Neuroscience
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Obesity is associated with augmented peripheral inflammation and pain sensitivity in response to inflammatory stimulation, but the underlying mechanisms remain unclear. Emerging evidence has shown that activation of peroxisome proliferator-activated receptor-α (PPARα) in the central nervous system controls peripheral inflammation and pain. We hypothesized that obesity might down-regulate PPARα in the spinal cord, leading to enhanced peripheral inflammation and inflammatory hyperalgesia. ⋯ However, the increase was more pronounced in HF-fed rats and corrected by PEA. Intrathecal injection of small interfering RNA (siRNA) against PPARα in HF-fed rats completely abolished PEA effects on peripheral pain sensitivity and paw edema. These findings suggest that diet-induced obesity causes down-regulation of spinal PPARα, which facilitates the susceptibility to peripheral inflammatory challenge by increasing inflammatory response in the spinal cord, contributing to augmented peripheral inflammation and inflammatory hyperalgesia in obesity.
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Low intensity static magnetic fields (SMFs) interact with various biological tissues including the CNS, thereby affecting key biological processes such as gene expression, cell proliferation and differentiation, as well as apoptosis. Previous studies describing the effect of SMFs on apoptotic cell death in several non-neuronal cell lines, emphasize the importance of such a potential modulation in the case of neurodegenerative disorders, where apoptosis constitutes a major route via which neurons degenerate and die. In this study, we examine the effect of SMFs on neuronal survival in primary cortical and hippocampal neurons that constitute a suitable experimental system for modeling the neurodegenerative state in vitro. ⋯ Using the L-type voltage-gated Ca(2+) channel inhibitor nifedipine, which is selective to Ca(2+) influx through Cav1.2, we found that the anti-apoptotic effect of SMFs was mediated by Ca(2+) influx through these channels. Our findings demonstrating altered Ca(2+)-influx in response to thapsigargin stimulation in SMF-exposed cortical neurons, along with enhanced inhibition of KCl-induced Ca(2+)-influx through Cav1.2 channels and enhanced expression of Cav1.2 and Cav1.3 channels, allude to the involvement of voltage- and store-operated Ca(2+) channels in various aspects of the protective effect exerted by SMFs. These findings show the potential susceptibility of the CNS to weak SMF exposure and have implications for the design of novel strategies for the treatment and/or prevention of neurodegenerative diseases.
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Neurons in the superficial layers of the entorhinal cortex provide the hippocampus with the majority of its cortical sensory input, and also receive the major output projection from the parasubiculum. This puts the parasubiculum in a position to modulate the activity of entorhinal neurons that project to the hippocampus. These brain areas receive cholinergic projections that are active during periods of theta- and gamma-frequency electroencephalographic (EEG) activity. ⋯ Application of the K(+) channel antagonist Ba(2+) depolarized neurons and enhanced temporal summation, but did not block further facilitation of train-evoked responses by ZD7288. The Ih-dependent facilitation of synaptic responses can therefore occur during reductions in inward-rectifying potassium current (IKir) associated with dendritic depolarization. Thus, in addition to cholinergic reductions in transmitter release that are known to facilitate train-evoked responses, these findings emphasize the role of inhibition of Ih in the integration of synaptic inputs within the entorhinal cortex during cholinergically-induced oscillatory states, likely due to enhanced summation of excitatory postsynaptic potentials (EPSPs) induced by increases in dendritic Rin.
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High levels of 17β-estradiol (E2) have been found to reduce inflammatory temporomandibular joint (TMJ) pain. A search for genes effected by a high concentration of estradiol showed an increase in GABAA receptor subunit alpha 6 (Gabrα6) in the trigeminal ganglia (TG). Blockade of Gabrα6 expression in the TG increases masseter muscle nociception in male rats, but the relationship between estradiol's effect on nociception and Gabrα6 expression remains unclear in females. ⋯ Ligature significantly increased the nociceptive response but a high proestrus concentration of 17β-estradiol attenuated this response. Gabrα6 siRNA infusion decreased Gabrα6 expression in the TG and Vc-C1 but increased the nociceptive response after 17β-estradiol treatment. The results suggest estradiol decreased the orofacial nociceptive response, in part, by causing an increase in Gabrα6 expression.
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The tetrameric kainate receptors can be assembled from a combination of five different subunit subtypes. While GluK1-3 subunits can form homomeric receptors, GluK4 and GluK5 require a heteromeric partner to assemble, traffic to the membrane surface, and produce a functional channel. Previous studies have shown that incorporation of a GluK4 or GluK5 subunit changes both receptor pharmacology and channel kinetics. ⋯ In addition, mutation of the agonist binding site of GluK5 results in a heteromeric receptor with a glutamate sensitivity similar to homomeric GluK1 or GluK2 receptors, but which requires higher agonist concentrations to produce desensitization. This suggests that onset of desensitization in heteromeric receptors is determined more by the number of subunits bound to agonist than by the identity of those subunits. The distinct, concentration-dependent properties observed with heteromeric receptors in response to glutamate or kainate are consistent with a model in which either subunit can activate the channel, but in which occupancy of both subunits within a dimer is needed to allow desensitization of GluK2/K5 receptors.