A thalamic circuit facilitates stress susceptibility via melanocortin 4 receptor-mediated activation of nucleus accumbens shell.

AIMS: Central melanocortin 4 receptor (MC4R) has been reported to induce anhedonia via eliciting dysfunction of excitatory synapses. It is evident that metabolic signals are closely related to chronic stress-induced depression. Here, we investigated that a neural circuit is involved in melanocortin signaling contributing to susceptibility to stress. METHODS: Chronic social defeat stress (CSDS) was used to develop depressive-like behavior. Electrophysiologic and chemogenetic approaches were performed to evaluate the role of paraventricular thalamus (PVT) glutamatergic to nucleus accumbens shell (NAcsh) circuit in stress susceptibility. Pharmacological and genetic manipulations were applied to investigate the molecular mechanisms of melanocortin signaling in the circuit. RESULTS: CSDS increases the excitatory neurotransmission in NAcsh through MC4R signaling. The enhanced excitatory synaptic input in NAcsh is projected from PVT glutamatergic neurons. Moreover, chemogenetic manipulation of PVTGlu -NAcsh projection mediates the susceptibility to stress, which is dependent on MC4R signaling. Overall, these results reveal that the strengthened excitatory neurotransmission in NAcsh originates from PVT glutamatergic neurons, facilitating the susceptibility to stress through melanocortin signaling. CONCLUSIONS: Our results make a strong case for harnessing a thalamic circuit to reorganize excitatory synaptic transmission in relieving stress susceptibility and provide insights gained on metabolic underpinnings of protection against stress-induced depressive-like behavior.

Dimethyl sulfide protects against oxidative stress and extends lifespan via a methionine sulfoxide reductase A-dependent catalytic mechanism.

Methionine (Met) sulfoxide reductase A (MsrA) is a key endogenous antioxidative enzyme with longevity benefits in animals. Only very few approaches have been reported to enhance MsrA function. Recent reports have indicated that the antioxidant capability of MsrA may involve a Met oxidase activity that facilities the reaction of Met with reactive oxygen species (ROS). Herein, we used a homology modeling approach to search the substrates for the oxidase activity of MsrA. We found that dimethyl sulfide (DMS), a main metabolite that produced by marine algae, emerged as a good substrate for MsrA-catalytic antioxidation. MsrA bounds to DMS and promoted its antioxidant capacity via facilitating the reaction of DMS with ROS through a sulfonium intermediate at residues Cys72, Tyr103, and Glu115, followed by the release of dimethyl sulfoxide (DMSO). DMS reduced the antimycin A-induced ROS generation in cultured PC12 cells and alleviated oxidative stress. Supplement of DMS exhibited cytoprotection and extended longevity in both Caenorhabditis elegans and Drosophila. MsrA knockdown abolished the cytoprotective effect and the longevity benefits of DMS. Furthermore, we found that the level of physiologic DMS was at the low micromolar range in different tissues of mammals and its level decreased after aging. This study opened a new window to elucidate the biological role of DMS and other low-molecular sulfides in the cytoprotection and aging.

Chronic administration tetrahydroxystilbene glucoside promotes hippocampal memory and synaptic plasticity and activates ERKs, CaMKII and SIRT1/miR-134 in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum Thunb is a traditional Chinese medicine with anti-aging effect. 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) is generally considered as the main active component in Polygonum multiflorum Thunb. However, the effect of TSG on memory in adult is unclear till now. AIM OF STUDY: 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) is a polyphenols compound from Polygonum multiflorum Thunb. The present study aimed to evaluate the effect of chronic administration of TSG on hippocampal memory in normal mice. MATERIALS AND METHODS: Behavioral test, electrophysiology and golgi staining were used to evaluate the effect of TSG on hippocampus-dependent memory and synaptic plasticity. Western blotting was used to determine the expression of ERK1/2, CaMKII, and SIRT1. Real-time quantitative PCR was explored to measure miR-134. RESULTS: It was found that TSG enhanced hippocampus-dependent contextual fear memory and novel object recognition, facilitated hippocampal LTP and increased dendrite spine density in the CA1 region of hippocampus. TSG obviously promoted the phosphorylations of ERK1/2, CaMKII, CREB and the expression of BDNF in the hippocampus, with upregulation of silent information regulator 1 (SIRT1) and downregulation of miR-134. CONCLUSIONS: Chronic administration of TSG promotes hippocampal memory in normal mice, suggesting that supplementary of TSG might serve as an enhancement of memory.

A specific and rapid colorimetric method to monitor the activity of methionine sulfoxide reductase A.

Considerable evidence indicates that methionine sulfoxide (MetO) reductase A (MsrA) plays an important role in cytoprotection against oxidative stress and serves as a potential drug target. To screen for MsrA regulators, a rapid and specific assay to monitor MsrA activity is required. Most of current assays for MsrA activity are based on the reduction of radioactive substrates such as [3H]-N-acetyl-MetO or fluorescent derivatives such as dimethylaminoazo-benzenesulfonyl-MetO. However, these assays require extraction procedures and special instruments. Here, we developed a specific colorimetric microplate assay for testing MsrA activity quickly, which was based on the fact that MsrA can catalyze the reduction of methyl sulfoxides and simultaneously oxidize dithiothreitol (DTT), whose color can be produced by reacting with Ellman's reagent (dithio-bis-nitrobenzoic acid, DTNB). The corresponding absorbance change at 412nm was recorded with a microplate reader as the reaction proceeded. This method to monitor MsrA activity is easy to handle. Our findings may serve as a rapid method for the characterization of recombinant enzyme and for the screening of enzyme inhibitors, pharmacological activators, gene expression regulators and novel substrates.

Activation of phosphatidylinositol-linked novel D1 dopamine receptor contributes to the calcium mobilization in cultured rat prefrontal cortical astrocytes.

Recent evidences indicate the existence of an atypical D(1) dopamine receptor other than traditional D(1) dopamine receptor in the brain that mediates PI hydrolysis via activation of phospholipase C(beta) (PLC(beta)). To further understand the basic physiological function of this receptor in brain, the effects of a selective phosphoinositide (PI)-linked D(1) dopamine receptor agonist SKF83959 on cytosolic free calcium concentration ([Ca(2+)](i)) in cultured rat prefrontal cortical astrocytes were investigated by calcium imaging. The results indicated that SKF83959 caused a transient dose-dependent increase in [Ca(2+)](i). Application of D(1) receptor, but not D(2), alpha(1) adrenergic, 5-HT receptor, or cholinergic antagonist prevented SKF83959-induced [Ca(2+)](i) rise, indicating that activation of the D(1) dopamine receptor was essential for this response. Increase in [Ca(2+)](i) was a two-step process characterized by an initial increase in [Ca(2+)](i) mediated by release from intracellular stores, supplemented by influx through voltage-gated calcium channels, receptor-operated calcium channels, and capacitative Ca(2+) entry. Furthermore, SKF83959-stimulated increase in [Ca(2+)](i) was abolished following treatment with a PLC inhibitor. Overall, these results suggested that activation of D(1) receptor by SKF83959 mediates a dose-dependent mobilization of [Ca(2+)](i) via the PLC signaling pathway in cultured rat prefrontal cortical astrocytes.