Neuroscience
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The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that is expressed in several brain nuclei playing a crucial role in the regulation of energy balance controlling the homeostasis of the organism. It displays both agonist-evoked and constitutive activity, and moreover, it can couple to different G proteins. Most of the research on MC4R has been focused on agonist-induced activity, while the molecular and cellular basis of MC4R constitutive activity remains scarcely studied. ⋯ We also explored the signaling pathways mediating this inhibition, and thus propose that agonist-dependent and basal MC4R activation modes signal differentially through Gs and Gi/o pathways to impact on different CaV subtypes. In addition, we found that chronic incubation with MC4R endogenous inverse agonist, agouti and agouti-related peptide (AgRP), occludes CaV inhibition in a cell line and in amygdaloid complex cultured neurons as well. Thus, we define new mechanisms of control of the main mediators of depolarization-induced calcium entry into neurons by a GPCR that displays constitutive activity.
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Brain dysfunction is a frequent complication of the systemic inflammatory response to bacterial infection or sepsis. In the present work, the effects of intravenous bacterial lipopolysaccharide (LPS) administration on cerebral arterial blood flow were assessed with time-of-flight (TOF)-based magnetic resonance angiography (MRA) in mice. Cerebral expression of the transcription factors nuclear factor-kappaB (NF-κB) and c-Fos and that of enzymes synthesizing vasoactive mediators, such as prostaglandins and nitric oxide, known to be increased under inflammatory conditions, were studied in the same animals. ⋯ LPS also increased cerebral expression of cyclooxygenase-2 and prostaglandin E synthase mRNAs, but de novo expression occurred in veins rather than in arteries. In conclusion, our work indicates that LPS-induced systemic inflammation does not necessarily affect filling of the circle of the Willis from the periphery, but that circulating LPS alters outflow from the circle of Willis to the middle and anterior cerebral arteries. These modifications in arterial flow were not related to increased cerebral synthesis of prostaglandins, but may instead be the consequence of the action of circulating prostaglandins and other vasoactive mediators on brain-irrigating arteries during systemic inflammation.
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Multiple sclerosis (MS) patients are three to six times more likely to develop epilepsy compared to the rest of the population. Seizures are more common in patients with early onset or progressive forms of the disease and prognosticate rapid progression to disability and death. ⋯ Immunohistochemical (IHC) analyses within the hippocampal CA1 region revealed extensive demyelination, loss of parvalbumin (PV+) interneurons, widespread gliosis, and changes in aquaporin-4 (AQP4) expression. Our results suggest that chronically demyelinated mice are a valuable model with which we may begin to understand the mechanisms underlying demyelination-induced seizures.
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The cerebellum is known to be involved in temporal information processing. However, the underlying neuronal mechanisms remain unclear. In our previous study, monkeys were trained to make a saccade in response to a single omission of periodically presented visual stimuli. ⋯ We found that electrical stimulation just before the stimulus omission shortened the latencies of both contraversive and ipsiversive saccades. Because the changes in saccade latency non-linearly depended on the timing of stimulation in each inter-stimulus interval, and electrical stimulation just before the early stimulus in the sequence failed to evoke saccades, the neuronal activity in the dentate nucleus might regulate temporal prediction rather than facilitating saccade execution. Our results support the hypothesis that the firing modulation in each inter-stimulus interval in the dentate nucleus represents neuronal code for the temporal prediction of next stimulus.
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In adult stroke models, the neuroprotective protein, Iduna, inhibits poly (ADP-ribose) polymerase-1 (PARP-1)-dependent cell death by decreasing apoptosis-inducing factor (AIF) nuclear translocation. Because the PARP1-dependent pathway and Iduna, which promotes AIF degradation, contribute to hypoxic-ischemic (HI) brain damage in the immature brain, we examined the relationship between Iduna expression and AIF nuclear translocation in the cerebral cortex of postnatal day 7 rats after HI. Ninety rats were divided into three groups: sham, 1-h hypoxia and 2-h hypoxia. ⋯ Furthermore, Iduna downregulation negatively correlated with nuclear AIF abundance in the 2-h HI group (r=-0.950; P<0.0001). Additionally, learning and memory ability decreased with hypoxic time. These results suggest that AIF nuclear translocation and neuronal cell death are associated with Iduna loss after severe HI in the immature brain.