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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Antagonism of the kappa opioid receptor (KOR) has been reported to have anti-depressant-like properties. The dynorphin/KOR system is a crucial neurochemical substrate underlying the pathologies of addictive diseases, affective disorders and other disease states. However, the molecular underpinnings and neuroanatomical localization of the dysregulation of this system have not yet been fully elucidated. ⋯ The corresponding brain regions from the opposite hemisphere were analyzed for underlying chromatin modifications of the prodynorphin gene promoter region using chromatin immunoprecipitation with antibodies against specifically methylated histones H3K27Me2, H3K27Me3, H3K4Me2, and H3K4Me3, as well as CREB-1 and MeCP2. Significant alterations in proteins bound to DNA in the Cre-3, Cre-4, and Sp1 regions of the prodynorphin promoter were found in the caudate putamen of the FST saline-treated animals compared to control animals, with no changes observed in the hippocampus. Epigenetic changes resulting in elevated dynorphin levels specifically in the caudate putamen may in part underlie the enduring effects of stress.
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Seasonal affective disorder (SAD), a major depressive disorder recurring in the fall and winter, is caused by the reduction of light in the environment, and its depressive symptoms can be alleviated by bright light therapy. Both circadian and monoaminergic systems have been implicated in the etiology of SAD. However, the underlying neural pathways through which light regulates mood are not well understood. ⋯ The animals were injected with the selective orexin receptor type 1 (OXR1) antagonist SB-334867 prior to the light exposure. The treatment of SB-334867 significantly inhibited the Fos induction in the DRN. The results collectively point to the role of orexin neurons in mediating the effects of light on the mood-regulating monoaminergic areas, suggesting an orexinergic pathway that underlies light-dependent mood fluctuation and the beneficial effects of light therapy.
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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.