Shu-Cheng An

D2 receptors (D2Rs) located in both pre- and postsynaptic membranes of medium spiny neurons (MSNs) in the nucleus accumbens (NAc) are involved in the stress response and associated behaviours. The role of D2Rs in chronic unpredictable stress (CUS)-induced depression-like behaviours is not clear. Quinpirole (a D2R agonist) and eticlopride (a D2R antagonist) were stereotactically delivered into the NAc before Sprague Dawley rats underwent CUS. CUS-induced depression-like behaviours were accompanied by a significant decrease in both the dopamine (DA) level and D2R expression in the NAc. Eticlopride reversed CUS-induced depression-like behaviour and rescued the DA levels in the NAc, and microinjection of DA into the NAc of CUS individuals had the same effect as eticlopride. By contrast, delivery of quinpirole into the NAc of control animals induced depression-like behaviours accompanied by a decrease in the DA level in the NAc. These results show that DA plays a key role in CUS-induced depression-like behaviours and the D2R exerts a presynaptic negative feedback on DA levels during CUS. Microinjection of quinpirole into the NAc also decreased the level of the kalirin-7 protein in the NAc of both control and stressed animals, while eticlopride increased its level in the NAc of rats. In agreement with these results, intraperitoneal injection of eticlopride in mice also caused an increase in both the kalirin-7 protein level in the NAc and spine density in MSNs, while quinpirole reduced them. These results suggest that regulation of kalirin-7 through D2R in the NAc is a general pathway in rats and mice, and is involved in CUS-induced depression-like behaviours. Kalirin-7 may be directly regulated through the D2R postsynaptic pathway or indirectly through the presynaptic pathway in the NAc. The interaction between D2R and kalirin-7 needs to be investigated further.

Myostatin (MSTN) is not only a key negative regulator of skeletal muscle secretion, however is also an endocrine factor that is transmitted to bone. To investigate the effect and possible mechanism of weight‑bearing treadmill running on bone with poorly controlled Type 1 diabetes, rats were randomly divided into three groups: Normal control (NC), diabetic mellitus (DM) and diabetic exercise training groups (DM‑WTR). The DM‑WTR rats were trained with weight‑bearing running. The results demonstrated that the levels of serum insulin, body weight, bone mass, muscle mass, grip strength, and serum calcium in the DM‑WTR rats were significantly increased, whereas the levels of blood glucose, alkaline phosphatase, and tartrate‑resistant acid phosphatase were markedly reduced in the DM‑WTR rats compared with the DM rats. Weight‑bearing running inhibited streptozocin (STZ)‑induced MSTN mRNA and protein expression in the diabetic rats. The mRNA and protein expression levels of activin type IIB receptor and mothers against decapentaplegic homolog 2/3 and its phosphorylation in femur DM‑WTR rats were reduced compared with DM rats. In addition, weight‑bearing running enhanced the STZ‑induced Wnt and β‑catenin expression levels and reduced the STZ‑induced glycogen synthase kinase (GSK)‑3β expression in diabetic rats' femora. In conclusion, the results suggested that weight‑bearing running could partially ameliorate STZ‑induced femur atrophy via MSTN downregulation, and this may be associated with the inactivation of Activin A Receptor Type 2B/Smad2/3 signaling pathways and the activation of the Wnt/GSK3β/β‑catenin signaling pathway. Further studies are needed to verify these conclusions.

Diabetic muscle atrophy causes a reduction of skeletal muscle size and strength, which affects normal daily activities. However, pulsed electromagnetic fields (PEMFs) can retard the atrophy of type II fibers (ActRIIB) in denervated muscles. Therefore, the purpose of the present study was to determine whether PEMFs can alleviate streptozotocin (STZ)‑induced diabetic muscle atrophy. To do this, 40 Sprague‑Dawley (SD) rats were randomly divided into four groups (n=10 per group): The normal control group (NC; nondiabetic rats without treatment); the diabetic mellitus group (DM; STZ‑induced rats without treatment); the diabetic insulin‑treated group (DT; diabetic rats on insulin treatment, 6‑8 U/d twice a day for 6 weeks) as a positive control; and the diabetic PEMFs therapy group (DP; diabetic rats with PEMFs exposure treatment, 15 Hz, 1.46 mT, 30 min/day for 6 weeks). Body weight, muscle strength, muscle mass and serum insulin level were significantly increased in the DP group compared with the DM group. PEMFs also decreased the blood glucose level and altered the activity of metabolic enzymes. PEMFs significantly increased the cross‑sectional area of muscle fiber. In addition, PEMFs significantly activated protein kinase B (Akt) and mammalian target of rapamycin (mTOR), and inhibited the activity of myostatin (MSTN), ActRIIB and forkhead box protein O1 (FoxO1) compared with the DM group. Thus indicating that the Akt/mTOR and Akt/FoxO1 signaling pathways may be involved in the promotion of STZ‑induced diabetic muscle atrophy by PEMFs. The results of the present study suggested that PEMFs stimulation may alleviate diabetic muscle atrophy in the STZ model, and that this is associated with alterations in multiple signaling pathways in which MSTN may be an integral factor. MSTN‑associated signaling pathways may provide therapeutic targets to attenuate severe diabetic muscle wasting.

The present study was to investigate the role of the quinolinic acid (QUIN) and its relationship with N-methyl-D-aspartic acid (NMDA) receptor and metabotropic glutamate receptor 1 (mGluR1) in depression induced by chronic unpredictable mild stress (CUMS) in hippocampus. CUMS-induced depression model was established in Sprague-Dawley rats. Intrahippocampal injections of QUIN, QUIN antagonist Ro61-8048, non-competitive NMDA receptor antagonist MK-801 and mGluR1 antagonist AIDA were respectively adopted by rat brain stereotaxic coordinates. The behavioral observations were conducted by measurement of weight changes, sucrose preference test, open-field test and tail suspension test. The concentration of glutamic acid (Glu) and the expression of its receptor subunits in hippocampus were detected by HPLC and Western blot, respectively. The QUIN content in hippocampus was determined by enzyme linked immunosorbent assay (ELISA). The result showed that CUMS significantly induced the depressive-like behaviors in rats, increased the contents of QUIN and Glu, and upregulated the expression of NMDA receptor subunits NR2B and mGluR1 in hippocampus. Microinjection of QUIN into hippocampus resulted in animal depressive-like behaviors, and increased the content of Glu and the expression of NR2B and mGluR1 significantly. QUIN antagonist Ro61-8048 effectively restrained the depression-like behaviors induced by CUMS, and decreased the content of Glu and the expression of NR2B and mGluR1 significantly. Intrahippocampal injections of MK-801 and AIDA effectively improved the depression-like behaviors induced by CUMS and decreased the Glu content. The results suggest that CUMS may contribute to the production and release of QUIN in hippocampal microglia. QUIN results in elevation of Glu level via NMDA receptor and mGluR1, and the increase of expression of NR2B and mGluR1 in hippocampus, which leads to depression-like behaviors in the end.

The study was to investigate the role of homocysteine (Hcy) which was released by hippocampal glial cells and its relationship with NMDA receptor and AMPA receptor in depression induced by chronic unpredictable mild stress (CUMS), and explore the mechanism of changes of Glu/Glu receptor in glial cells and neurons. CUMS-induced depression model was established. The body weight of rats was weighed on the 1st, 7th, 14th, and 21st days during the experiment. The behavioral performances were observed by means of sucrose consumption test, open field test and tail suspension test. Intrahippocampal microinjection of Hcy, NMDA receptor antagonist MK-801 and AMPA receptor antagonist NBQX was performed under stereotaxic guide cannula. The concentration of Glu and the expression of its receptors' subunits were detected respectively by high performance liquid chromatography (HPLC) and Western blot. The Hcy content and the levels of phosphorylation of NMDA receptor and AMPA receptor in hippocampus were separately determined by enzyme linked immunosorbent assay (ELISA). The results showed that CUMS significantly induced the depression-like behaviors in rats, and the content of Glu and Hcy, the expression of NMDA receptors' subunits NR1/NR2B and the level of phosphorylation of NMDA receptor (p-NMDAR) in hippocampus increased significantly, while the expression of AMPA receptors' subunits GluR2/3 and the level of phosphorylation of AMPA receptor (p-AMPAR) decreased significantly. Microinjection of Hcy into hippocampus resulted in similar animal depression-like behaviors and increased Glu content compared to the CON/SAL group, the expression of NR1/NR2B/GluR2/3 and the level of p-NMDAR increased significantly, but the level of p-AMPAR reduced observably. Intrahippocampal injections of MK-801 effectively improved the depression-like behaviors induced by CUMS and Hcy, and attenuated the elevation of Glu content induced by Hcy in hippocampus, whereas NBQX could not improve the depression-like behaviors, but also decreased the Glu content induced by Hcy remarkably. These results suggest that CUMS may contribute to the production and release of Hcy via hippocampal astrocytes. Through the increase of expression of NR1/NR2B/GluR2/3 and level of p-NMDAR, and the decrease of level of p-AMPAR, Hcy results in elevation of Glu level, which leads to depression-like behaviors in the end. In a word, the Hcy released by astrocytes plays an important role in stress-induced elevation of Glu content and variation of NMDA/AMPA receptors in hippocampus.