
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Review
Brain Stem Neural Circuits of Horizontal and Vertical Saccade Systems and Their Frame of Reference.
Sensory signals for eye movements (visual and vestibular) are initially coded in different frames of reference but finally translated into common coordinates, and share the same final common pathway, namely the same population of extraocular motoneurons. From clinical studies in humans and lesion studies in animals, it is generally accepted that voluntary saccadic eye movements are organized in horizontal and vertical Cartesian coordinates. However, this issue is not settled yet, because neural circuits for vertical saccades remain unidentified. ⋯ Comparing well-known vestibuloocular pathways with our findings of commissural excitation and inhibition between both superior colliculi, we proposed that the saccade system uses the same frame of reference as the vestibuloocular system, common semicircular canal coordinate. This proposal is mainly based on marked similarities (1) between output neural circuitry from one superior colliculus to extraocular motoneurons and that from a respective canal to its innervating extraocular motoneurons, (2) of patterns of commissural reciprocal inhibitions between upward saccade system on one side and downward system on the other, and between anterior canal system on one side and posterior canal system on the other, and (3) between the neural circuits of saccade and quick phase of vestibular nystagmus sharing brainstem burst neurons. In support of the proposal, commissural excitation of the superior colliculi may help to maintain Listing's law in saccades in spite of using semicircular canal coordinate.
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Rhythmic actions are characterizable as a repeating invariant pattern of movement together with variability taking the form of cycle-to-cycle fluctuations. Variability in behavioral measures is atypically random, and often exhibits serial temporal dependencies and statistical self-similarity in the scaling of variability magnitudes across timescales. Self-similar (i.e. fractal) variability scaling is evident in measures of both brain and behavior. ⋯ The changes in hemodynamics were observed in both motor and sensorimotor cortical areas in the contralateral hemisphere. These results were observed only for the longer timescales of the detrended fluctuation analysis used to measure the exponent α. These findings suggest that complex auditory stimuli engage both brain and behavior at the level of variability scaling structures.
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Alterations in excitatory and inhibitory neurotransmitters (glutamate and GABA, respectively) have been found in various neuropsychiatric disorders, but have not been examined in individuals with prodigious cognitive abilities. Understanding exceptional brain processing is critical for developing biomedical interventions for cognitive and neurodevelopmental atypicalities. ⋯ We found substantially lower frontal glutamate/GABA compared to non-prodigy controls, but not glutamate or GABA individually, measured with magnetic resonance spectroscopy. We suggest that prefrontal glutamate/GABA is a potential marker of extraordinary cognitive skills.
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Histamine dysregulation has been identified as a rare genetic cause of tic disorders; mice with a knockout of the histidine decarboxylase (Hdc) gene represent a promising model of this pathophysiology. How alterations in the histamine system lead to neuropsychiatric disease, however, remains unclear. The H3R histamine receptor is elevated in the striatum of Hdc KO mice, and H3R agonists, acting in the dorsal striatum, trigger tic-like movements in the model. ⋯ Similarly, in iMSNs, Akt phosphorylation was reduced at baseline in the KO model, resembling what is seen after H3R activation in WT animals. H3R activation in Hdc-KO mice further enhanced the baseline effect on Akt phosphorylation in iMSNs but attenuated the abnormality in MAPK signaling in dMSNs. These observations support the hypothesis that constitutive activity of upregulated H3R receptors in the Hdc-KO model mediates the observed alterations in baseline MSN signaling; but further activation of H3R, which produces tic-like repetitive movements in the model, has more complex effects.