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Major depressive disorder (MDD) is a prevalent debilitating psychiatric mood that contributes to increased rates of disability and suicide. However, the pathophysiology underlying MDD remains poorly understood. A growing number of studies have associated dysfunction of the prefrontal cortex (PFC) with depression, but no proteomic study has been conducted to assess PFC protein expression in a preclinical model of depression. Using the chronic unpredictable mild stress (CUMS) rat model of depression, differential protein expression between the PFC proteomes of CUMS and control rats was assessed through two-dimensional electrophoresis followed by matrix-assisted laser desorption ionization-time of flight-tandem mass spectrometry. Differential protein expression was analyzed for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway over-representation. Four differential proteins were selected for Western blotting validation. Twenty-nine differential proteins were identified in the PFC of CUMS rats relative to control rats. Through KEGG analysis, energy and glutathione metabolic pathways were determined to be the most significantly altered biological pathways. Two of the four differential proteins selected for Western blotting validation - glyoxalase 1 and dihydropyrimidinase-related protein 2 - were found to be significantly downregulated in CUMS relative to control rats. In conclusion, proteomic analysis reveals that energy and glutathione metabolism are the most significantly altered biological pathways in the CUMS rat model of depression. Further investigation on these processes and proteins in the PFC is key to a better understanding of the underlying pathophysiology of MDD., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is associated with beta-amyloid deposition, glial activation, and increased levels of the cytokines, as well as cholinergic dysfunction. Liver X receptor (LXR) has been found to inhibit the expression of pro-inflammatory genes. However, the effects of LXR activation on inflammatory response and on cholinergic system in AD are not yet clear. The present results revealed that LXR activation markedly attenuated several inflammatory markers and decreased microglial activation and reactive astrocytes in amyloid precursor protein (APP)/PS1 transgenic mice. Additionally, LXR activation significantly increased the number of cholinergic neurons in the medial septal regions and the basal nucleus of Meynert (NBM), and attenuated cognitive impairment. Furthermore, we observed that LXR activation inhibited the production of COX-2 and iNOS from Aβ(25-35)-induced microglia. LXR activation and nuclear factor kappa B (NF-κB) inhibitor PDTC both attenuated Aβ(25-35) induction of NF-κB activation. These results suggest that LXR agonists suppress the production of pro-inflammatory molecules, at least in part, by modulating NF-κB-signaling pathway. Collectively, these studies suggest that LXR agonists may have therapeutic significance in AD., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

In a natural acoustic environment, sound stimuli often occur in a contextual acoustic stream. The aim of the present study was to determine how the frequency tuning of auditory cortical neurons is affected by an acoustic context. A forward masking paradigm was used to determine the frequency receptive fields of rat auditory cortex neurons under quiet and sequential sound conditions. The frequency receptive fields of a cortical neuron were modulated dynamically by a preceding sound stimulus. At a fixed interstimulus interval (ISI), if the preceding sound level was constant, the receptive fields of most neurons were modulated to the greatest extent when the preceding sound frequency was at or near the characteristic frequency of the neuron; if the preceding sound frequency was constant, the modulation was increased with increasing sound stimulus level. When both the frequency and the level of the preceding sound were fixed, the modulation decreased with increasing interstimulus interval. The results indicate that the frequency tuning of auditory cortical neurons is plastic and dynamically modulated in a reverberant acoustical environment, and the degree of modulation depends on both the frequency tuning of the neuron and the contextual acoustical stream., (Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

Alpha-secretase (alpha-secretase), cleaves the amyloid precursor protein (APP) within the amyloid-beta (Abeta) sequence, resulting in the release of a secreted fragment of APP (alphaAPPs) and precluding Abeta generation. We investigated the effects of the acetylcholinesterase inhibitor, huperzine A (Hup A), on APP processing and Abeta generation in human neuroblastoma SK-N-SH cells overexpressing wild-type human APP695. Hup A dose-dependently (0-10 microM) increased alphaAPPs release. Therefore, we evaluated two alpha-secretase candidates, a disintegrin and metalloprotease (ADAM) 10 and ADAM17 in Hup A-induced non-amyloidogenic APP metabolism. Hup A enhanced the level of ADAM10, and the inhibitor of tumor necrosis factor-alpha converting enzyme (TACE)/ADAM17 inhibited the Hup A-induced rise in alphaAPPs levels, further suggesting Hup A directed APP metabolism toward the non-amyloidogenic alpha-secretase pathway. Hup A had no effect on Abeta generation in this cell line. The steady-state levels of full-length APP and cell viability were unaffected by Hup A. Alpha-APPs release induced by Hup A treatment was significantly reduced by muscarinic acetylcholine receptor antagonists (particularly by an M1 antagonist), protein kinase C (PKC) inhibitors, GF109203X and calphostin C, and the mitogen-activated kinase kinase (MEK) inhibitors, U0126 and PD98059. Furthermore, Hup A markedly increased the phosphorylation of p44/p42 mitogen-activated protein (MAP) kinase, which was blocked by treatment with U0126 and PD98059. In addition, Hup A inhibited acetylcholinesterase activity by 20% in neuroblastoma cells. Our results indicate that the activation of muscarinic acetylcholine receptors, PKC and MAP kinase may be involved in Hup A-induced alphaAPPs secretion in neuroblastoma cells and suggest multiple pharmacological mechanisms of Hup A regarding the treatment of Alzheimer's disease (AD).

The transcription factor, activator protein 1 (AP-1) complexes (c-Jun and c-Fos heterodimers) has been shown to interact with transforming growth factor beta signaling in mammalian cells and Drosophila embryo. Here we show that c-Jun alone is involved in the anti-neuralizing activity of bone morphogenetic protein 4, a transforming growth factor beta superfamily member, in Xenopus neurogenesis. Co-injection of mRNAs encoding c-jun and a dominant negative bone morphogenetic protein receptor completely inhibits dominant negative bone morphogenetic protein receptor-induced neuralization and reverses the epidermal fate in the animal cap. Surprisingly, a dominant negative c-Jun does not induce neural tissue in the animal cap, but it synergizes with dominant negative bone morphogenetic protein receptor for neural induction. Temporal analysis using a dexamethasone-inducible c-Jun shows that exogenous c-Jun activity must be turned on before or at stage 11 to fulfill the anti-neuralizing effect. Neural inhibition by c-Jun does not occur until stage 13 suggesting that c-Jun probably acts by suppressing neural maintenance rather than neural initiation. This is also supported by the fact that c-Jun does not inhibit expression of the neural-initializing gene Zic-r1 but the neural cofactor Sox2, and that ectopic expression of Sox2 attenuates the anti-neuralizing effect of c-Jun. Finally, we display that the c-Jun effect is enhanced by an auto-regulatory loop between c-Jun and bone morphogenetic protein. These studies suggest that c-Jun/AP-1 is a converging point in both the fibroblast growth factor and transforming growth factor beta signaling pathways. Based on our findings, we propose that c-Jun synergizes with bone morphogenetic protein 4 signaling to inhibit neural development in Xenopus ectoderm.

Relationships between leucine-enkephalin fibers and cholinergic neurons in the rat sacral intermediolateral nucleus were examined by light and electron microscopy using double-immunostaining method. Cholinergic neurons in the sacral intermediolateral nucleus were labeled by a rat-mouse monoclonal antibody to choline acetyltransferase and stained bluish green with 5-bromo-4-chloro-3-indolyl-beta-D- galactoside reaction products using beta-galactosidase as a marker. On the same sections, leucine-enkephalin fibers were labeled by a rabbit polyclonal antiserum to leucine-enkephalin and stained brown by diaminobenzidine reaction products using peroxidase as a marker. After embedding in Epon, the sections were examined in light and electron microscopes. In the light microscope, choline acetyltransferase-like immunoreactive cells were seen in the sacral intermediolateral nucleus. In the same region, leucine-enkephalin-like immunoreactive cells. In the electron microscope, 5-bromo-4-chloro-3-indolyl-beta-D-galactoside reaction products were in the form of coarse electron dense deposits in the choline acetyltransferase-like immunoreactive structures and could be distinguished from the much finer grained diaminobenzidine reaction products. Choline acetyltransferase-like immunoreactive neurons received synaptic inputs from leucine-enkephalin fibers-like immunoreactive terminals. These findings suggest that leucine-enkephalin fibers may affect the activity of cholinergic parasympathetic preganglionic neurons.