Neuroscience
-
Neuroinflammation plays an important role in epileptic disorders. Toll-like receptors (TLRs) are the key signal transduction tools by which neuroinflammation may promote epileptogenesis. Depending on the stimulus nature, TLRs may engage a distinct signaling pathway. ⋯ Pilocarpine induced profound hyperexcitability in the DG granule cells accompanied by potentiated excitatory postsynaptic currents (EPSCs) and dampened inhibitory postsynaptic currents (IPSCs), in contrast to the control group. However, pretreatment with TLR ligands preserved almost normal excitability and synaptic transmission against the pilocarpine. In conclusion, early activation of TLR4 and TLR2, probably through preserving normal hippocampal cytokine profile and neuronal function attenuates seizure severity in the rat model of TLE.
-
Growing research indicates oxytocin may be involved in relieving anxiety and attenuating the rewarding effects of psychostimulants. This study investigated the effects of subchronic oxytocin treatments on mesolimbic dopamine transmission in areas associated with anxiety and addiction, the amygdala and the nucleus accumbens (NAc), respectively. Using in vivo fixed potential amperometry, stimulation-evoked dopamine release was recorded in anesthetized mice pretreated with subchronic oxytocin (four i.p. injections of 1 mg/kg oxytocin or saline with 48 h between injections). ⋯ Furthermore, oxytocin pretreated mice displayed a reduced dopaminergic response to the drug challenge of nomifensine relative to control mice. Together these results suggest that oxytocin may be useful at treating aspects of anxiety and drug abuse. Elucidating the neural effects of oxytocin is critical given the multitude of potential therapeutic uses for this drug.
-
Amyloid beta peptide (Aβ) is implicated in the development of pathological reactions associated with Alzheimer's disease (AD), such as oxidative stress, neuro-inflammation and death of brain cells. Current pharmacological approaches to treat AD are not able to control the deposition of Aβ and suppression of Aβ-induced cellular response. There is a growing body of evidence that exposure to radiofrequency electromagnetic field (RF-EMF) causes a decrease of beta-amyloid deposition in the brains and provides cognitive benefits to Alzheimer's Tg mice. ⋯ Our data demonstrate that EMF is able to reduce Aβ42- and H2O2-induced cellular ROS, abrogate Aβ₄₂-induced production of mitochondrial ROS and the co-localization between the cytosolic (p47-phox) and membrane (gp91-phox) subunits of NADPH oxidase, while increasing MMP, and inhibiting H2O2-induced phosphorylation of p38MAPK and ERK1/2 in primary astrocytes. Yet, EMF was not able to modulate alterations in the phosphorylation state of the MAPKs triggered by Aβ42. Our findings provide an insight into the mechanisms of cellular and molecular responses of astrocytes on RF-EMF exposure and indicate the therapeutic potential of RF-EMF for the treatment of Alzheimer's disease.
-
Maternal malnutrition is one of the major early-life adversities affecting the development of newborn's brain and is associated with an increased risk to acquire cognitive and emotional deficiencies later in life. Studies in rodents have demonstrated that exposure to an enriched environment (EE) can reverse the negative consequences of early adversities. However, rescue of emotional disorders caused by perinatal malnutrition and the mechanisms involved has not been determined. ⋯ The predicted mRNA targets of these miRNAs are mostly related to axon guidance pathway. Accordingly, we also found that perinatal malnutrition leads to reduction in the cingulum size and altered oligodendrocyte morphology. These results suggest that EE-rescue of anxiety disorders derived from perinatal malnutrition is mediated by the modulation of miRNAs associated with the regulation of genes involved in axonal guidance.
-
M1 muscarinic receptors have long been identified as a potential therapeutic target for the treatment of cognitive impairment in Alzheimer's disease (AD). Our previous study has shown that M1 receptors promote membrane insertion and synaptic delivery of AMPA receptor GluA1 subunit. In this study, we sought to determine whether activation of M1 receptor would rescue the cognitive impairment in AD model mice through modulation of GluA1 subunit. ⋯ Moreover, for 9-month-old APP/PS1 transgenic AD model mice, which may resemble the late AD, M1 receptor activation could not improve the cognitive impairment significantly. In addition, the enhancement of GluA1 expression and its phosphorylation at Ser845 were not observed in their hippocampi. Taken together, the study indicated that M1 receptor activation rescued the cognitive deficit through modulating the trafficking of GluA1-containing AMPA receptors and the therapeutics targeting M1 receptors should aim at mild AD or even pre-AD.