Journal of Advanced Research
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2025
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IF 13
Qu-Nan Wang,Chunzhi Wang,Yán Wāng
Introduction The extensive use of 6PPD in tire rubber has led to its increase in atmospheric tire wear particles. 6PPD reacts with ozone to form 6PPD-quinone (6PPD-Q), a respiratory toxicant enriched in tire and road wear particles. Objectives The aim of this study is to decipher the potential sensitive target organs and toxic actions by inhalation exposure to atmospheric 6PPD-Q. Methods This study employed a mouse inhalation exposure model to simulate environmental levels of 6PPD-Q at three concentrations of 0, 0.14, and 14 mg/m 3 . Using a 28-day exposure period followed by an equivalent recovery phase, we systematically evaluated the toxicological targets and effects of subacute exposure. Results The findings revealed that, compared to pulmonary, cardiovascular, and metabolic organ damage, 6PPD-Q-induced neurotoxicity was more persistent and irreversible, particularly characterized by prolonged anxiety-like behaviors. Histopathological analyses of the basolateral amygdala, using Nissl staining and markers of neuronal aging, indicated substantial neuronal degeneration linked to elevated oxidative stress, identifying this region as a critical target of 6PPD-Q neurotoxicity. Transcriptomic analysis uncovered that the expression of Egr1 , a transcription factor crucial for neuronal plasticity, was markedly dysregulated. Findings of significant downregulation at the gene level and an upward trend in protein expression suggest that Egr1 expression is influenced by translational efficiency, epigenetic modifications, and post-translational regulatory mechanisms. Egr1 dysregulation disrupted downstream networks involving solute carrier proteins and calcium-binding proteins, contributing to aberrant neurobehavioral outcomes. Notably, the elevation of Egr1 protein levels in the basolateral amygdala but not in the cerebral cortex highlights the region-specific nature of 6PPD-Q’s neurotoxic effects. Conclusion This study provides the first insights into the neurotoxicity and irreversibility of inhaled 6PPD-Q exposure, paving the way for future research into the long-term neurological consequences and regulatory mechanisms of 6PPD-Q.
研究领域:
毒理学
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神经科学
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环境健康
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DOI
PubMed
高影响因子
BEHAVIOURAL BRAIN RESEARCH
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2025
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IF 2.3
Yue-Heng Yan,Hong-Kun Wang,Zi-Hao Wang,Rui-Ze Wang,Ruo-Xuan Li,Li-Li Huang,Yan-Yan Wang
NMDA receptors (NMDAR) are vital in CNS activities such as anxiety, memory, and cognition, and the neurobiological mechanisms behind anxiety disorders are exceedingly complicated. The "glutamic acid theory" posits that glutamate excitotoxicity is a key pathophysiological mechanism in anxiety disorders. However, the exact mechanism by which conditioned fear contributes to anxiety disorders remains unknown.Based on the conditioned fear-induced anxiety disorder model, this work aims to investigate changes in NMDAR and related proteins throughout the acquisition and expression of fear memory, as well as the impact on synaptic structural and functional plasticity. Injecting the NMDA receptor endogenous agonist D-Serine (50 μg/μL) and the noncompetitive antagonist MK-801 (1 μg/μL) into the lateral ventricle of the conditioned fear model rats, as well as conducting behavioral observations, show that NMDAR are closely involved in the development of conditioned fear-induced anxiety. Model rats showed significant changes in glutamate (Glu) and γ-aminobutyric acid (GABA) levels in the amygdala (BLA), as well as expression of NMDAR and downstream BDNF/TrkB signaling pathway components. At the same time, model rats exhibited synaptic and neuronal injury, aberrant long-term potentiation (LTP), and decreased expression of essential synaptic proteins SYP and PSD-95. In conclusion, our study demonstrates that NMDAR and synaptic plasticity play a critical role in the development of conditioned fear-induced anxiety, serving as an important reference for understanding the neurobiological underpinnings of anxiety disorders and providing insights into their treatment and new possible targets.
研究领域:
神经科学
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行为学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Rong-Xin Song,Xiao-Yi Ma,Ting-Ting Zhou,Zhi-Fang Yu,Jun Wang,Bao-Dong Li,Yu-Mo Jing,Han Wang,Yue Fu,Rui-Zhao Lv,Shi-Yan Jia,Xiao-Ming Li,Li-Min Zhang
Objective Hemorrhagic shock and resuscitation (HSR) cause inflammatory responses in the gastrointestinal tract and is associated with substantial morbidity and mortality rates. Hydrogen sulfide (H 2 S), a gasotransmitter with pleiotropic activity, exhibits anti-inflammatory benefits at physiological levels. However, deleterious effects are observed when its concentration increases. In this investigation, we employed a mouse model of HSR to examine the effects of an H 2 S scavenger on the gastrointestinal tract and brain, with emphasis on N-Methyl- d -Aspartate (NMDA) receptor function. Methods Mice were immediately administered dl -propargylglycine (PAG) intragastrically as an H 2 S scavenger after HSR exposure. The O-maze and buried beads tests were used to assess compulsive- and anxiety-like behaviors. Pathological changes in the intestine were evaluated at 24 and 30 days after HSR. Subsequently, at 30 days after HSR, we examined electrophysiological and pathological changes in the amygdala. Results Within 24 h of HSR exposure, animals treated with PAG showed significantly lower colonic injury. Additionally, compared to the HSR-treated mice 30 days after HSR, the PAG-treated mice displayed reduced buried beads, increased open-arm time, lower blood levels of Diamine Oxidase (DAO) and considerably improved ZO-1 intensity, a stronger association between the delta rhythm phase and beta activity amplitude, and lower neuroinflammatory response in the amygdala. MK-801, an NMDA receptor inhibitor, significantly reversed H 2 S-induced intestinal and cerebral injury. Conclusion This experimental data suggests that H 2 S-induced excessive activation of NMDA receptors contributes to anxiety- and compulsive-like behaviors caused by HSR.
研究领域:
神经科学
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药理学
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病理生理学
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行为科学
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DOI
PubMed
高影响因子
NEURON
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2024
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IF 14.7
Xinyi Zhou,Qian Xiao,Yaohui Liu,Shuai Chen,Xirong Xu,Zhigang Zhang,Yuchuan Hong,Jie Shao,Yuewen Chen,Yu Chen,Liping Wang,Fan Yang,Jie Tu
Assessing and responding to threats is vital in everyday life. Unfortunately, many mental illnesses involve impaired risk assessment, affecting patients, families, and society. The brain processes behind these behaviors are not well understood. We developed a transgenic mouse model (disrupted-in-schizophrenia 1 [DISC1]-N) with a disrupted avoidance response in risky settings. Our study utilized single-nucleus RNA sequencing and path-clamp coupling with real-time RT-PCR to uncover a previously undescribed group of glutamatergic neurons in the basolateral amygdala (BLA) marked by Wolfram syndrome 1 (WFS1) expression, whose activity is modulated by adjacent astrocytes. These neurons in DISC1-N mice exhibited diminished firing ability and impaired communication with the astrocytes. Remarkably, optogenetic activation of these astrocytes reinstated neuronal excitability via D-serine acting on BLA WFS1 neurons’ NMDA receptors, leading to improved risk-assessment behavior in the DISC1-N mice. Our findings point to BLA astrocytes as a promising target for treating risk-assessment dysfunctions in mental disorders.
研究领域:
神经科学
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分子生物学
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行为科学
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精神病学
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DOI
PubMed
高影响因子
Advanced Science
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2024
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IF 14.3
Ping-Fen Yang,Tai-Lei Nie,Xia-Nan Sun,Lan-Xin Xu,Cong Ma,Fang Wang,Li-Hong Long,Jian-Guo Chen
Physical exercise has beneficial effect on anxiety disorders, but the underlying molecular mechanism remains largely unknown. Here, it is demonstrated that physical exercise can downregulate the S-nitrosylation of gephyrin (SNO-gephyrin) in the basolateral amygdala (BLA) to exert anxiolytic effects. It is found that the level of SNO-gephyrin is significantly increased in the BLA of high-anxiety rats and a downregulation of SNO-gephyrin at cysteines 212 and 284 produced anxiolytic effect. Mechanistically, inhibition of SNO-gephyrin by either Cys212 or Cys284 mutations increased the surface expression of GABA A R γ2 and the subsequent GABAergic neurotransmission, exerting anxiolytic effect in male rats. On the other side, overexpression of neuronal nitric oxide synthase in the BLA abolished the anxiolytic-like effects of physical exercise. This study reveals a key role of downregulating SNO-gephyrin in the anxiolytic effects of physical exercise, providing a new explanation for protein post-translational modifications in the brain after exercise.
研究领域:
神经科学
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分子生物学
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行为科学
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DOI
PubMed
高影响因子
Molecular Brain
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2019
·Vol. 12
·期 1
·1-12
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IF 4.051
Wang Xin-shang,Guan Shao-yu,Liu An,Yue Jiao,Hu Li-ning,Zhang Kun,Yang Liu-kun,Lu Liang,Tian Zhen,Zhao Ming-gao,Liu Shui-bing
Chronic pain is commonly accompanied with anxiety disorder, which complicates treatment. In this study, we investigated the analgesic and anxiolytic effects of Formononetin (FMNT), an active component of traditional Chinese medicine red clover ( Trifolium pratense L.) that is capable of protecting neurons from N-methyl-D-aspartate (NMDA)-evoked excitotoxic injury, on mice suffering from complete Freund’s adjuvant (CFA)-induced chronic inflammatory pain. The results show that FMNT administration significantly reduces anxiety-like behavior but does not affect the nociceptive threshold in CFA-injected mice. The treatment reverses the upregulation of NMDA, GluA1, and GABA A receptors, as well as PSD95 and CREB in the basolateral amygdala (BLA). The effects of FMNT on NMDA receptors and CREB binding protein (CBP) were further confirmed by the potential structure combination between these compounds, which was analyzed by in silico docking technology. FMNT also inhibits the activation of the NF-κB signaling pathway and microglia in the BLA of mice suffering from chronic inflammatory pain. Therefore, the anxiolytic effects of FMNT are partially due to the attenuation of inflammation and neuronal hyperexcitability through the inhibition of NMDA receptor and CBP in the BLA.
研究领域:
药理学
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神经科学
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疼痛研究
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传统中药
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DOI
PubMed
高影响因子
ANDROLOGIA
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2018
·Vol. 51
·期 1
·e13160
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IF 1.588
Guotao Chen,Jianhuai Chen,Baibing Yang,Wen Yu,Yun Chen,Yutian Dai
Nonorganic erectile dysfunction is a problem with unknown central mechanisms. Changes in brain activity in the amygdala have been observed in human patients. This study aimed to investigate the dopamine system in the basolateral amygdala of male rats with nonorganic erectile dysfunction. We applied chronic mild stress to induce nonorganic erectile dysfunction. After exposure to chronic mild stress, the sucrose consumption test, sexual behaviour test and apomorphine test were used to select depression-like rats with erectile dysfunction as nonorganic erectile dysfunction model rats. The sexual behaviour of these rats after central infusion of a dopamine D1/D2 receptor agonist/antagonist was observed. The expression levels of dopamine D1/D2 receptors and tyrosine hydroxylase in the basolateral amygdala were also measured. The result of the sucrose consumption test, sexual behaviour test and apomorphine test indicated a successful nonorganic erectile dysfunction model. Central infusion of a dopamine D2 receptor agonist increased intromission ratio in model rats. Lower expression levels of tyrosine hydroxylase and the dopamine D2 receptor in the basolateral amygdala were observed in rats with nonorganic erectile dysfunction. These results suggest that impairment of the dopamine D2 receptor pathway in the basolateral amygdala may contribute to the development of nonorganic erectile dysfunction.
研究领域:
神经科学
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药理学
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性医学
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DOI
PubMed
高影响因子
Frontiers in Neuroscience
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2022
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IF 5.152
Fan Penghui,Song Yilin,Lu Botao,Wang Yiding,Dai Yuchuan,Xie Jingyu,He Enhui,Xu Zhaojie,Yang Gucheng,Mo Fan,Liu Juntao,Wang Mixia,Cai Xinxia
The medial amygdala (MA) plays an important role in the innate fear circuit. However, the electrophysiological mechanism of MA for processing innate fear needs to be further explored. In this study, we fabricated microelectrode arrays (MEAs) with detecting sites arranged to match the location and shape of MA in mice and detected the electrophysiology in freely behaving mice under 2-methyl-2-thiazoline (2MT)-induced fear. The detection performance of MEA is improved by modifying metal nanoparticles and conductive polymers (PtNPs/PEDOT:PSS). After modification, the impedance magnitude and phase of electrodes were decreased to 27.0 ± 2.3 kΩ and −12.30 ± 0.52°, respectively, leading to a signal-to-noise ratio of 10. Its electrochemical stability and mechanical stability were also verified by cyclic voltammetry (CV) sweeping and ultrasonic vibration. MEAs were then implanted into the MA of mice, and the electrophysiology and behavioral characteristics were synchronously recorded and analyzed. The results showed that 2MT induced strong defensive behaviors in mice, accompanied by increases in the average spike firing rate and local field potential (LFP) power of MA neurons. According to principles commonly applied to cortical extracellular recordings, the recorded neurons are divided into two classes based on waveforms. Statistics showed that about 37% of type 1 neurons (putative GABAergic neurons) and 87% of type 2 neurons (putative glutamatergic neurons) were significantly activated under innate fear. At the same time, the firing rate of some activated neurons had a good linear correlation with the freezing rate.
研究领域:
神经科学
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电生理学
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行为科学
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DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
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2024
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IF 14.7
Ruizhe Nie,Xinting Zhou,Jiaru Fu,Shanshan Hu,Qilu Zhang,Weikai Jiang,Yizi Yan,Xian Cao,Danhua Yuan,Yan Long,Hao Hong,Susu Tang
Anxiety disorders are one of the most epidemic and chronic psychiatric disorders. An incomplete understanding of anxiety pathophysiology has limited the development of highly effective drugs against these disorders. GPR17 has been shown to be involved in multiple sclerosis and some acute brain injury disorders. However, no study has investigated the role of GPR17 in psychiatric disorders. In a well-established chronic restraint stress (CRS) mouse model, using a combination of pharmacological and molecular biology techniques, viral tracing, in vitro electrophysiology recordings, in vivo fiber photometry, chemogenetic manipulations and behavioral tests, we demonstrated that CRS induced anxiety-like behaviors and increased the expression of GPR17 in basolateral amygdala (BLA) glutamatergic neurons. Inhibition of GPR17 by cangrelor or knockdown of GPR17 by adeno-associated virus in BLA glutamatergic neurons effectively improved anxiety-like behaviors. Overexpression of GPR17 in BLA glutamatergic neurons increased the susceptibility to anxiety-like behaviors. What's more, BLA glutamatergic neuronal activity was required for anxiolytic-like effects of GPR17 antagonist and GPR17 modulated anxiety-like behaviors via BLA to ventral hippocampal CA1 glutamatergic projection. Our study finds for the first and highlights the new role of GPR17 in regulating anxiety-like behaviors and it might be a novel potential target for therapy of anxiety disorders.
研究领域:
神经科学
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药理学
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分子生物学
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行为科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NEUROSCIENCE
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2024
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IF 4.4
Jing Chen,Yuan Gao,Shu-Ting Bao,Ying-Di Wang,Tao Jia,Cui Yin,Cheng Xiao,Chunyi Zhou
The comorbidity of chronic pain and depression poses tremendous challenges for the treatment of either one because they exacerbate each other with unknown mechanisms. As the posterior insular cortex (PIC) integrates multiple somatosensory and emotional information and is implicated in either chronic pain or depression, we hypothesize that the PIC and its projections may contribute to the pathophysiology of comorbid chronic pain and depression. We show that PIC neurons were readily activated by mechanical, thermal, aversive, and stressful and appetitive stimulation in naïve and neuropathic pain male mice subjected to spared nerve injury (SNI). Optogenetic activation of PIC neurons induced hyperalgesia and conditioned place aversion in naïve mice, whereas inhibition of these neurons led to analgesia, conditioned place preference (CPP), and antidepressant effect in both naïve and SNI mice. Combining neuronal tracing, optogenetics, and electrophysiological techniques, we found that the monosynaptic glutamatergic projections from the PIC to the basolateral amygdala (BLA) and the ventromedial nucleus in the thalamus (VM) mimicked PIC neurons in pain modulation in naïve mice; in SNI mice, both projections were enhanced accompanied by hyperactivity of PIC, BLA and VM neurons, and inhibition of these projections led to analgesia, CPP, and antidepressant-like effect. The present study suggests that potentiation of the PIC-BLA and PIC-VM projections may be important pathophysiological bases for hyperalgesia and depression-like behavior in neuropathic pain, and reversing the potentiation may be a promising therapeutic strategy for comorbid chronic pain and depression.Significance Statement Treatment of chronic pain is quite challenging because of the involvement of central sensitization and emotional disorders. It is keenly demanding to search for brain circuits commonly or separately contributing to hyperalgesia and emotional dysfunction in chronic pain. The PIC is involved in both pain and emotional processing. But, the relationship between the malfunction in the PIC and the comorbidity of chronic pain and depression has not been elucidated. Here, we demonstrate that in chronic pain, PIC neurons became hyperactive, and their projections to the BLA and the VM of the thalamus were augmented; these alterations may confer hyperalgesia and depression-like behaviors in chronic pain. Therefore, these pathways may be potential therapeutic targets for comorbid chronic pain and depression.
研究领域:
神经科学
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疼痛研究
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行为神经科学
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神经回路
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DOI
PubMed
高影响因子
NEURON
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2024
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IF 14.7
Ming Li,Xue-Ke Yang,Jian Yang,Tong-Xia Li,Chi Cui,Xiang Peng,Jie Lei,Kun Ren,Jie Ming,Pei Zhang,Bo Tian
Erasing traumatic memory during memory reconsolidation is a promising retrieval-extinction strategy for post-traumatic stress disorder (PTSD). Here, we developed an acute social defeat stress (SDS) mouse model with short-term and re-exposure-evoked long-term social avoidance. SDS-associated traumatic memories were identified to be stored in basolateral amygdala (BLA) engram cells. A single intraperitoneal administration of subanesthetic-dose ketamine within, but not beyond, the re-exposure time window significantly alleviates SDS-induced social avoidance, which reduces the activity and quantity of reactivated BLA engram cells. Furthermore, activation or inhibition of dopaminergic projections from the ventral tegmental area to the BLA effectively mimics or blocks the therapeutic effect of re-exposure with ketamine and is dopamine D2 receptor dependent. Single-cell RNA sequencing reveals that re-exposure with ketamine triggered significant changes in memory-related pathways in the BLA. Together, our research advances the understanding of how ketamine mitigates PTSD symptoms and offers promising avenues for developing more effective treatments for trauma-related disorders.
研究领域:
神经科学
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精神病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Neuroscience
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2022
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IF 5.152
Ting-Ting Pan,Chao Liu,De-Min Li,Tian-Hao Zhang,Wei Zhang,Shi-Lun Zhao,Qi-Xin Zhou,Bin-Bin Nie,Gao-Hong Zhu,Lin Xu,Hua Liu
Animal contextual fear conditioning (CFC) models are the most-studied forms used to explore the neural substances of posttraumatic stress disorder (PTSD). In addition to the well-recognized hippocampal-amygdalar system, the retrosplenial cortex (RSC) is getting more and more attention due to substantial involvement in CFC, but with a poor understanding of the specific roles of its two major constituents-dysgranular (RSCd) and granular (RSCg). The current study sought to identify their roles and underlying brain network mechanisms during the encoding processing of the rat CFC model. Rats with pharmacologically inactivated RSCd, RSCg, and corresponding controls underwent contextual fear conditioning. [ 18 F]-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) scanning was performed for each animal. The 5-h and 24-h retrieval were followed to test the formation of contextual memory. Graph theoretic tools were used to identify the brain metabolic network involved in encoding phase, and changes of nodal (brain region) properties linked, respectively, to disturbed RSCd and RSCg were analyzed. Impaired retrieval occurred in disturbed RSCd animals, not in RSCg ones. The RSC, hippocampus (Hip), amygdala (Amy), piriform cortex (Pir), and visual cortex (VC) are hub nodes of the brain-wide network for contextual fear memory encoding in rats. Nodal degree and efficiency of hippocampus and its connectivity with amygdala, Pir, and VC were decreased in rats with disturbed RSCd, while not in those with suppressed RSCg. The RSC plays its role in contextual fear memory encoding mainly relying on its RSCd part, whose condition would influence the activity of the hippocampal-amygdalar system.
研究领域:
神经科学
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行为神经科学
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精神病学
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神经成像
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DOI
PubMed
高影响因子
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