Stress-altering anterior insular cortex activity affects risk decision-making behavior in mice of different sexes.

Stress can affect people's judgment and make them take risky decisions. Abnormal decision-making behavior is a core symptom of psychiatric disorders, such as anxiety, depression, and substance abuse. However, the neuronal mechanisms underlying such impairments are largely unknown. The anterior insular cortex (AIC) is a crucial structure to integrate sensory information with emotional and motivational states. These properties suggest that AIC can influence a subjective prediction in decision-making. In this study, we demonstrated that stressed mice prefer to take more risky choices than control mice using a gambling test. Manipulating the neural activity of AIC or selectively inhibiting the AIC-BLA pathway with chemogenetic intervention resulted in alterations in risk decision-making in mice. Different sexes may have different decision-making strategies in risky situations. Endogenous estrogen levels affect emotional cognition by modulating the stress system function in women. We observed decision-making behavior in mice of different sexes with or without stress experience. The result showed that female mice did not change their choice strategy with increasing risk/reward probability and performed a lower risk preference than male mice after stress. Using the pharmacological method, we bilaterally injected an estrogen receptor (ER) antagonist that resulted in more risky behavior and decreased synaptic plasticity in the AIC of female mice. Our study suggested that the AIC is a crucial region involved in stress-induced alteration of decision-making, and estrogen in the AIC may regulate decision-making behavior by regulating synaptic plasticity.

A modified mouse model for observational fear learning and the influence of social hierarchy.

Background: Indirectly experiencing traumatic events either by witnessing or learning of a loved one's suffering is associated with the highest prevalence rates of epidemiological features of PTSD. Social species can develop fear by observing conspecifics in distress. Observational fear learning (OFL) is one of the most widely used paradigms for studying fear contagion in mice. However, the impact of empathic fear behavior and social hierarchy on fear transfer in mice is not well understood. Methods: Fear emotions are best characterized in mice by using complementary tests, rather than only freezing behavior, and simultaneously avoiding behavioral variability in different tests across time. In this study, we modified the OFL model by implementing freezing (FZ), open field (OF), and social interaction (SI) tests in a newly designed experimental facility and applied Z-normalization to assess emotionality changes across different behaviors. Results: The integrated emotionality scores revealed a robustly increased emotionality of observer mice and, more importantly, contributed to distinguishing susceptible individuals. Interestingly, fos-positive neurons were mainly found in the interoceptive network, and mice of a lower social rank showed more empathy-like behaviors. Conclusion: Our findings highlight that combining this experimental model with the Z-scoring method yields robust emotionality measures of individual mice, thus making it easier to screen and differentiate between empathic fear-susceptible mice and resilient mice, and refining the translational applicability of these models.

Glaucocalyxin A alleviates lipopolysaccharide-induced inflammation and apoptosis in pulmonary microvascular endothelial cells and permeability injury by inhibiting STAT3 signaling.

Glaucocalyxin A (GLA), an ent-kauranoid diterpene derived from Rabdosia japonica var. glaucocalyx, possesses antibacterial, anti-oxidative and anti-neuroinflammatory properties. The present study aimed to investigate the potential mechanisms underlying GLA in the pathogenesis of pneumonia. Human pulmonary microvascular endothelial cells (hPMVECs) treated with lipopolysaccharide (LPS) were treated with GLA, followed by the detection of cell viability, inflammation, apoptosis and cell permeability. Furthermore, the protein expression levels of apoptosis- and permeability-associated proteins were determined using western blot analysis. Following treatment with a signal transducer and activator of transcription 3 (STAT3) activator, the protein expression levels of STAT3 and endoplasmic reticulum stress-associated proteins were determined, to confirm whether STAT3 signaling was mediated by GLA. Lastly, the mRNA expression level of inflammatory cytokines, apoptosis and permeability injury were also determined following treatment with a STAT3 activator. The results revealed that GLA ameliorated inflammation, apoptosis and permeability injury in LPS-induced hPMVECs. Following treatment with a STAT3 activator, the therapeutic effects of GLA on LPS-induced hPMVECs were abrogated. In conclusion, GLA alleviated LPS-induced inflammation, apoptosis and permeability injury in hPMVECs by inhibiting STAT3 signaling, which highlighted the potential therapeutic value of GLA in the treatment of pneumonia.

Active Fraction Combination From Liuwei Dihuang Decoction Improves Adult Hippocampal Neurogenesis and Neurogenic Microenvironment in Cranially Irradiated Mice.

Background: Cranial radiotherapy is clinically used in the treatment of brain tumours; however, the consequent cognitive and emotional dysfunctions seriously impair the life quality of patients. LW-AFC, an active fraction combination extracted from classical traditional Chinese medicine prescription Liuwei Dihuang decoction, can improve cognitive and emotional dysfunctions in many animal models; however, the protective effect of LW-AFC on cranial irradiation-induced cognitive and emotional dysfunctions has not been reported. Recent studies indicate that impairment of adult hippocampal neurogenesis (AHN) and alterations of the neurogenic microenvironment in the hippocampus constitute critical factors in cognitive and emotional dysfunctions following cranial irradiation. Here, our research further investigated the potential protective effects and mechanisms of LW-AFC on cranial irradiation-induced cognitive and emotional dysfunctions in mice. Methods: LW-AFC (1.6 g/kg) was intragastrically administered to mice for 14 days before cranial irradiation (7 Gy γ-ray). AHN was examined by quantifying the number of proliferative neural stem cells and immature neurons in the dorsal and ventral hippocampus. The contextual fear conditioning test, open field test, and tail suspension test were used to assess cognitive and emotional functions in mice. To detect the change of the neurogenic microenvironment, colorimetry and multiplex bead analysis were performed to measure the level of oxidative stress, neurotrophic and growth factors, and inflammation in the hippocampus. Results: LW-AFC exerted beneficial effects on the contextual fear memory, anxiety behaviour, and depression behaviour in irradiated mice. Moreover, LW-AFC increased the number of proliferative neural stem cells and immature neurons in the dorsal hippocampus, displaying a regional specificity of neurogenic response. For the neurogenic microenvironment, LW-AFC significantly increased the contents of superoxide dismutase, glutathione peroxidase, glutathione, and catalase and decreased the content of malondialdehyde in the hippocampus of irradiated mice, accompanied by the increase in brain-derived neurotrophic factor, insulin-like growth factor-1, and interleukin-4 content. Together, LW-AFC improved cognitive and emotional dysfunctions, promoted AHN preferentially in the dorsal hippocampus, and ameliorated disturbance in the neurogenic microenvironment in irradiated mice. Conclusion: LW-AFC ameliorates cranial irradiation-induced cognitive and emotional dysfunctions, and the underlying mechanisms are mediated by promoting AHN in the dorsal hippocampus and improving the neurogenic microenvironment. LW-AFC might be a promising therapeutic agent to treat cognitive and emotional dysfunctions in patients receiving cranial radiotherapy.

Role of the anterior agranular insular cortex in the modulation of fear and anxiety.

The insular cortex, anatomically close to amygdala, is also an integrative hub for sensory, emotional and cognitive function. Growing body of evidences suggest that alterations in insular structure and function have also been implicated in anxiety disorders. However, the reciprocal connections and precise subdivision of insular cortex involved in anxiety activities remains mechanistically unclear. In the present study, using anterograde and retrograde tracing methods, we verified that the anterior (AIa) but not posterior (AIp) agranular insular cortex is a major source of projections to the amygdala. Consistently, excitotoxic lesions only in AIa induced the anxiolytic behaviors and impaired fear memory. Using optogenetics methods, we found that selectively photoactivation of AIa GABAergic neurons remarkably promoted cued fear extinction and relieved anxiety in PSTD mice model. Finally, the participation of AIa in the storage of learned fear is also supported by the abolished LTP after fear conditioning and decreased the cued freezing using protein synthesis inhibitor immediately following training. Our results underscore the importance of AIa in fear and anxiety behavior and suggest that the AIa might share functions and interaction with amygdala in in anxiety related disorders.

[Efficacy analysis of prussian blue or its combination with hemoperfusion in the treatment of acute thallium poisoning].

OBJECTIVE: To investigate the efficacy of prussian blue (PB) or its combination with hemoperfusion (HP) in the treatment of acute thallium poisoning. METHODS: Forty-seven patients with acute thallium poisoning with complete data hospitalized in the 307th Hospital of PLA from September 2002 to December 2017 were enrolled, and they were divided into mild poisoning group (blood thallium < 150 µg/L, urinary thallium < 1 000 µg/L) and moderate-severe poisoning group (blood thallium ≥ 150 µg/L, urinary thallium ≥ 1 000 µg/L) according to the toxic degrees. All patients were given symptomatic supportive treatments such as potassium supplementation, catharsis, vital organ protections, neurotrophic drugs, and circulation support. The mild poisoning patients were given PB with an oral dose of 250 mg×kg-1×d-1, while moderate-severe poisoning patients were given PB combined HP continued 2-4 hours each time. The PB dose or frequency of HP application was adjusted according to the monitoring results of blood and urine thallium. Data of gender, age, pain grading (numeric rating scale NRS), clinical manifestations, blood and urine thallium before and after treatment, length of hospitalization and prognosis were collected. RESULTS: Of the 47 patients, patients with incomplete blood and urine test results, and used non-single HP treatment such as plasmapheresis and hemodialysis for treatment were excluded, and a total of 29 patients were enrolled in the analysis. (1) Among 29 patients, there were 20 males and 9 females, median age of 40.0 (34.0, 49.0) years old; the main clinical manifestations were nervous system and alopecia, some patients had digestive system symptoms. There were 13 patients (44.8%) in the mild poisoning group with painless (grade 0) or mild pain (grade 1-3) with mild clinical symptoms, the length of hospitalization was 17.0 (14.2, 21.5) days. There were 16 patients (55.2%) in the moderate-severe poisoning group with moderate pain (grade 4-6) or severe pain (grade 7-10) with severe clinical symptoms, the length of hospitalization was 24.0 (18.0, 29.0) days. (2) After treatment, the thallium concentrations in blood and urine in the mild poisoning group were significantly lower than those before treatment [µg/L: blood thallium was 0.80 (0, 8.83) vs. 60.00 (40.00, 120.00), urine thallium was 11.30 (0, 70.10) vs. 370.00 (168.30, 610.00), both P < 0.01], the thallium concentrations in blood and urine in the moderate-severe poisoning group were also significantly lower than those before treatment [µg/L: blood thallium was 6.95 (0, 50.50) vs. 614.50 (245.00, 922.00), urinary thallium was 20.70 (1.95, 283.00) vs. 5 434.00 (4 077.20, 10 273.00), both P < 0.01]. None of the 29 patients died, and their clinical symptoms were improved significantly. All the 27 patients had good prognosis without sequela in half a year follow-up, and 2 patients with severe acute thallium poisoning suffered from nervous system injury. CONCLUSIONS: In the acute thallium poisoning patients, on the basis of general treatment, additional PB in mild poisoning group and PB combined with HP in moderate-severe poisoning group can obtain satisfactory curative effects.

Kainate receptor mediated presynaptic LTP in agranular insular cortex contributes to fear and anxiety in mice.

Anxiety disorders represent serious social problems worldwide. Recent neuroimaging studies have found that elevated activity and altered connectivity of the insular cortex might account for the negative emotional states in highly anxious individuals. However, the exact synaptic mechanisms of specific insular subregions have yet to be studied in detail. To assess the electrophysiological properties of agranular insular cortex (AIC) neurons, basic synaptic transmission was recorded and different protocols were used to induce presynaptic and postsynaptic long-term potentiation in mice with anxiety-related behaviors. The presynaptic membrane expression of kainate receptors (KARs) and pharmacologic manipulations were quantified to examine the role of Gluk1 subtype in anxiety-like behaviors. Fear conditioning occludes electrically induced postsynaptic-LTP in the AIC. Quantal analysis of LTP expression in this region revealed a significant presynaptic component reflected by an increase in the probability of transmitter release. A form of presynaptic-LTP that requires KARs has been characterized. Interestingly, a simple emotional anxiety stimulus resulted in selective occlusion of presynaptic-LTP, but not of postsynaptic-LTP. Finally, injecting GluK1-specific antagonists into the AIC reduced behavioral responses to fear or anxiety stimuli in the mouse. These findings suggest that activity-dependent synaptic plasticity takes place in the AIC due to exposure to fear or anxiety, and inhibiting the presynaptic KAR function may help to prevent or treat anxiety disorder.

Notch1 deficiency in postnatal neural progenitor cells in the dentate gyrus leads to emotional and cognitive impairment.

It is well known that Notch1 signaling plays a crucial role in embryonic neural development and adult neurogenesis. The latest evidence shows that Notch1 also plays a critical role in synaptic plasticity in mature hippocampal neurons. So far, deeper insights into the function of Notch1 signaling during the different steps of adult neurogenesis are still lacking, and the mechanisms by which Notch1 dysfunction is associated with brain disorders are also poorly understood. In the current study, we found that Notch1 was highly expressed in the adult-born immature neurons in the hippocampal dentate gyrus. Using a genetic approach to selectively ablate Notch1 signaling in late immature precursors in the postnatal hippocampus by cross-breeding doublecortin (DCX)+ neuron-specific proopiomelanocortin (POMC)-α Cre mice with floxed Notch1 mice, we demonstrated a previously unreported pivotal role of Notch1 signaling in survival and function of adult newborn neurons in the dentate gyrus. Moreover, behavioral and functional studies demonstrated that POMC-Notch1-/- mutant mice showed anxiety and depressive-like behavior with impaired synaptic transmission properties in the dentate gyrus. Finally, our mechanistic study showed significantly compromised phosphorylation of cAMP response element-binding protein (CREB) in Notch1 mutants, suggesting that the dysfunction of Notch1 mutants is associated with the disrupted pCREB signaling in postnatally generated immature neurons in the dentate gyrus.-Feng, S., Shi, T., Qiu, J., Yang, H., Wu, Y., Zhou, W., Wang, W., Wu, H. Notch1 deficiency in postnatal neural progenitor cells in the dentate gyrus leads to emotional and cognitive impairment.

A new chiral pyrrolyl α-nitronyl nitroxide radical attenuates ß-amyloid deposition and rescues memory deficits in a mouse model of Alzheimer disease.

The generation of reactive oxygen species causes cellular oxidative damage, and has been implicated in the etiology of Alzheimer's disease (AD). L-NNNBP, a new chiral pyrrolyl α-nitronyl nitroxide radical synthesized in our department, shows potential antioxidant effects. The purpose of this study was to investigate the protective effects of L-NNNBP on ß-amyloid (Aß) deposition and memory deficits in an AD model of APP/PS1 mice. In cultured cortical neurons, L-NNNBP acted as an antioxidant by quenching reactive oxygen species, inhibiting lipid peroxidation, nitrosative stress, and stimulating cellular antioxidant defenses. L-NNNBP inhibited cell apoptosis induced by Aß exposure. In vivo treatment with L-NNNBP for 1 month induced a marked decrease in brain Aß deposition and tau phosphorylation in the blinded study on APP/PS1 transgenic mice (1 mM in drinking water, initiated when the mice were 6 months old). The L-NNNBP-treated APP/PS1 mice showed decreased astrocyte activation and improved spatial learning and memory compared with the vehicle-treated APP/PS1 mice. These actions were more potent compared with that of curcumin, a natural product, and TEMPO, a nitroxide radical, which are used as free radical scavengers in clinics. These results proved that the newly synthesized L-NNNBP was an effective therapeutic agent for the prevention and treatment of AD.

Long-lasting effects of chronic rTMS to treat chronic rodent model of depression.

Repetitive transcranial magnetic stimulation (rTMS) has been demonstrated in the pre-clinical and clinical settings to have an antidepressant effect. However, studies on the long-lasting effect of rTMS, especially when the effect is measured after treatment has ceased for a few weeks is lacking. We examined this question in a chronic unpredicted mild stress (CUMS) rat model of depression. We gave 3 weeks of high frequency (15 Hz) rTMS, venlafaxine, or these two treatments combined to a modified CUMS paradigm, and then investigated the prolonged effect of treatments. Behavioral testing (sucrose preference test, open field test, forced swimming test, novelty suppressed feeding test), plasma hormone level, hippocampal BrdU labeling, and amount of related neurotropic factors were used to assess the effects of stress and treatments. Long-term chronic rTMS significantly reversed andehonic-like behavior, increased hippocampus cell proliferation, BDNF protein level, phosphorylation of ERK1/2 compared with CUMS rats two weeks after the cessation of rTMS treatment. However, the changes in plasma hormone level were not sustained for that amount of time. Venlafaxine had no interaction with the physical stimulation. Our results suggest that high frequency rTMS has long-lasting effects, which may have some relationship with neuroplasticity.

G-protein-coupled receptor 30 mediates rapid neuroprotective effects of estrogen via depression of NR2B-containing NMDA receptors.

17-ß-estradiol (E2) is a steroid hormone involved in neuroprotection against excitotoxicity and other forms of brain injury. Through genomic and nongenomic mechanisms, E2 modulates neuronal excitability and signal transmission by regulating NMDA and non-NMDA receptors. However, the mechanisms and identity of the receptors involved remain unclear, even though studies have suggested that estrogen G-protein-coupled receptor 30 (GPR30) is linked to protection against ischemic injury. In the culture cortical neurons, treatment with E2 and the GPR30 agonist G1 for 45 min attenuated the excitotoxicity induced by NMDA exposure. The acute neuroprotection mediated by GPR30 is dependent on G-protein-coupled signals and ERK1/2 activation, but independent on transcription or translation. Knockdown of GPR30 using short hairpin RNAs (shRNAs) significantly reduced the E2-induced rapid neuroprotection. Patch-clamp recordings revealed that GPR30 activation depressed exogenous NMDA-elicited currents. Short-term GPR30 activation did not affect the expression of either NR2A- or NR2B-containing NMDARs; however, it depressed NR2B subunit phosphorylation at Ser-1303 by inhibiting the dephosphorylation of death-associated protein kinase 1 (DAPK1). DAPK1 knockdown using shRNAs significantly blocked NR2B subunit phosphorylation at Ser-1303 and abolished the GPR30-mediated depression of exogenous NMDA-elicited currents. Lateral ventricle injection of the GPR30 agonist G1 (0.2 µg) provided significant neuroprotection in the ovariectomized female mice subjected to middle cerebral artery occlusion. These findings provide direct evidence that fast neuroprotection by estradiol is partially mediated by GPR30 and the subsequent downregulation of NR2B-containing NMDARs. The modulation of DAPK1 activity by GPR30 may be an important mediator of estradiol-dependent neuroprotection.

Electroconvulsive therapy improves antipsychotic and somnographic responses in adolescents with first-episode psychosis--a case-control study.

OBJECTIVE: Previous studies have demonstrated the effectiveness of electroconvulsive therapy (ECT) in pharmacotherapy-resistant neuropsychiatric conditions. This study aimed to evaluate the efficacy and safety of ECT in adolescents with first-episode psychosis. METHOD: This case-control study was conducted in inpatients aged 13-20 years with first-episode psychosis. Every three similar age and same gender patients consecutively recruited were randomly allocated to control and ECT group at a ratio of 1:2, while they had antipsychotic treatment. ECT treatment was performed for 3 sessions per week with a maximum of 14 sessions. The endpoint was discharge from hospital. Clinical outcomes were measured using hospital stay days, the Positive and Negative Syndrome Scale (PANSS) and response rate. Polysomnography (PSG) was conducted at baseline and at week 2. Safety and tolerability were also evaluated. RESULTS: Between March 2004 and November 2009, 112 eligible patients were allocated to control (n=38) and ECT (n=74) group. Additional ECT treatment significantly reduced hospital stay compared to controls (23.2±8.2 days versus 27.3±9.3 days, mean±SD, P=0.018). Survival analysis revealed that the ECT-treated group had a significantly higher cumulative response rate than controls (74.3% versus 50%, relative risk (RR)=1.961, P=0.001). Additional ECT also produced significantly greater improvement in sleep efficiency, rapid eye movement (REM) latency and density than control condition. The PSG improvement significantly correlated with reduction in scores on overall PANSS, positive symptoms, and general psychopathology. No patients discontinued ECT treatment regimen during hospital stay. The incidence of most adverse events was not different in the two groups, but ECT-treated group had more complaints of transient headache and dizziness than controls. CONCLUSIONS: ECT is an effective and safe intervention used in adolescents with first-episode psychosis. Its antipsychotic effects are associated with improved PSG variables. ECT can be considered as an early psychosis intervention.

Neuroprotective effects of Salidroside and its analogue tyrosol galactoside against focal cerebral ischemia in vivo and H2O2-induced neurotoxicity in vitro.

Salidroside (Sal) is a natural antioxidant extracted from the root of Rhodiola rosea L. that elicits neuroprotective effects in vivo and in vitro. Tyrosol galactoside (Tyr), an analog of Sal, was recently synthesized in our laboratory. The purpose of the current study was to investigate and compare the neuroprotective effects of Sal and Tyr against focal cerebral ischemia in vivo and H(2)O(2)-induced neurotoxicity in vitro. Sal and Tyr significantly prevented a cerebral ischemic injury induced by a 2 h middle cerebral artery occlusion and a 24 h reperfusion in rats in vivo. Furthermore, the oxidative insult was markedly attenuated by treatments of Sal and Tyr in the cultured rat cortical neurons after a 30 min exposure to 50 µM of H(2)O(2). Western blot analysis revealed that Sal and Tyr decreased the expression of Bax and restored the balance of pro- and anti-apoptotic proteins. The neuroprotective effects of these two analogues show that Tyr has a better antioxidative action compared with Sal both in vivo and in vitro, and suggest that the antioxidant activity of Sal and Tyr may be partly due to their different substituents in their glycosyl groups. This gives a new insight into the development of therapeutic natural antioxidants against oxidative stress.

Electroacupuncture pretreatment ameliorates hypergravity-induced impairment of learning and memory and apoptosis of hippocampal neurons in rats.

High-sustained positive acceleration (+Gz) exposures might lead to impairment in cognitive function. Our previous studies have shown that electroacupuncture (EA) pretreatment can attenuate transient focal cerebral ischemic injury in the rats. In this study we aimed to investigate whether EA pretreatment could ameliorate the impairment of learning and memory induced by a sustained +Gz exposure. Using the centrifuge model, rats of experimental groups were exposed to +10 Gz for 5 min. Morris water maze was used for assessing the cognitive ability, and the apoptotic hippocampal CA1 pyramidal neuronal cells were evaluated by caspase-3 activity and TUNEL staining. Our results showed that +Gz exposure significantly caused pyramidal neuronal damage, increased neuronal apoptosis and caspase-3 activity in hippocampal CA1 region, as well as resulted in an impairment of spatial learning and memory, as compared to the sham group animals. Furthermore, the EA pretreatment significantly attenuated the neuronal apoptosis, preserved neuronal morphology and inhibited the caspase-3 activity in hippocampal CA1 region resulted from +Gz exposure. The EA pretreatment also ameliorated the learning and memory function in rats exposed to +Gz. These findings indicate that EA pretreatment provides a novel method to prevent the cognitive damage caused by +Gz, which could significantly protect neuronal damage and impairment of learning and memory.

Hyperbaric oxygen preconditioning ameliorates anxiety-like behavior and cognitive impairments via upregulation of thioredoxin reductases in stressed rats.

The present study examined the protective effect of hyperbaric oxygen preconditioning (HBO-PC) and the role of thioredoxin reductase (TrxR) in a post-traumatic stress disorder (PTSD)-induced rat model by using single prolonged stress (SPS). Rats were randomly divided into Sham, HBO, SPS and HBO+SPS groups. HBO-PC was conducted by exposing rats to 100% oxygen at 2.5atm absolute for 1h each day for 5 consecutive days. SPS was performed 24h after the last HBO-PC conditioning event. At 1h, 6h, 12h, 24h and 72h after SPS, TrxR mRNA expression was analyzed in the hippocampus; Nissl and TUNEL staining were performed at 72h after SPS. The results indicated that HBO-PC was able to significantly preserve viable neurons in the CA1 subfield of hippocampus following SPS exposure, as evidenced by reduced amounts of CA1 neuronal apoptosis. Furthermore, HBO-PC upregulate the expression of TrxR-1 and TrxR-2 mRNA in the hippocampus at 6h and 12h after SPS exposure and ameliorated anxiety-like behavior and cognitive impairments normally induced by SPS. Taken together, these findings suggest that HBO-PC is beneficial for the improvement of anxiety-like behavior and cognitive impairments induced by SPS exposure, and this effect might be associated with inhibition of neuronal apoptosis via upregulation of TrxR in stressed rats.