Role of the anterior insular cortex microcircuits in observation fear of mice / 中国药理学与毒理学杂志

OBJECTIVE Fear can be learned indi-rectly,but excessive transmission of fear is essential for the development of mental illness.Previous research has indicated that the anterior insular cortex(AIC)may play a crucial role in the process of fear transmission,and abnormal AIC activity is a possible mechanism under-lying various affective disorders.Inhibitory neurons are crucial for maintaining local microcircuit homeostasis.With the support of novel specific neuroregulatory tech-niques,it is now possible to monitor and regulate differ-ent types of neurons in real-time.Therefore,investigating distinct subtypes of inhibitory neurons in the AIC that are involved in fear contagion may provide valuable insights into potential mechanisms underlying mental disorders.METHODS We established a modified observational fear(OF)model.A demonstrator(DM)mouse was placed in an acrylic cup at the center of the apparatus,and two observer(OB)mice were allowed to explore the DM mouse simultaneously from separate areas on either side.During the OF training,electric foot shocks were administered to the DM mouse and freezing,the side and corner time,and social interaction behavior were scored.Next,we characterized the activity patterns of distinct neuronal subtypes in the AIC using GCaMP-based calcium recording.Finally,we employed a Cre-dependent optogenetic approach to selectively modulate excitatory or inhibitory neurons in the AIC,and investigat-ed empathic fear behavior across different Cre transgenic mouse lines(CK2-Cre,PV-Cre,SOM-Cre,VIP-Cre).RESULTS During the training phase,the OB mice exhib-ited significantly higher levels of fear compared to the control group(which did not observe a traumatic event),as evidenced by increased freezing time,decreased interaction time,and increased corner zone time.Calcium fiber recording results suggested that CK2 neurons are involved in risk prediction,while PV and VIP neurons exert inhibitory control on this behavior.Optogenetic silencing of CK2-positive neurons in the AIC through injection of AAV-DIO-NpHR-mCherry in mice demon-strated a significant reduction in empathic fear.Similarly,activation of PV or VIP inhibitory neurons expressing ChR2-eYFP also resulted in a similar effect.However,activation of SOM neurons led to a significant increase in empathic fear.CONCLUSION Our study demonstrated that VIP and PV neuron activity in the AIC attenuates empathetic fear,while SOM and CK2 neuron activity enhances fear expression.These findings shed light on the distinct contributions of various inhibitory interneu-rons in the AIC to fear contagion,indicating their mutual interaction for maintaining local microcircuit homeostasis that regulates empathetic fear behaviors.

A new mouse model to study the empathic fear and pain behavior / 中国药理学与毒理学杂志

OBJECTIVE Human beings possess the ability to indirectly acquire the emotions of others.This also known as emotional contagion or empathy,enables us to rapidly perceive the emotions of others.However,an excessive empathy may result in heightened fear and sensitivity to pain.Therefore,the establishment of appropri-ate animal models for analyzing neural mechanisms underlying empathy would contribute to pharmacological research on pain sensitivity caused by psychological sus-ceptibility.METHODS We used the observed fear para-digm for assessing contagion of negative emotions in mice.To minimize the impact of emotional contagion dif-ferences caused by the subject change,we established a bilateral observation area and the two mice were trained to observe fear simultaneously.First,two observer(OB)mice were placed on either side of the observational area.Next,a demonstrator(DM)mouse was introduced into the cylindrical shock cage located at the center of the apparatus.The shock cage is made of transparent organic plastic with air holes and has provided ample space for free movement by the DM mouse.During the shock stage,DM mice were subjected to electric stimulation while the behaviors of OB mice on both sides was observed,including freezing,the side and corner time,social interaction behavior.Additionally,c-Fos staining was utilized to confirm distinct local brain activities.RESULTS In the habituation stage,OB mice on both sides showed more social preference for DM mouse,as evidenced by an increase in duration time in the designat-ed interaction zone.During the shock phase,OB mice observed the DM mouse receiving electric shocks and displayed significantly higher levels of fear contagion;however,their fear behavior was not entirely consistent.Some mice exhibited a significant increase in freezing time,while others demonstrated a significant increase in corner and side exploration time.We utilized Z-normal-ization to evaluate changes in emotionality across vari-ous behaviors and identified mice with distinct susceptibil-ities.Fos-positive neurons exhibited higher expression levels in susceptible OB mice,primarily concentrated within brain regions associated with the ascending path-ways of pain perception,such as thalamus,the anterior insular cortex,and anterior cingulate cortex.CONCLU-SION In this study,we have developed an innovative experimental facility that integrates various behavioral tests to evaluate empathic behavior in mice.Our findings highlight the robustness of emotionality measures obtained from individual mice by combining this experi-mental model with the Z-scoring method,facilitating screening for empathic fear or pain-susceptible mice and will helpful for pharmacological evaluation.

Poly(ADP-ribose)polymerase inhibitors for ovarian cancer treatment:research advances / 国际药学研究杂志

Ovarian cancer is the leading cause of death in women suffering from cancer,with a high mortality rate in gyneco?logical cancer. Poly(ADP-ribose)polymerase(PARP)inhibitors cause targeted tumor cell death in homologous recombination(HR)-deficient cancers,including breast cancer susceptibility gene(BRCA)tumors,and the mechanism is calledsynthetic lethality. At present,there are three PARP inhibitors approved by FDA for the treatment of advanced ovarian cancer with BRCA-mutation. This pa?per reviews the role of PARP inhibitors in the treatment of ovarian cancer in clinical trial,elaborates the therapeutic mechanism of PARP inhibitors,and lights the way for the development of anti-ovarian cancer drugs.

Effects of diterpene ginkgolides meglumine injection on neurotransmitters in cerebral ischemia-reperfusion injury rats / 中国药理学通报

Aim To investigate the effects of diterpene ginkgolides meglumine injection (DGMI ) on amino acids and monoamine neurotransmitters in rats with cerebral ischemia/reperfusion injury.Methods In-traluminal suture was applied to establish middle cere-bral artery occlusion (MCAO/R)model with ischemia for 1.5 h and reperfusion for 24 h.After the adminis-tration of DGMI (i.v.),the levels of amino acid and monoamine neurotransmitters in brain tissue were de-tected through HPLC-ECD.Results DGMI down-reg-ulated the concentrations of aspartic acid, glutamic acid,glycine and γ-aminobutyric acid which were in-creased in MCAO/R group.DGMI also reduced the levels of norepinephrine epinephrine,glyoxylic acid, serotonin and 5-HIAA in cortex and hippocampus,and increased adrenaline content compared to the model group.Conclusion DGMI exhibits a protective role in rats with cerebral ischemia /reperfusion injury through regulating amino acids and monoamine neuro-transmitters.

Exploration of the experimental conditions of drug affinity responsive target stability / 国际药学研究杂志

Objective To explore the optimal proteolysis condition for the new technology of target discovery ,drug affinity responsive target stability(DARTS). Methods First,in order to determine the suitable pronase concentration range for DARTS,the extraction of human acute T lymphoblastic leukemia cells(Jurkat)were digested with a range of pronase concentrations(the mass ratio of pronase to protein was 1∶100 to 1∶10000)at room temperature and detected by SDS-PAGE and Coomassie brilliant blue stain?ing. On this basis,in order to obtain the optimal proteolysis condition,we performed DARTS onα-ketoglutarate in combination with SDS-PAGE and gel staining,and observed the effect of different concentrations of pronase(1∶500-1∶5000)and different proteolysis time(5-30 min)on DARTS. The feasibility of the optimum condition was verified by using it on a target known small molecule ,myco?phenolic acid. Results When the protein extraction of Jurkat was hydrolyzed by a range of pronase concentrations,it was entirely hy?drolysed by pronase 1∶100 while showing no significant effect under the condition of pronase 1∶10000. The effect of pronase 1∶500 to 1∶5000 on protein mixture was milder. And approximately 30%-60%of the protein was digested. The protein bands which were protected byα-ketoglutarate could be observed apparently under the conditon of pronase 1∶1000 when the proteolysis time was about 15 min. Then we performed DARTS on mycophenolic acid utilizing this condition(pronase 1∶1000,hydrolysed for 15 min)and obtained sev?eral visible protected protein bands between(4-7)×104. Western blotting results showed that the target protein of mycophenolic acid , IMPDH1,was contained in the protected protein bands. Conclusion The optimal proteolysis condition for DARTS on protein mix?ture throughα-ketoglutarate is obtained.

Epidemic situation and prevention strategy of schistosomiasis in Ya’an City after Lushan Earthquake on April 20,2013 / 中国血吸虫病防治杂志

This paper analyzes the recently epidemic status of schistosomiasis,the change of natural and social factors,and field survey and evaluation data of schistosomiasis in Ya’an City after Lushan Earthquake on April 20,2013,and proposes that it is necessary to strengthen the conventional schistosomiasis control measures,the control of exogenous infection sources,the con-trol of Oncomelania hupensis snails and health education for ensuring no major epidemics after the disaster. This paper also recom-mends the direction and suggestions for future schistosomiasis control in Ya’an City.