Neuroscience
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D-2-hydroxyglutaric acid (D-2-HG) accumulates and is the biochemical hallmark of D-2-hydroxyglutaric acidurias (D-2-HGA) types I and II, which comprehend two inherited neurometabolic diseases with severe cerebral abnormalities. Since the pathogenesis of these diseases is poorly established, we tested whether D-2-HG could be neurotoxic to neonatal rats. D-2-HG intracerebroventricular administration caused marked vacuolation in cerebral cortex and striatum. ⋯ Furthermore, the antagonist of NMDA glutamate receptor MK-801 and the antioxidant melatonin were able to prevent most of D-2-HG-induced pro-oxidant effects, implying the participation of these receptors in D-2-HG-elicited oxidative damage. Our results also demonstrated that D-2-HG markedly reduced the respiratory chain complex IV and creatine kinase activities. It is presumed that these deleterious pathomechanisms caused by D-2-HGA may be involved in the brain abnormalities characteristic of early-infantile onset D-2-HGA.
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Pragmatic competence demands linguistic, but also communicative, social and cognitive competence. Successful use of language in social interaction requires mutual understanding of the speaker's intentions; without it, a conversation cannot proceed. The term speech act refers to what a speaker intends to accomplish when saying something. ⋯ The recognition of speech acts resulted in greater activation of frontal regions, precuneus and posterior cingulate gyrus. From all cognitive and behavioral measures obtained, only the scores in mental flexibility predicted the change in blood oxygen level dependent (BOLD) signal in the precuneus. These results, support the idea that speech act recognition requires the inference of intention, executive functions, including memory and entails the activation of areas of social cognition that participate in several brain networks i.e., the Intention Processing, the Default Mode and Theory of Mind networks, and areas involved in planning and guiding behavior.
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Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed to pregnant women suffering with depression, although the long-term impact of these medications on exposed offspring are poorly understood. Perinatal SSRI exposure alters human offspring's neurodevelopment and increases risk for psychiatric illness in later life. Rodent studies suggest that perinatal SSRI-induced behavioral abnormalities are driven by changes in the serotonin system as well as epigenetic and transcriptomic changes in the developing hippocampus. ⋯ To determine translational implications of this work, we examined expression of BAI3 and related molecules in hippocampus and prefrontal cortex from patients that suffered with depression or schizophrenia relative to healthy control subjects. We found sex- and region-specific changes in mRNA expression of BAI3 and its ligands C1QL2 and C1QL3 in men and women with a history of psychiatric disorders compared to healthy controls. Together these results suggest that abnormal BAI3 signaling may contribute to molecular mechanisms that drive adverse effects of perinatal SSRI exposure, and show evidence for alterations of BAI3 signaling in the hippocampus of patients that suffer depression and schizophrenia.
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Death-associated protein kinase (DAPK) is a Ca2+/CaM-regulated protein kinase that is involved in cell death processes by multiple pathways. It has been reported that DAPK may play a role in brain ischemia-induced neuronal death, but this mechanism is not well understood. DANGER, a membrane-associated protein that binds to DAPK physiologically, inhibits DAPK activation. ⋯ Moreover, the expression of DANGER and the interaction between DANGER and IP3R on the endoplasmic reticulum was significantly increased at I/R 6 h, which may be related to a reduction of DAPK/DANGER binding under I/R condition. Furthermore, MK-801, DAPK inhibitor and FK-506 had neuroprotective effects against hippocampal CA1 neuronal death 5 days after I/R. In conclusion, our data suggest that the dissociation of DANGER from DAPK may mediate DAPK activation, which is involved in DAPK-related neuronal death following I/R injury.
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Arousal is a potent mechanism that provides the brain with functional flexibility and adaptability to external conditions. Within the wake state, arousal levels driven by activity in the neuromodulatory systems are related to specific signatures of neural activation and brain synchrony. However, direct evidence is still lacking on the varying effects of arousal on macroscopic brain characteristics and across a variety of cognitive states in humans. ⋯ Increased integration in the salience network was also related to faster pupil dilation in the two attentional tasks. Furthermore, task performance was related to arousal level, with lower accuracy at higher level of arousal. Taken together, our study provides evidence in humans for pupil size as an index of brain network state, and supports the role of arousal as a switch that drives brain coordination in specific brain regions according to the cognitive state.