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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.

Obesogenic diets (ODs) are known to trigger metabolic and inflammatory disturbances. However, the effects of short-term OD withdrawal on systemic and neuroinflammatory parameters remain unclear. This study investigated the short-term effects of OD withdrawal on metabolic, inflammatory, and anxiety-like behaviors in young male Wistar rats. Three-week-old male Wistar rats were fed either a control (Ct, n = 5) or high-sugar/high-fat (HSHF) diet for 14 days. Animals in the HSHF group were further divided into no-withdrawal (NWt, n = 5) and withdrawal (Wt, n = 5) groups, where Wt received a control diet for 48 h. Food intake, body mass, adiposity, serum metabolic parameters, hepatic energy stores, inflammatory markers (serum, liver, hypothalamus, hippocampus, mesenteric fat), and oxidative stress markers in the hippocampus were measured. Elevated plus maze and open field were used to characterize behavioral phenotype. OD intake significantly increased caloric intake, visceral adiposity, hepatic glycogen, and triacylglycerol (TAG) levels. The 48-h withdrawal reduced TAG, induced hyperinsulinemia and hypoglycemia, and heightened inflammation in mesenteric fat, serum, and the hippocampus. Oxidative stress markers (superoxide dismutase [SOD] and malondialdehyde [MDA]) increased in the hippocampus, correlating with elevated serum corticosterone and heightened anxiety-like behavior in the Wt group compared to the other groups. Short-term withdrawal after only 2 weeks of OD intake exacerbates systemic and neuroinflammation, hippocampal oxidative stress, and anxiety-like behaviors, indicating rapid negative responses to dietary transition. These findings identify short-term dietary withdrawal during early development as a distinct and biologically active phase, rather than an immediate recovery period.

Purpose Growing evidence implicates gut microbiota dysbiosis in social anxiety disorder (SAD), yet direct causal evidence remains limited. This study investigated whether fecal microbiota transplantation (FMT) from individuals with SAD was associated with general anxiety‐like behaviors and accompanying gut microbial and predicted metabolic alterations in mice. Methods Fecal samples were collected from five patients diagnosed with SAD and five matched healthy controls and transplanted into antibiotic‐treated mice. Anxiety‐like behaviors were evaluated using the open‐field test (OFT) and elevated‐plus maze test (EPMT). Gut microbiota composition was assessed by 16S rRNA gene sequencing, microbial functional potential was inferred using PICRUSt2, and plasma tryptophan‐pathway metabolites were quantified. Results Mice receiving SAD microbiota (SAD group) showed general anxiety‐like behaviors, characterized by more time spent in the periphery of the OFT and fewer entries and less time in the open arms of the EPMT compared to mice receiving healthy control microbiota (control group). Although α‐diversity did not differ significantly, β‐diversity was distinct between groups. The SAD group showed enrichment of Bacteroidota/Bacteroidales‐related bacteria (e.g., Muribaculum), whereas the control group had higher abundance of butyrate producers (e.g., Butyricimonas). Functional prediction indicated lower predicted abundance of selected DNA‐repair and biosynthetic pathways in the SAD group. Plasma tryptophan levels were nominally lower in the SAD group. Conclusions These findings suggest that specific gut microbiota alterations and predicted functional pathway changes in individuals with SAD may be associated with anxiety‐related behavioral phenotypes, supporting the gut microbiome as a potential contributing factor to the pathophysiology of SAD. Fecal microbiota transplantation from patients with social anxiety disorder (SAD) into mice induces anxiety‐like behaviors, accompanied by gut microbiota alterations (increased Bacteroidota, decreased butyrate producers), downregulation of microbial metabolic pathways, and reduced plasma tryptophan, suggesting a causal role of gut dysbiosis in SAD‐related behaviors.

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.

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.

Despite ongoing challenges in developing effective non‐surgical and non‐hormonal treatments for endometriosis, the psychological manifestations of the disease—particularly anxiety—remain comparatively underexplored. In this study, a hydrogen sulfide (H2S)‐releasing aspirin derivative, ACS14, was encapsulated in albumin nanoparticles (ACS14@BSA) for targeted delivery. Upon intraperitoneal injection in a mouse model of endometriosis, ACS14@BSA was selectively transported to ectopic lesions via a neutrophil hitchhiking strategy. There, it inhibited ectopic cell proliferation by modulating the PI3K/Akt pathway and reduced inflammation by suppressing the NF‐κB pathway, exerting a comprehensive therapeutic effect on endometriosis. Simultaneously, the H2S released at lesion sites was conveyed through the bloodstream to the anterior cingulate cortex (ACC), a brain region critical for anxiety regulation, as demonstrated by in vivo fiber photometry recordings in mice. Importantly, in the ACC, H2S upregulated glutamate transporter 1 (GLT‐1), decreased extracellular glutamate levels, and dampened glutamatergic neuron hyperactivity, thereby alleviating endometriosis‐associated anxiety. This study presents a novel gasotransmitter‐releasing nanoplatform that offers a non‐invasive and non‐hormonal approach for the concurrent treatment of endometriosis and associated anxiety. Albumin nanoparticles loaded with an H2S‐releasing aspirin derivative (ACS14) hitchhiking neutrophils after intraperitoneal injection and preferentially accumulate in endometriosis lesions in mice. The treatment suppresses lesion growth by regulating PI3K/Akt and reduces inflammation by inhibiting NF‐κB. Meanwhile, H2S reaching the anterior cingulate cortex lowers glutamatergic neuron activity and alleviates endometriosis‐associated anxiety.

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 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).