Neuroscience
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Persistent inflammation is associated with a shift in spinal GABA(A) signaling from inhibition to excitation such that GABA(A)-receptor activation contributes to inflammatory hyperalgesia. We tested the hypothesis that the primary afferent is the site of the persistent inflammation-induced shift in GABA(A) signaling which is due to a Na(+)-K(+)-Cl(-)-co-transporter (NKCC1)-dependent depolarization of the GABA(A) current equilibrium potential (E(GABA)). Acutely dissociated retrogradely labeled cutaneous dorsal root ganglion (DRG) neurons from naïve and inflamed (3 days after a subcutaneous injection of complete Freund's adjuvant) adult male rats were studied with Ca(2+) imaging, western blot and gramicidin-perforated patch recording. ⋯ Furthermore, the increase in excitatory response was comparable in both HEPES- and HCO(3)(-)-buffered solutions, but was only associated with a depolarization of E(GABA) in HCO(3)(-)-based solution. In contrast, under both recording conditions, the excitatory response was associated with an increase in GABA(A) current density, a decrease in low threshold K(+) current density, and resting membrane potential depolarization. Our results suggest that increasing K(+) conductance in afferents innervating a site of persistent inflammation may have greater efficacy in the inhibition of inflammatory hyperalgesia than attempting to drive a hyperpolarizing shift in E(GABA).
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In the brain of neonatal chicks, tryptophan has a sedative effect, and a part of this effect might be dependent upon its metabolite, serotonin. However, the functional mechanisms have not been fully clarified, since l-tryptophan produces kynurenic acid (KYNA) through the kynurenine pathway. ⋯ KYNA dose-dependently induced sedative and hypnotic effects under CRH-augmented social isolation stress. Taken together, these results indicate that KYNA is a likely candidate for the sedative and hypnotic effects of tryptophan under acutely stressful conditions.
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Spinal muscular atrophy (SMA), a fatal genetic motor disorder of infants, is caused by diminished full-length survival of motor neuron (SMN) protein levels. Normally involved in small nuclear ribonucleoprotein (snRNP) assembly and pre-mRNA splicing, recent studies suggest that SMN plays a critical role in regulating apoptosis. Interestingly, the anti-apoptotic Bcl-x isoform, Bcl-xL, is reduced in SMA. ⋯ We also found that exogenous SMN expression increased full-length SMN transcripts, possibly by promoting exon 7 inclusion. Finally, co-expression of SMN and Bcl-xL produced an additive anti-apoptotic effect following PI3-kinase inhibition in SH-SY5Y cells. Our findings implicate Bcl-xL as another potential target in SMA therapeutics, and indicate that therapeutic increases in SMN may arise from modest increases in total SMN.
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In Alzheimer's disease (AD) the complex interplay between environment and genetics has hampered the identification of effective therapeutics. However, epigenetic mechanisms could underlie this complexity. Here, we explored the potential role of epigenetic alterations in AD by investigating gene expression levels and chromatin remodeling in selected AD-related genes. ⋯ Neither gene was altered in AD PBMCs. The ADORA2A gene was not altered in patients or in the 3xTg-AD mice. Overall, our results suggest that chromatin remodeling plays a role in mRNA alterations in AD, prompting for broader and more detailed studies of chromatin and other epigenetic alterations and their potential use as biomarkers in AD.
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Signal detection theory (SDT) provides a framework for interpreting psychophysical experiments, separating the putative internal sensory representation and the decision process. SDT was used to analyse ferret behavioural responses in a (yes-no) tone-in-noise detection task. Instead of measuring the receiver-operating characteristic (ROC), we tested SDT by comparing responses collected using two common psychophysical data collection methods. ⋯ The data suggest trial-by-trial reward-driven optimization of the decision process. Understanding the factors determining behavioural responses is important for correlating neural activity and behaviour. SDT provides a good account of animal psychoacoustics, and can be validated using standard psychophysical methods and computer simulations, without recourse to ROC measurements.