Neuroscience
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The prominent morphometric alterations of Alzheimer's disease (AD) occur both in gray matter and in white matter. Multimodal fusion can examine joint information by combining multiple neuroimaging datasets to identify the covariant morphometric alterations in AD in greater detail. ⋯ The joint IC maps revealed that the simultaneous changes in the gray matter and FA values primarily involved the following areas: (1) the temporal lobe/hippocampus-cingulum, (2) the frontal/cingulate gyrus-corpus callosum, and (3) the temporal/occipital/parietal lobe-corpus callosum/corona radiata. Our findings suggest that gray matter atrophy is associated with reduced white matter fiber integrity in AD and possibly expand the understanding of the neuropathological mechanisms in AD.
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GABA receptor type A (GABA(A)R)-mediated inhibition is divided into phasic and tonic inhibition. GABA(A)Rs mediating the two inhibitory modalities exhibit differences in subcellular localization and subunit composition. We previously demonstrated that phasic and tonic inhibition are independently regulated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and protein kinase A (PKA), respectively. ⋯ Thus, phasic and tonic inhibition might be independently regulated even by a single neuromodulator. Functionally, the opposite modulation of phasic and tonic inhibition decreased the summation of consecutive excitatory postsynaptic potentials (EPSPs) without affecting the shape of single EPSPs, which might underlie the suppression of the induction of long-term potentiation by 5-HT. These results suggest that the integrative regulation of phasic and tonic inhibition provides mechanisms for elaborate modulation of shape and summation of EPSPs and long-term synaptic plasticity.
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While spinal cord astrocytes play a key role in the generation of cancer pain, there have been no studies that have examined the relationship of tumor-induced astrocyte activation and aromatase expression during the development of cancer pain. Here, we examined tumor-induced mechanical hyperalgesia and cold allodynia, and changes in Glial fibrillary acid protein (GFAP) and aromatase expression in murine models of painful and non-painful bone cancer. We demonstrate that implantation of fibrosarcoma cells, but not melanoma cells, produces robust mechanical hyperalgesia and cold allodynia in tumor-bearing mice compared to saline-injected controls. ⋯ Finally, administration of an aromatase inhibitor reduced tumor-induced hyperalgesia in fibrosarcoma-bearing animals. We conclude that a painful fibrosarcoma tumor induces a significant increase in spinal astrocyte activation and aromatase expression and that the up-regulation of aromatase plays a role in the development of bone tumor-induced hyperalgesia. Since spinal aromatase is also upregulated, but to a lesser extent, in non-painful melanoma bone tumors, it may also be neuroprotective and responsive to the changing tumor environment.
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Stimuli paired with rewards acquire reinforcing properties to promote reward-seeking behavior. Previous work supports the role of ventral tegmental area (VTA) nicotinic acetylcholine receptors (nAChRs) in mediating conditioned reinforcement elicited by drug-associated cues. However, it is not known whether these cholinergic mechanisms are specific to drug-associated cues or whether VTA cholinergic mechanisms also underlie the ability of cues paired with natural rewards to act as conditioned reinforcers. ⋯ AP-5 robustly attenuated conditioned reinforcement and blocked discrimination between CR and NCR noseports at the 1-μg dose. MEC infusion decreased responding for both CR and NCR while 66.7-μg SCOP disrupted the subject's ability to discriminate between CR and NCR. Together, our data suggest that VTA NMDARs and mAChRs, but not nAChRs, play a role in the ability of natural reward-associated cues to act as conditioned reinforcers.
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Brain ischemia and reperfusion (I/R) injury occurs in various pathological conditions, but there is no effective treatment currently available in clinical practice. Methylene blue (MB) is a century-old drug with a newly discovered protective function in the ischemic stroke model. In the current investigation we studied the MB-induced neuroprotective mechanism focusing on stabilization and activation of hypoxia-inducible factor-1α (HIF-1α) in an in vitro oxygen and glucose deprivation (OGD)-reoxygenation model. ⋯ We conclude that MB protects the hippocampus-derived neuronal cells against OGD-reoxygenation injury by enhancing energy metabolism and increasing HIF-1α protein content accompanied by an activation of the EPO signaling pathway.