Neuroscience
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Several conditions related to the intrauterine environment are associated with neuropsychiatric conditions in later life. In humans, approximately 2% of infants are exposed to perinatal hypoxia-ischemia or prolonged anoxic insult, a condition to which very low birth weight preterm infants exhibit the highest susceptibility. Analyses of postmortem tissue link some presentations of these conditions to changes in GABA pathway functionality in the brains of affected subjects. ⋯ Finally, changes in guidance molecules in the developing cortex, including increases in hypoxia-inducible factor 1-alpha levels and intracellular distribution, decreases in reelin levels in the cortical plate and altered organization of radial glia, were observed. These changes in the molecular landscape of the immediate environment of the immature neurons may contribute to the observed outcomes in neuronal migration to, and establishment in, the correct cortical layers. We suggest that the interneuron loss may be related to these early events.
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Pain remains a major concern in patients suffering from metastatic cancer to the bone and more knowledge of the condition, as well as novel treatment avenues, are called for. Neuropeptide Y (NPY) is a highly conserved peptide that appears to play a central role in nociceptive signaling in inflammatory and neuropathic pain. However, little is known about the peptide in cancer-induced bone pain. ⋯ This effect was diminished by both Y1 (BIBO3304) and Y2 (BIIE0246) receptor antagonists, indicating that both receptors participate in mediating the antinociceptive effect of NPY. Y1 and Y2 receptor binding in the spinal cord was unchanged in the cancer state as compared to sham-operated rats, consistent with the notion that increased NPY results in a net antinociceptive effect in the MRMT-1 model. In conclusion, the data indicate that NPY is involved in the spinal nociceptive signaling of cancer-induced bone pain and could be a new therapeutic target for patients with this condition.
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Clinical and basic science research have revealed persistent effects of early-life injury on nociceptive processing and resulting pain sensitivity. While recent work has identified clear deficits in fast GABAA- and glycine receptor-mediated inhibition in the adult spinal dorsal horn after neonatal tissue damage, the effects of early injury on slow, metabotropic inhibition within spinal pain circuits are poorly understood. Here we provide evidence that neonatal surgical incision significantly enhances postsynaptic GABAB receptor signaling within the mature superficial dorsal horn (SDH) in a cell type-dependent manner. ⋯ This could reflect enhanced postsynaptic expression of downstream G protein-coupled inward-rectifying potassium channels (GIRKs), as the response to the GIRK agonist ML297 was greater in projection neurons from neonatally incised mice compared to naive littermate controls. Meanwhile, presynaptic GABAB receptor-mediated reduction of spontaneous neurotransmitter release onto both neuronal populations was unaffected by early-life injury. Collectively, our findings suggest that ascending nociceptive transmission to the adult brain is under stronger control by spinal metabotropic inhibition in the aftermath of neonatal tissue damage.
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Editorial Comment
Frontal Cortical Thickness, Marriage and Life Satisfaction.
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The perineuronal net (PN), a highly organized extracellular matrix structure, is believed to play an important role in synaptic function, including maturation and stabilization. In addition to its role in restricting plasticity, alterations in the PN are implicated in disorders such as epilepsy and schizophrenia. However, the time course of PN development is not known in humans. ⋯ A similar developmental time course was observed in specimens from epilepsy patients. Our data suggest that aggrecan is present early in development but the structured PN develops throughout early childhood, similar to what has been observed in rodents. This timeline provides information for future pathological studies on the role of the PN in disease and an additional parallel between human and rodent development.