Neuroscience
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Accumulation of hypoxia-inducible transcription factors (HIFs) by prolyl-4-hydroxylase inhibitors (PHI) has been suggested to induce neuroprotection in the ischemic rodent brain. We aimed to investigate in vivo effects of a novel PHI on HIF-regulated neurotrophic and pro-apoptotic factors in the developing normoxic and hypoxic mouse brain. ⋯ PHI treatment modulates neurotrophic factors known to be crucially involved in hypoxia-induced cerebral adaptive mechanisms as well as early brain maturation. Pre-treatment with FG-4497 seems to protect the developing brain from hypoxia-induced apoptosis. Present observations provide basic information for further evaluation of neuroprotective properties of PHI treatment in hypoxic injury of the developing brain. However, potential effects on maturational processes need special attention in experimental research targeting HIF-dependent neuroprotective interventions during the very early stage of brain development.
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Short- and long-term treatment with modafinil differentially affects adult hippocampal neurogenesis.
The generation of new neurons in the dentate gyrus of the adult brain has been demonstrated in many species including humans and is suggested to have functional relevance for learning and memory. The wake promoting drug modafinil has popularly been categorized as a so-called neuroenhancer due to its positive effects on cognition. We here show that short- and long-term treatment with modafinil differentially effects hippocampal neurogenesis. ⋯ Interestingly, long-term treatment for 14days resulted in an increased number of newborn Prox1(+) granule cells, but we could not detect an additive effect of the prolonged treatment on proliferation and survival of newborn cells. Moreover, daily administration for 14days did not influence the number of proliferating cells in the dentate gyrus. Together, modafinil has an acute impact on precursor cell proliferation as well as survival but loses this ability during longer treatment durations.
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Over recent years evidence from animal studies strongly suggests that a decrease in local inhibitory signaling is necessary for synaptic plasticity to occur. However, the role of GABAergic modulation in human motor plasticity is less well understood. Here, we summarize the techniques available to quantify GABA in humans, before reviewing the existing evidence for the role of inhibitory signaling in human motor plasticity. We discuss a number of important outstanding questions that remain before the role of GABAergic modulation in long-term plasticity in humans, such as that underpinning recovery after stroke, can be established.
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Age-related increases in right frontal cortex activation are a common finding in the neuroimaging literature. However, neurocognitive factors contributing to right frontal over-recruitment remain poorly understood. Here we investigated the influence of age-related reaction time (RT) slowing and white matter (WM) microstructure reductions as potential explanatory factors for age-related increases in right frontal activation during task switching. ⋯ In addition, the older adult group showed longer RT and decreased fractional anisotropy in regions of the corpus callosum with direct connections to the fMRI ROIs. Subsequent mediation analyses indicated that age-related increases in right insula activation were mediated by RT slowing and age-related increases in right DLPFC activation were mediated by WM microstructure. Our results suggest that age-related RT slowing and WM microstructure declines contribute to age-related increases in right frontal activation during cognitive task performance.
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Gliomas are the most common malignant intracranial tumors. Newly developed targeted therapies for these cancers aim to inhibit oncogenic signals, many of which emanate from receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR). Unfortunately, the first-generation treatments targeting these oncogenic signals provide little survival benefit in both mouse xenograft models and human patients. ⋯ GPCRs constitute a large family of membrane receptors that influence oncogenic pathways through canonical and non-canonical signaling. Accordingly, evidence indicates that GPCRs display a unique ability to crosstalk with receptor tyrosine kinases, making them important molecular components controlling tumorigenesis. This review summarizes the current research on GPCR functionality in gliomas and explores the potential of modulating these receptors to treat this devastating disease.