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Aims Negative emotions induced by chronic pain are a serious clinical problem. Electroacupuncture (EA) is a clinically proven safe and effective method to manage pain‐related negative emotions. However, the circuit mechanisms underlying the effect of EA treatment on negative emotions remain unclear. Methods Plantar injection of complete Freund's adjuvant (CFA) was performed to establish a rat model of chronic inflammatory pain‐induced anxiety‐like behaviors. Adeno‐associated virus (AAV) tracing was used to identify excitatory synaptic transmission from the rostral anterior cingulate cortex (rACC) to the dorsal raphe nucleus (DRN). Employing chemogenetic approaches, we examined the role of the rACC‐DRN circuit in chronic pain‐induced anxiety‐like behaviors and investigated whether EA could reverse chronic pain‐induced dysfunctions of the rACC‐DRN circuit and anxiety‐like behaviors. Results We found that chemogenetic activation of the rACC‐DRN circuit alleviated CFA‐induced anxiety‐like behaviors, while chemogenetic inhibition of the rACC‐DRN circuit resulted in short‐term CFA‐induced anxiety‐like behaviors. Further research revealed that the development of CFA‐induced anxiety‐like behaviors was attributed to the dysfunction of rACC CaMKII neurons projecting to DRN serotonergic neurons (rACCCaMKII‐DRN5‐HT neurons) but not rACC CaMKII neurons projecting to DRN GABAergic neurons (rACCCaMKII‐DRNGABA neurons). This is supported by the findings that chemogenetic activation of the rACCCaMKII‐DRN5‐HT circuit alleviates anxiety‐like behaviors in rats with chronic pain, whereas neither chemogenetic inhibition nor chemogenetic activation of the rACCCaMKII‐DRNGABA circuit altered CFA chronic pain‐evoked anxiety‐like behaviors in rats. More importantly, we found that EA could reverse chronic pain‐induced changes in the activity of rACC CaMKII neurons and DRN 5‐HTergic neurons and that chemogenetic inhibition of the rACCCaMKII‐DRN5‐HT circuit blocked the therapeutic effects of EA on chronic pain‐induced anxiety‐like behaviors. Conclusions Our data suggest that the reversal of rACCCaMKII‐DRN5‐HT circuit dysfunction may be a mechanism underlying the therapeutic effect of EA on chronic pain‐induced anxiety‐like behaviors. Chronic inflammatory pain induces anxiety‐like behaviors, and electroacupuncture ameliorates negative emotions by intervening rACCCaMKII‐DRN5‐HT neural circuit but not the rACCCaMKII‐DRNGABA circuit.

Introduction Women are more vulnerable to stress‐related disorders than men, which is counterintuitive as female sex hormones, especially estrogen, have been shown to be protective against stress disorders. Methods In this study, we investigated whether two different models of stress act differently on ovariectomized (OVX) rats and the impact of estrogen on physical or psychological stress‐induced impairments in cognitive‐behaviors. Adult female Wistar rats at 21–22 weeks of age were utilized for this investigation. Sham and OVX rats were subjected to physical and psychological stress for 1 hr/day for 7 days, and cognitive performance was assessed using morris water maze (MWM) and passive avoidance (PA) tests. The open field and elevated plus maze tests (EPM) evaluated exploratory and anxiety‐like behaviors. Results In sham and OVX rats, both physical and psychological stressors were associated with an increase in EPM‐determined anxiety‐like behavior. OVX rats exhibited decreased explorative behavior in comparison with nonstressed sham rats (p < .05). Both physical stress and psychological stress resulted in disrupted spatial cognition as assayed in the MWM (p < .05) and impaired learning and memory as determined by the PA test when the OVX and sham groups were compared with the nonstressed sham group. Estrogen increased explorative behavior, learning and memory (p < .05), and decreased anxiety‐like behavior compared with vehicle in OVX rats exposed to either type of stressor. Conclusions When taken together, estrogen and both stressors had opposite effects on memory, anxiety, and PA performance in a rat model of menopause, which has important implications for potential protective effects of estrogen in postmenopausal women exposed to chronic stress. Findings from the current study delineated that exposure to both physical stress and psychological stress can cause cognitive disorders and increase anxiety‐like behaviors. These findings suggest that female rats are vulnerable to both stressor types, and effects impact motor and cognitive behaviors of the animals.

Aims This study aimed to investigate the relationship between ulcerative colitis (UC) and anxiety and explore its central mechanisms using colitis mice. Methods Anxiety‐like behavior was assessed in mice induced by 3% dextran sodium sulfate (DSS) using the elevated plus maze and open‐field test. The spatial transcriptome of the hippocampus was analyzed to assess the distribution of excitatory and inhibitory synapses, and Toll‐like receptor 4 (TLR4) inhibitor TAK‐242 (10 mg/kg) and AAV virus interference were used to examine the role of peripheral inflammation and central molecules such as Glutamate Receptor Metabotropic 1 (GRM1) in mediating anxiety behavior in colitis mice. Results DSS‐induced colitis increased anxiety‐like behaviors, which was reduced by TAK‐242. Spatial transcriptome analysis of the hippocampus showed an excitatory‐inhibitory imbalance mediated by glutamatergic synapses, and GRM1 in hippocampus was identified as a critical mediator of anxiety behavior in colitis mice via differential gene screening and AAV virus interference. Conclusion Our work suggests that the hippocampus plays an important role in brain anxiety caused by peripheral inflammation, and over‐excitation of hippocampal glutamate synapses by GRM1 activation induces anxiety‐like behavior in colitis mice. These findings provide new insights into the central mechanisms underlying anxiety in UC and may contribute to the development of novel therapeutic strategies for UC‐associated anxiety. Anxious behavior in mice with colitis was associated with an imbalance in hippocampal excitatory inhibition due to the overactivation of glutamate synapses. Peripheral suppression of colon inflammation or downregulation of GRM1 expression by AAV virus interference can significantly improve anxiety‐like behavior.

Objective Chronic stress is considered a severe risk factor leading to various disorders, including anxiety and cognitive decline. The present study aimed to investigate the effects of Origanum vulgare (oregano) extract on improving anxiety‐like behavior and learning and memory defection caused by chronic unpredictable stress (CUS). Method A 10‐day CUS protocol was executed on male rats, and on day 10, their anxiety, learning, and memory status were evaluated. After that, in addition to the CUS, the rats were treated with the oregano extract for 2 weeks. Then, the expression of BDNF, TrkB, and TLR2/4 genes in the hippocampus and prefrontal cortex of the rats was evaluated. Also, the liver‐ and kidney‐related serum parameters, including triglycerides, total cholesterol, HDL, LDL, creatinine, urea, serum glucose, alanine aminotransferase, and aspartate aminotransferase were assessed. Further, the extract's lethal effect and its impact on animals’ body weight were investigated. Results Behavioral tests confirmed the anxiety‐like behavior and learning–memory function impairment caused by CUS. In contrast, the administration of the extract could significantly alleviate the mental deficiencies and diminished anxiety‐like behaviors. Molecular assessments showed that CUS could markedly decrease the BDNF and TrkB genes’ expression levels while increasing that of TLR2 and TLR4. In contrast, in extract‐treated animals, mRNA levels of BDNF and TrkB considerably increased, yet TLR2 and TLR4 mRNA levels reduced. Additionally, consumption of the extract caused weight gain, while having no lethality and detrimental effect on the liver and kidneys functions. Conclusions These findings indicate the anxiolytic properties of the extract and its improving effect on cognitive dysfunction.

Purpose Research has documented a high prevalence of cognitive and affective impairments in individuals with spinal cord injury (SCI). However, the molecular mechanisms underlying these deficits remain poorly understood. In this study, to investigate the molecular basis of cognitive and affective dysfunctions following SCI, we examined the role of calcium/calmodulin‐dependent kinase II (CaMKII) activation, with a specific focus on its phosphorylated form (pCaMKII), using a rat model of SCI. Method Experimental results demonstrated that SCI led to spatial memory deficits as well as depression‐ and anxiety‐like behaviors, as evidenced by performance in the Morris water maze (MWM), elevated plus maze (EPM), and forced swim test (FST). Compared to the sham group, increased levels of pCaMKII were observed in the medial prefrontal cortex (mPFC) at Day 56 after SCI. Moreover, inhibiting CaMKII phosphorylation via microinjection of KN‐93—a CaMKII activation inhibitor—into the mPFC alleviated depression‐like behavior and cognitive deficits, but not anxiety‐like behavior. Finds and Conclusion These findings suggest that CaMKII activation in the mPFC may play an important role in mediating negative emotional states following SCI. Research has documented a high prevalence of cognitive and affective impairments in individuals with spinal cord injury (SCI). Our findings suggest that CaMKII activation in the mPFC might play an important role in mediating negative emotional states following SCI.

Background Long‐term non‐traumatic noise exposure, such as heavy traffic noise, can elicit emotional disorders in humans. However, the underlying neural substrate is still poorly understood. Methods We exposed mice to moderate white noise for 28 days to induce anxiety‐like behaviors, measured by open‐field, elevated plus maze, and light–dark box tests. In vivo multi‐electrode recordings in awake mice were used to examine neuronal activity. Chemogenetics were used to silence specific brain regions. Viral tracing, immunofluorescence, and confocal imaging were applied to define the neural circuit and characterize the morphology of microglia. Results Exposure to moderate noise for 28 days at an 85‐dB sound pressure level resulted in anxiety‐like behaviors in open‐field, elevated plus maze, and light–dark box tests. Viral tracing revealed that fibers projecting from the auditory cortex and auditory thalamus terminate in the lateral amygdala (LA). A noise‐induced increase in spontaneous firing rates of the LA and blockade of noise‐evoked anxiety‐like behaviors by chemogenetic inhibition of LA glutamatergic neurons together confirmed that the LA plays a critical role in noise‐induced anxiety. Noise‐exposed animals were more vulnerable to anxiety induced by acute noise stressors than control mice. In addition to these behavioral abnormalities, ionized calcium‐binding adaptor molecule 1 (Iba‐1)‐positive microglia in the LA underwent corresponding morphological modifications, including reduced process length and branching and increased soma size following noise exposure. Treatment with minocycline to suppress microglia inhibited noise‐associated changes in microglial morphology, neuronal electrophysiological activity, and behavioral changes. Furthermore, microglia‐mediated synaptic phagocytosis favored inhibitory synapses, which can cause an imbalance between excitation and inhibition, leading to anxiety‐like behaviors. Conclusions Our study identifies LA microglial activation as a critical mediator of noise‐induced anxiety‐like behaviors, leading to neuronal and behavioral changes through selective synapse phagocytosis. Our results highlight the pivotal but previously unrecognized roles of LA microglia in chronic moderate noise‐induced behavioral changes. Chronic noise exposure activates LA microglia, which engulf more inhibitory than excitatory postsynaptic components, resulting in imbalanced excitatory transmission, potentially accounting for increased neuronal activity in the LA, and consequently leading to the development of anxiety‐like behaviors.

This study aimed to investigate the treatment effect of G protein-coupled receptor 30 (GPR30) agonist G1 combined with hypothermia (HT) on cognitive impairment and anxiety-like behavior after subarachnoid hemorrhage (SAH) in rats. Fifty male rats were randomly assigned to one of five groups: Sham group, SAH group, SAH + G1 group, SAH + HT group, and SAH + G1 + HT group. The SAH rat model was established by modified endovascular puncture in all groups except the Sham group. Neurological function after the operation was assessed by Garcia scoring. The degree of rat cerebral edema was determined using dry-wet weighing method on the 28th day after operation. Moreover, the behavioral test was performed on rats on the 4th and 28th days after operation. Compared with Sham group, the Garcia score of each SAH rat model group decreased significantly on the first day and thereafter increased gradually. However, the recovery rate of each treatment group was higher than the SAH group (no treatment), and the Garcia score of SAH + G1 + HT group was much higher than the SAH group on the seventh day after operation. In addition, each treatment group could obviously reduce the cerebral edema degree of SAH rats, among which rats in SAH + G1 + HT group had lower cerebral edema degree than SAH + G1 group and SAH + HT group. Behavioral test results showed that the combination of GPR30 agonist G1 and HT markedly improved the learning and memory ability of SAH rats, alleviated their anxiety- and emotion-related behavior, and enhanced their social interaction. GPR30 agonist G1 combined with HT reduces cognitive impairment and anxiety-like behavior in rats with SAH.

Background Studies in experimental animals revealed that acute and chronic treatment with small‐molecule immunosuppressive drugs lead to neurobehavioral alterations in rodents. Methods Against this background, this study investigated behavioral alterations in rats after repeated administration of FTY720, an immunosuppressive drug used for the treatment of multiple sclerosis, employing the open field, elevated plus maze, and dark/light tests. Results Compared to controls, repeated FTY720 treatment affected behavior in rats, reflected by a reduction in distance traveled as well as increased time engaged in freezing in the open field and elevated plus maze. Furthermore, the time spent freezing in the elevated plus maze test positively correlated with FTY720 concentrations in the amygdala and insular cortex, two brain regions involved in regulation of emotionality. Since no changes in plasma corticosterone levels were observed, stress effects due to treatment, behavioral testing, or handling can be ruled out. Conclusion The present findings indicate that treatment with FTY720 did not induce typical anxiety‐like behavioral patterns in otherwise healthy rats as seen following treatment with other immunosuppressive drugs. Nevertheless, it remains of great importance to evaluate behavioral effects in clinical practice to shed more light onto possible detrimental side effects emerging during treatment with small‐molecule immunosuppressive drugs. Peripheral administered FTY720 accumulates in the insular cortex and amygdala and induces anxiety‐like behavior in dark agouti rats (created with BioRender.com).

The use of oxytetracycline (OTC) in aquaculture is crucial for fish health and disease prevention, but it might accumulate in humans through the food chain, potentially affecting neural tissues and ultimately inducing anxiety‐like behaviors. This study assessed the effect of Lactobacillus paracasei subsp. paracasei (LPSP) in reversing OTC‐induced anxiety‐like behaviors through the gut–brain axis in zebrafish model. By novel tank diving test and the light/dark preference test, LPSP could inhibit exacerbated thigmotaxis and scototaxis behavior of zebrafish induced by OTC. Brain metabolomics revealed that LPSP supplement ameliorated the OTC‐induced suppression of α‐linolenic acid, linoleic acid, and glycerophospholipid metabolism and further elevated brain neurotransmitter levels. In addition, intestinal 16S rRNA analysis showed that LPSP helped to restore the richness and diversity of intestinal microbiota reduced by OTC. It could mitigate the increase in Proteobacteria abundance induced by OTC. Besides, the LPSP supplement was beneficial for increasing the relative abundance of native Firmicutes in the intestinal microbiota of zebrafish, including Lactobacillus reuteri, Lactobacillus johnsonii, and Lactococcus lactis subsp. cremoris. According to the correlation network analysis, the increased abundance of the species was largely correlated with the restoration of α‐linolenic acid, linoleic acid, and glycerophospholipid metabolism in brain tissue. LPSP exhibited considerable potential in reversing OTC‐induced anxiety‐like behavior. Combined with gut microbiomics and metabolomics, we revealed the underlying mechanisms.

Depression and anxiety are common mental health disorders affecting thoughts, behaviors, and emotions. This study aimed to investigate the effect of the angiotensin II type I receptor blocker (AT1RB), valsartan, on menopause‐induced depression and anxiety‐like behaviors, and to elucidate possible mechanisms of action by measuring levels of nod‐like receptor protein 3 (NLRP3), interleukin‐1beta (IL‐1β), brain‐derived neurotrophic factor (BDNF), and oxidative stress in brain tissue. Thirty‐two Wistar albino female rats were randomly divided into four groups (n = 8 per group): Control, AT1RB, OVX, and AT1RB + OVX. Following the bilateral ovariectomy (OVX) protocol, physiological saline was used as valsartan solvent, in a maximum volume of 0.4 mL, and valsartan was administered via intragastric gavage at a dose of 40 mg/kg/day. Depression and anxiety‐like behaviors were assessed using the forced swimming test and open field test. Levels of oxidative stress markers, NLRP3, IL‐1β, BDNF, and CREB were analyzed in the hippocampus and prefrontal cortex tissues. Behavioral tests indicated that depression and anxiety‐like behaviors significantly increased in OVX rats (p < 0.01), while AT1RB treatment significantly reduced these behaviors (p < 0.05). In the hippocampus of OVX rats, oxidative stress (p < 0.01), NLRP3 (p < 0.05), and IL‐1β (p < 0.01) levels were elevated, whereas BDNF levels were significantly decreased (p < 0.01). AT1RB treatment significantly improved oxidative stress parameters (p < 0.05) and BDNF levels (p < 0.01) but did not significantly affect the increased levels of NLRP3 and IL‐1β in OVX rats. In conclusion, AT1RB has a therapeutic effect on menopause‐induced depression and anxiety‐like behaviors, likely by reducing oxidative stress and increasing BDNF production in the hippocampus. In female Wistar albino rats, an experimental menopause model was induced with a bilateral overoectomy protocol. Forced swimming and open field behavioral tests were applied to analyze the effects of the experimental menopause model and valsartan treatment on depression and anxiety‐like behaviors. At the end of the experimental procedure, MDA, GSH, BDNF, IL‐1B, and NLRP3 levels were analyzed in the hippocampus to analyze the physiopathological mechanism of menopause‐related depression and the therapeutic effects of valsartan on these mechanisms.