Publications by authors named "Chen-Yao Wang"

9 Publications

  • Page 1 of 1

Amygdala dynorphin/κ opioid receptor system modulates depressive-like behavior in mice following chronic social defeat stress.

Acta Pharmacol Sin 2021 May 25. Epub 2021 May 25.

Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Major depression disorder is a severe and recurrent neuropsychological disorder characterized by lowered mood and social activity and cognitive impairment. Owing to unclear molecular mechanisms of depression, limited interventions are available in clinic. In this study we investigated the role of dynorphin/κ opioid receptor system in the development of depression. Mice were subjected to chronic social defeat stress for 14 days. Chronic social defeat stress induced significant social avoidance in mice characterized by decreased time duration in the interaction zone and increased time duration in the corner zone. Pre-administration of a κ opioid receptor antagonist norBNI (10 mg/kg, i.p.) could prevent the development of social avoidance induced by chronic social defeat stress. Social avoidance was not observed in κ opioid receptor knockout mice subjected to chronic social defeat stress. We further revealed that social defeat stress activated c-fos and ERK signaling in the amygdala without affecting the NAc, hippocampus and hypothalamus, and ERK activation was blocked by systemic injection of norBNI. Finally, the expression of dynorphin A, the endogenous ligand of κ opioid receptor, was significantly increased in the amygdala following social defeat stress; microinjection of norBNI into the amygdala prevented the development of depressive-like behaviors caused by social defeat stress. The present study demonstrates that upregulated dynorphin/κ opioid receptor system in the amygdala leads to the emergence of depression following chronic social defeat stress, and sheds light on κ opioid receptor antagonists as potential therapeutic agents for the prevention and treatment of depression following chronic stress.
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http://dx.doi.org/10.1038/s41401-021-00677-6DOI Listing
May 2021

Chronic modafinil therapy ameliorates depressive-like behavior, spatial memory and hippocampal plasticity impairments, and sleep-wake changes in a surgical mouse model of menopause.

Transl Psychiatry 2021 02 8;11(1):116. Epub 2021 Feb 8.

Department of Pharmacology, School of Basic Medical Sciences; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China.

Depression, cognitive deficits, and sleep disturbances are common and often severe in menopausal women. Hormone replacement cannot effectively alleviate these symptoms and sometimes elicits life-threatening adverse reactions. Exploring effective therapies to target psychological problems is urgently needed. In this work, we developed a mouse model of menopause by bilateral ovariectomies (OVXs) and investigated whether menopausal mental symptoms can be ameliorated by psychostimulant modafinil (MOD) as well as explored the underlying mechanisms. At ~3 weeks after OVXs, mice got daily intraperitoneal administrations of MOD at the beginning of the active phase. Several behavioral tests and electroencephalogram (EEG) recordings were conducted. Electrophysiological and immunohistochemical experiments were carried out to evaluate the synaptic plasticity and neurogenesis, respectively. We found that chronic MOD administration in OVX mice significantly decreased immobility time. The spatial memory performance of OVX mice improved significantly in response to MOD administration in the Morris water-maze test. The OVX mice were characterized by an attenuation of hippocampal synaptic transmission and synaptic long-term potentiation and had fewer 5-ethynyl-2'-deoxyuridine-labeled cells in the dentate gyrus, which were restored after MOD administration. Antagonists of dopamine D and D receptors and GABA receptor agonists were involved in MOD-exerted anti-depressant actions and augments of hippocampal neurogenesis in OVX mice. Moreover, night-dosed MOD therapy significantly promoted the night-time delta-band EEG power during wakefulness and the day-time rapid eye movement sleep amount, which were significantly reduced by OVXs. Collectively, these findings suggest that MOD is a promising therapeutic candidate for menopausal women.
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http://dx.doi.org/10.1038/s41398-021-01229-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870893PMC
February 2021

The Rostromedial Tegmental Nucleus: Anatomical Studies and Roles in Sleep and Substance Addictions in Rats and Mice.

Nat Sci Sleep 2020 24;12:1215-1223. Epub 2020 Dec 24.

Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, People's Republic of China.

The rostromedial tegmental nucleus (RMTg), a brake of the dopamine system, is specifically activated by aversive stimuli, such as foot shock. It is principally composed of gamma-aminobutyric acid neurons. However, there is no exact location of the RMTg on the brain stereotaxic atlas. The RMTg can be defined by c-Fos staining elicited by psychostimulants, the position of retrograde-labeled neurons stained by injections into the ventral tegmental area (VTA), the terminal field formed by axons from the lateral habenula, and some molecular markers identified as specifically expressed in the RMTg such as FoxP1. The RMTg receives a broad range of inputs and produces diverse outputs, which indicates that the RMTg has multiple functions. First, the RMTg plays an essential role for non-rapid eye movement sleep. Additionally, the RMTg serves a vital role in response to addiction. Opiates increase the firing rates of dopaminergic neurons in the VTA by acting on μ-opioid receptors on RMTg neurons and their terminals inside the VTA. In this review, we summarize the recent research advances on the anatomical location of the RMTg in rats and mice, its projections, and its regulation of sleep-wake behavior and addiction.
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http://dx.doi.org/10.2147/NSS.S278026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769149PMC
December 2020

[Dry eye syndrome of deficient lacrima production treated with the acupoint thread-embedding therapy: a randomized controlled trial].

Zhongguo Zhen Jiu 2019 Jul;39(7):721-5

Zhejiang Chinese Medical University, Hangzhou 310053.

Objective: To compare the therapeutic effects on the relevant symtoms in the patients with dry eye syndrome treated with the acupoint thread-embedding therapy versus topical artificial tears eye drops.

Methods: A total of 88 patients with dry eye syndrome of deficiency lacrima production were randomized into an acupoint thread-embedding therapy group (thread-embedding group) and a control group with topical artificial tears eye drops (medication group), 44 cases in each one. In the thread-embedding group, 3 cases were dropped out. In the thread-embedding group, Ganshu (BL 18), Pishu (BL 20) and Shenshu (BL 23) etc. were selected and the acupoint thread-embedding therapy was operated once every 30 days, totally for two treatments. In the medication group, the topical artificial tears eye drops was used, 4 to 6 times a day, one drop each time, for 8 weeks totally. Separately, before treatment, after 4-week treatment and 8-week treatment as well as in 8 weeks and 12 weeks of the follow-up, the levels of lactoferrin in tears were determined and the scores of the relevant symptoms of ocular surface such as eye dryness, foreign body sensation in the eyes and eye fatigue were evaluated.

Results: In the thread-embedding group, after 4-week and 8-week of treatment as well as in 8-week and 12-week follow-up, the scores of eye dryness, foreign body sensation, burning sensation of eye, phengophobia and eye fatigue were reduced significantly as compared with those before treatment (all <0.05). In the medication group, the relevant symptoms of ocular surface were reduced after 4-week and 8-week treatment as compared with those before treatment (all <0.05). In the follow-up, the scores of the relevant symptoms of ocular surface in the thread-embedding group were significantly lower than the medication group (all <0.05). Separately, after 4-week treatment and 8-week treatment as well as in 8 weeks and 12 weeks of the follow-up, the levels of lactoferrin in tears in the thread-embedding group were significantly increased as compared with those before treatment (all <0.05). The change was not obvious as compared with that before treatment in the medication group (>0.05). The levels of lactoferrin in tears at each time point after treatment in the thread-embedding group were higher than the medication group (<0.05).

Conclusion: The acupoint thread-embedding therapy effectively improves in the relevant symptoms of ocular surface, such as eye dryness, foreign body sensation, burning sensation of eye, phengophobia and eye fatigue, and increases the level of lactoferrin in tears in the patients with dry eye syndrome of deficiency aqueous production. In the follow-up, the therapeutic effects of the acupoint thread-embedding therapy are significantly better than artificial tears eye drops.
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http://dx.doi.org/10.13703/j.0255-2930.2019.07.011DOI Listing
July 2019

Oxidative Stress Induces Neuronal Apoptosis Through Suppressing Transcription Factor EB Phosphorylation at Ser467.

Cell Physiol Biochem 2018 19;46(4):1536-1554. Epub 2018 Apr 19.

Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences University of Chinese Academy of Sciences, Shanghai, China.

Background/aims: This study determined the role and mechanism of action of transcription factor EB (TFEB) in H2O2-induced neuronal apoptosis.

Methods: SH-SY5Y cells were treated with Akt inhibitor/activator and different concentrations of H2O2. Cell apoptosis was detected by flow cytometric analysis. Akt and TFEB phosphorylation and PARP cleavage were determined by Western blotting. HEK293T cells were transfected with different truncated TFEB mutants and HA-Akt-WT; SH-SY5Y cells were transfected with Flag-vector, Flag-TFEB, Flag-TFEB-S467A or Flag-TFEB-S467D; and TFEB interaction with Akt was determined by co-immunoprecipitation and GST pull-down assays.

Results: A low concentration of H2O2 induces TFEB phosphorylation at Ser467 and nuclear translocation, facilitating neuronal survival, whereas a high concentration of H2O2 promotes SH-SY5Y cell apoptosis via suppressing TFEB Ser467 phosphorylation and nuclear translocation. The TFEB-S467D mutant is more easily translocated into the nucleus than the non-phosphorylated TFEB-S467A mutant. Further, Akt physically binds to TFEB via its C-terminal tail interaction with the HLH domain of TFEB and phosphorylates TFEB at Ser467. Mutation of TFEB-Ser467 can prevent the phosphorylation of TFEB by Akt, preventing inhibition of oxidative stress-induced apoptosis.

Conclusions: Oxidative stress induces neuronal apoptosis through suppressing TFEB phosphorylation at Ser467 by Akt, providing a novel therapeutic strategy for neurodegenerative diseases.
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http://dx.doi.org/10.1159/000489198DOI Listing
July 2018

The rostromedial tegmental nucleus is essential for non-rapid eye movement sleep.

PLoS Biol 2018 04 13;16(4):e2002909. Epub 2018 Apr 13.

Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China.

The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep-wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep-wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation.
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http://dx.doi.org/10.1371/journal.pbio.2002909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919677PMC
April 2018

Activation of the ventral tegmental area increased wakefulness in mice.

Sleep Biol Rhythms 2017;15(2):107-115. Epub 2017 Feb 24.

Department of Pharmacology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Box 229, Shanghai, 200032 China.

The ventral tegmental area (VTA) is crucial for brain functions, such as voluntary movement and cognition; however, the role of VTA in sleep-wake regulation when directly activated or inhibited remains unknown. In this study, we investigated the effects of activation or inhibition of VTA neurons on sleep-wake behavior using the pharmacogenetic "designer receptors exclusively activated by designer drugs (DREADD)" approach. Immunohistochemistry staining was performed to confirm the microinjection sites, and combined with electrophysiological experiments, to determine whether the VTA neurons were activated or inhibited. The hM3Dq-expressing VTA neurons were excited confirmed by clozapine-N-oxide (CNO)-driven c-Fos expression and firing in patch-clamp recordings; whereas the hM4Di-expressing VTA neurons inhibited by reduction of firing. Compared with controls, the activation of VTA neurons at 9:00 (inactive period) produced a 120.1% increase in the total wakefulness amount for 5 h, whereas NREM and REM sleep were decreased by 62.5 and 92.2%, respectively. Similarly, when VTA neurons were excited at 21:00 (active period), the total wakefulness amount increased 81.5%, while NREM and REM sleep decreased 64.6 and 93.8%, respectively, for 8 h. No difference of the amount and EEG power density of the NREM sleep was observed following the arousal effects of CNO. The inhibition of VTA neurons during active or inactive periods gave rise to no change in the time spent in the wakefulness, REM, and NREM sleep compared with control. The results indicated that VTA neurons activated pharmacogentically played important roles in promoting wakefulness.
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http://dx.doi.org/10.1007/s41105-017-0094-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362655PMC
February 2017

PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L-associated PI3K activity.

EMBO J 2016 Mar 1;35(5):496-514. Epub 2016 Feb 1.

Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China School of Life Sciences and Technology, Shanghai Tech University, Shanghai, China

The Beclin1-VPS34 complex is recognized as a central node in regulating autophagy via interacting with diverse molecules such as ATG14L for autophagy initiation and UVRAG for autophagosome maturation. However, the underlying molecular mechanism that coordinates the timely activation of VPS34 complex is poorly understood. Here, we identify that PAQR3 governs the preferential formation and activation of ATG14L-linked VPS34 complex for autophagy initiation via two levels of regulation. Firstly, PAQR3 functions as a scaffold protein that facilitates the formation of ATG14L- but not UVRAG-linked VPS34 complex, leading to elevated capacity of PI(3)P generation ahead of starvation signals. Secondly, AMPK phosphorylates PAQR3 at threonine 32 and switches on PI(3)P production to initiate autophagosome formation swiftly after glucose starvation. Deletion of PAQR3 leads to reduction of exercise-induced autophagy in mice, accompanied by a certain degree of disaggregation of ATG14L-associated VPS34 complex. Together, this study uncovers that PAQR3 can not only enhance the capacity of pro-autophagy class III PI3K due to its scaffold function, but also integrate AMPK signal to activation of ATG14L-linked VPS34 complex upon glucose starvation.
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http://dx.doi.org/10.15252/embj.201592864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772855PMC
March 2016

[Analysis on therapeutic effect of variable-frequency electroacupuncture combined with herbal-moxa moxibustion for post-zoster neuralgia].

Zhen Ci Yan Jiu 2012 Feb;37(1):64-6

The Third Affiliated Hospital of Zhejiang University of Chinese Medicine, Hang-zhou 310005, China.

Objective: To observe the clinical therapeutic effect of variable-frequency electroacupuncture (EA) combined with herbal-moxa moxibustion for regional neuralgia in herpes zoster (HZ) patients.

Methods: A total of 37 cases of HZ outpatients were randomized into treatment group (18 cases) and medication group (19 cases). For patients of the treatment group, EA (100 Hz for the 1st 10 min, then 2 Hz for 30 min) plus herbal-moxa roll (15 cm in length, containing components of corydalis tuber, astragali radix, myrrh, etc.) moxibustion (till local skin flushing, and the patient's warm feeling penetrated from the skin surface to the deeper subcutaneous tissues, ignited nine times repeatedly) was applied to Jiaji (EX-B 2) and Ashi-point, once daily for 7 days. Patients of the medication group were ordered to take Brufen (0.3 g, b. i. d.), vitamin B 1 (10 mg, t. i. d.) and vitamin E (100 mg, b. i. d). The visual analog scale (VAS) was used to assess the HZ patients' pain reaction before and after the therapy.

Results: After one course of treatment, of the 19 and 18 HZ patients in the medication and treatment groups, 1 (5.26%) and 5 (27.77%) were cured, 13 (68.42%) and 12 (66.67%) ameliorated, 5 (26.32%) and 1 (5.56%) invalid, with the total effective rates being 73.68% and 94.44% respectively. The therapeutic effect of the treatment group was significantly superior to that of the medication group (P < 0.05). VAS scores of both groups were decreased considerably following the treatment (P < 0.05), but showed no significant difference between the two groups (P > 0.05).

Conclusion: Variable-frequency EA plus herbal-moxa roll moxibustion is effective in relieving neuralgia of HZ patients.
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February 2012