BRITISH JOURNAL OF PHARMACOLOGY
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2021
·Vol. 178
·期 24
·4808-4825
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IF 8.74
Yan-Fei Yang,Hui Dong,Yan Shen,Lei Li,Michael Lazarus,Wei-Min Qu,Zhi-Li Huang
Background and Purpose Modafinil is a potent eugeroic (wakefulness-promoting) drug that is prescribed to treat narcolepsy and has a low incidence of abuse. Although previous studies have shown that modafinil-induced arousal depends on the dopamine receptors and transporters, the specific part/s of the dopamine transmitter system underlying this mechanism remained unclear. Here, we investigated the role of mesencephalic dopamine neurons in modafinil-evoked arousal. Experimental Approach A dopamine indicator (dLight1.1) was employed to detect dopamine changes in the nucleus accumbens (NAc) and dorsal striatum. We specifically lesioned mesencephalic dopamine neurons via diphtheria toxin (DTA) in the dopamine transporter (DAT)-Cre mice. Then, the sleep–wake states were recorded to evaluate the effect of modafinil on arousal. Finally, the extent of DTA-induced lesions was determined by immunohistochemistry. Key Results Modafinil promptly increased dopamine levels in the NAc and dorsal striatum in a dose-dependent manner. Lesioning of dopamine neurons in the substantia nigra pars compacta (SNc) or ventral tegmental area (VTA) had no significant effects on physiological sleep–wake cycles. Modafinil at 90 mg·kg −1 increased continuous wakefulness for 355 min in control mice. However, these effects were slightly decreased by 6.7% in the SNc-lesioned mice and were prominently diminished by 32.8% in VTA-lesioned mice. Furthermore, the modafinil-induced arousal was completely blocked in the SNc-VTA-lesioned mice, whereas lesions of the dorsal raphé nucleus had no effect. Conclusion and Implications Taken together, our findings indicate that mesencephalic dopamine neurons are essential for modafinil-induced arousal. Graphical
研究领域:
神经科学
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药理学
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睡眠医学
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DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2020
·Vol. 19
·期 3
·2326-2334
·
IF 1.785
Zi‑Wen Chen,Chao‑Bao Peng,Zhong Pei,Meng‑Ruo Zhang,Tian‑Chan Yun,Zhi‑Min Yang,Fu‑Ping Xu
Insomnia is a common sleep disorder with a high prevalence and substantial adverse consequences. There is growing interest in identifying novel therapeutics from herbal medicine. Tenuifolin is a major constituent of the well‑known anti‑insomnia herb Radix Polygala. The present study investigated the neural activity in response to tenuifolin during rest/wake behaviour in zebrafish and identified the potential biological signalling pathways involved. An automatic video tracking system was used to monitor the behavioural response of zebrafish larvae for 24 h after treatment with tenuifolin. In total, six rest/wake parameters were measured and visualized with a behavioural fingerprint. Time series analysis was conducted by averaging the total rest and waking activity in 10 min intervals. A correlation analysis was performed between tenuifolin and well‑known compounds to analyse the underlying biological signalling pathways. Reverse transcription‑quantitative PCR was also performed to detect the effects of tenuifolin on the transcription of interesting genes associated with the signalling pathways that were potentially involved. The present results suggested tenuifolin significantly increased the total rest time during the dark phase, with a slight effect on the waking activity in zebrafish larvae. This behavioural phenotype induced by tenuifolin is similar to that of selective serotonin reuptake inhibitors and gamma‑aminobutyric acid (GABA) agonists. Furthermore, the expression levels of GABA transporter 1 were significantly increased after tenuifolin treatment. No significant difference was determined in other associated genes in untreated control and tenuifolin‑treated larvae. The present results suggested that tenuifolin caused sleep‑promoting activity in zebrafish and that these effects may be mediated by the serotoninergic systems and the GABAergic systems.
研究领域:
神经科学
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药理学
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中药学
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分子生物学
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DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-18
·
IF 15.7
Xu Xiang-Ying,Xiao Yue,Liu Xu,Huang Yue,Ji Ying,Ji Yawei,Gao Yuan,Liu Su,Yang Jian-Jun,Cao Jun-Li,Zhou Chunyi,Xiao Cheng
Much progress has been made in the understanding of the neural circuits associated with sleep and anesthesia. As an important component among these circuits, the forebrain nuclei have been frequently interrogated. This study demonstrates that glutamatergic (Glu) neurons in the ventral pallidum (VP) enhance activity upon salient stimuli and state-dependently modulate brain arousal and motor activity in freely behaving male mice, and bidirectionally regulate the induction of and emergence from isoflurane general anesthesia. We delineate a neural pathway, consisting of VP Glu neurons→ noradrenergic (NA) neurons in the locus coeruleus (LC)→the lateral hypothalamus (LH) in male mice, controlling the release of noradrenaline in the LH and state-dependently modulated brain arousal, motor activity, and isoflurane general anesthesia through α2a receptors in the LH. Therefore, the VP Glu -LC NA -LH pathway and α2a receptors in the LH may be promising state-dependent regulators of brain arousal in both freely behaving and anesthetized states.
研究领域:
神经科学
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麻醉学
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行为学
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DOI
PubMed
高影响因子
Cell Metabolism
·
2025
·
IF 30.9
Lianxia Guo,Yifei Xiao,Zanjin Li,Yuwei Huang,Haobin Cen,Zicong Wu,Hongbo Wang,Xinyu Liu,Zhehan Yang,Caifeng Zhao,Tingying Hao,Hui Chen,Meng Jin,Danyi Lu,Min Chen,Baojian Wu
The intestinal clock plays a role in transmitting feeding signals and generating circadian events, but how this clock system may time homeostatic processes related to sleep-wake regulation is unknown. Our functional dissections of the circadian clock in intestinal epithelial cells (IECs) demonstrate that its integrity is required for maintenance of the diurnal sleep-wake cycle. In IECs, BMAL1 generates diurnal rhythmic SLC6A19 expression that promotes intestinal absorption of glutamine during the active phase, which enhances glutamatergic neuron activities in hypothalamic nuclei and contributes to increased wakefulness and decreased sleep. The involvement of glutamine homeostasis in sleep-wake regulation is also pronounced during the rest phase, as an elevation of glutamine in the rest phase caused by IEC deficiency of REV-ERBα is causally linked to sleep abnormalities characterized by reduced sleep. Overall, the intestinal clock shapes the diurnal sleep-wake cycle through temporally gating glutamine homeostasis and serves as a potential target for boosting the sleep rhythm and for managing sleep disorders.
研究领域:
时间生物学
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神经科学
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代谢学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 23
·12888
·
IF 4.9
Ziwei Hao,Yuting Han,Qi Zhao,Minghui Zhu,Xiaoxuan Liu,Yingyu Yang,Ning An,Dinglin He,Etienne Lefai,Kenneth B. Storey,Hui Chang,Manjiang Xie
Hibernating mammals experience severe hemodynamic changes over the torpor–arousal cycle, with oxygen consumption reaching peaks during the early stage of torpor to re-enter arousal. Melatonin (MT) can improve mitochondrial function and reduce oxidative stress and inflammation. However, the regulatory mechanisms of MT action on the vascular protective function of hibernators are still unclear. Morphology, hemodynamic, mitochondrial oxidative stress, and inflammatory factors of the carotid artery were assessed in ground squirrels who were sampled during summer active (SA), late torpor (LT), and interbout arousal (IBA) conditions. Changes were assessed by methods including hematoxylin and eosin staining, color Doppler ultrasound, ELISA, Western blots, and qPCR. Changes in arterial blood and serum melatonin were also measured by blood gas analyzer and ELISA, whereas mitochondrial oxidative stress and inflammation factors of primary vascular smooth muscle cells (VSMCs) were assessed by qPCR. (1) Intima-media carotid thickness, peak systolic velocity (PSV), end diastolic blood flow velocity (EDV), maximal blood flow rate (Vmax) and pulsatility index (PI) were significantly decreased in the LT group as compared with the SA group, whereas there were no difference between the SA and IBA groups. (2) PO2, oxygen saturation, hematocrit and PCO2in the arterial blood were significantly increased, and pH was significantly decreased in the LT group as compared with the SA and IBA groups. (3) The serum melatonin concentration was significantly increased in the LT group as compared with the SA and IBA groups. (4) MT treatment significantly reduced the elevated levels of LONP1, NF-κB, NLRP3 and IL-6 mRNA expression of VSMCs under hypoxic conditions. (5) Protein expression of HSP60 and LONP1 in the carotid artery were significantly reduced in the LT and IBA groups as compared with the SA group. (6) The proinflammatory factors IL-1β, IL-6, and TNF-α were reduced in the carotid artery of the LT group as compared with the SA and IBA groups. The carotid artery experiences no oxidative stress or inflammatory response during the torpor–arousal cycle. In addition, melatonin accumulates during torpor and alleviates oxidative stress and inflammatory responses caused by hypoxia in vitro in VSMCs from ground squirrels.
研究领域:
生理学
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分子生物学
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神经科学
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心血管研究
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2023
·
IF 6.8
Jialu Luan,Shuhui Zhang,Yixin Xu,Liang Wen,Xizeng Feng
Polyglycolic acid (PGA) is an emerging biodegradable plastic material. Together with polylactic acid (PLA), PGA is considered a suitable alternative to conventional plastics and has been widely used in biomedical and food packaging industries. However, degradable plastics continue to face the drawbacks of harsh degradation environment and long degradation time, and may harm the environment and the human body. Therefore, our study focused on assessing the effects of degradable microplastics PGA and PLA on the development and neurobehavior of zebrafish. The results showed that PGA and PLA had little effect on 3–10 hpf embryos. However, developmental stunting was observed in a100 mg/L PGA and PLA-exposed group at 24 hpf. In addition, PGA and PLA exposure decreased the survival and hatching rates, increased wakefulness, and reduced sleep in zebrafish. This indicates that PGA and PLA may affect the circadian behavior of zebrafish by affecting the brain–derived neurotrophic factor (BDNF). Therefore, our results suggest that PGA and PLA exposure induces developmental toxicity, reduces voluntary locomotion, induces of anxiety–like behaviors, and impairs sleep/wake behaviors in zebrafish larvae. This also suggests that the potentially toxic effects of degradable plastics cannot be ignored and that the biological effects of PGA require further research.
研究领域:
环境科学
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毒理学
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发育生物学
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神经科学
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DOI
PubMed
高影响因子
NEURON
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2022
·
IF 18.688
Yu-Ting Tseng,Binghao Zhao,Shanping Chen,Jialin Ye,Jingjing Liu,Lisha Liang,Hui Ding,Bernhard Schaefke,Qin Yang,Lina Wang,Feng Wang,Liping Wang
Summary When an animal faces a threatening situation while asleep, rapid arousal is the essential prerequisite for an adequate response. Here, we find that predator stimuli induce immediate arousal from REM sleep compared with NREM sleep. Using in vivo neural activity recording and cell-type-specific manipulations, we identify neurons in the medial subthalamic nucleus (mSTN) expressing corticotropin-releasing hormone (CRH) that mediate arousal and defensive responses to acute predator threats received through multiple sensory modalities across REM sleep and wakefulness. We observe involvement of the same neurons in the normal regulation of REM sleep and the adaptive increase in REM sleep induced by sustained predator stress. Projections to the lateral globus pallidus (LGP) are the effector pathway for the threat-coping responses and REM-sleep expression. Together, our findings suggest adaptive REM-sleep responses could be protective against threats and uncover a critical component of the neural circuitry at their basis.
研究领域:
神经科学
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睡眠研究
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行为神经科学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 18
·10248
·
IF 6.208
Yuting Han,Weilan Miao,Ziwei Hao,Ning An,Yingyu Yang,Ziwen Zhang,Jiayu Chen,Kenneth B. Storey,Etienne Lefai,Hui Chang
Hibernators are a natural model of vascular ischemia–reperfusion injury; however, the protective mechanisms involved in dealing with such an injury over the torpor–arousal cycle are unclear. The present study aimed to clarify the changes in the thoracic aorta and serum in summer-active (SA), late-torpor (LT) and interbout-arousal (IBA) Daurian ground squirrels (Spermophilus dauricus). The results show that total antioxidant capacity (TAC) was unchanged, but malondialdehyde (MDA), hydrogen peroxide (H2O2), interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) were significantly increased for the LT group, whereas the levels of superoxide dismutase (SOD) and interleukin-10 (IL-10) were significantly reduced in the LT group as compared with the SA group. Moreover, the levels of MDA and IL-1β were significantly reduced, whereas SOD and IL-10 were significantly increased in the IBA group as compared with the SA group. In addition, the lumen area of the thoracic aorta and the expression of the smooth muscle cells (SMCs) contractile marker protein 22α (SM22α) were significantly reduced, whereas the protein expression of the synthetic marker proteins osteopontin (OPN), vimentin (VIM) and proliferating cell nuclear antigen (PCNA) were significantly increased in the LT group as compared with the SA group. Furthermore, the smooth muscle layer of the thoracic aorta was significantly thickened, and PCNA protein expression was significantly reduced in the IBA group as compared with the SA group. The contractile marker proteins SM22α and synthetic marker protein VIM underwent significant localization changes in both LT and IBA groups, with localization of the contractile marker protein α-smooth muscle actin (αSMA) changing only in the IBA group as compared with the SA group. In tunica intima, the serum levels of heparin sulfate (HS) and syndecan-1 (Sy-1) in the LT group were significantly reduced, but the serum level of HS in the IBA group increased significantly as compared with the SA group. Protein expression and localization of endothelial nitric oxide synthase (eNOS) was unchanged in the three groups. In summary, the decrease in reactive oxygen species (ROS) and pro-inflammatory factors and increase in SOD and anti-inflammatory factors during the IBA period induced controlled phenotypic switching of thoracic aortic SMCs and restoration of endothelial permeability to resist ischemic and hypoxic injury during torpor of Daurian ground squirrels.Keywords:torpor–arousal;ischemia–reperfusion;thoracic aortic;phenotypic switching;permeability
研究领域:
生理学
·
生物化学
·
分子生物学
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血管生物学
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产品关联
DOI
PubMed
高影响因子
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