Search Results (303)

Patients with traumatic brain injury (TBI) have an elevated risk of developing chronic psychiatric and behavioral disorders, including impairments in motor function, memory deficits, anxiety, and depression. Although a substantial body of work has addressed the treatment and rehabilitation of sensory, motor, and cognitive symptoms after TBI, there is a relative scarcity of comprehensive behavioral assessments targeting neuropsychiatric manifestations in preclinical models. This study aims to investigate the connections between emotional sequelae after TBI and modifications in local field potentials (LFPs). Following cryogenic lesion-induced TBI, animals exhibited anxiety-like behaviors as assessed by the open field test (p < 0.001), light/dark box test (p < 0.001), and elevated plus maze test (p < 0.01). Depression-like behavior was observed using the forced swim test (p < 0.001). LFP analysis demonstrated a marked elevation in neural oscillatory activity associated with anxiety and depression in the contralateral hemisphere relative to the ipsilateral side (p < 0.001). These results indicate that the emotional consequences triggered by TBI may be linked to dysregulated synchronous neural activity between the ipsilateral and contralateral hemispheres. Full article

Chronic stress disrupts neuroendocrine regulation, neurotransmitter balance, and neuronal redox homeostasis, thereby contributing to the development of anxiety-related neuropathology. Arecoline, the predominant alkaloid of Areca catechu L., displays diverse neuropharmacological properties, yet its role in stress-induced emotional dysfunction has not been fully elucidated. This study examined the anxiolytic-like and neuroprotective effects of arecoline in mice exposed to chronic unpredictable mild stress (CUMS). Arecoline administration markedly improved behavioral outcomes, reflected by increased central exploration in the open-field test, prolonged time in the light compartment, and enhanced open-arm activity in the elevated plus maze. These behavioral benefits were accompanied by normalization of serum corticosterone levels, restoration of hippocampal neurotransmitters, reinforcement of antioxidant enzyme activities, and attenuation of pro-inflammatory cytokines. At the molecular level, arecoline elevated brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), cAMP response element-binding protein (CREB), N-methyl-D-aspartate receptor (NMDAR), and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), indicating enhanced synaptic plasticity, while concurrently diminishing oxidative and inflammatory stress. Collectively, the findings suggest that arecoline exerts multifaceted neuroprotective actions under chronic stress by coordinating neuroendocrine modulation, neurotransmitter homeostasis, antioxidant defenses, and synaptic plasticity. This study provides new mechanistic evidence supporting the potential relevance of arecoline as a functional neuroactive compound for managing stress-induced anxiety disorders. Full article

Recent studies indicated a connection between trace amine-associated receptor 5 (TAAR5) and emotional behaviors related to anxiety and depression; however, the neurobiological basis of this link is still unclear. Using mutant TAAR5 knockout (TAAR5-KO) mice, we explored the consequences of receptor deletion on dopamine (DA) dynamics in the ventral striatum and stress-related behaviors. Voltammetric measurements of DA in the nucleus accumbens (NAc) coupled with electrical stimulation of the ventral tegmental area (VTA) revealed that mice lacking TAAR5 display a greater DA release, while its reuptake is not affected. Behaviorally, mutants were significantly less anxious in the elevated plus maze (EPM) and consumed more sucrose in comparison with wild-type (WT) controls. The new object recognition test (NOR) did not uncover a difference between these genotypes. During predator (rat) stress exposure, mutant and WT mice showed quite distinct responses versus the behavior observed in stressless conditions. Control animals demonstrated a substantial increase in “freezing” (a sign of passive coping), while “running” and “exploring” patterns (signs of active coping) were significantly extended in mice lacking TAAR5. Short-term consequences of stress were explored 24 h following the predator exposure. The absence of TAAR5 did not prevent or reduce stress-induced anxiety in the EPM. In fact, the level of anxiety in mutants reached that observed in control mice. Furthermore, activity in NOR was significantly decreased in mice lacking TAAR5 but not in WT animals. On the other hand, predator exposure resulted in impaired NOR in the WT control, whereas mutants’ performance was not altered. These findings indicate that TAAR5 deletion leads to significant DA imbalance, which might at least partly explain the better stress-coping strategy and other stress-induced behavioral consequences observed in mutant animals. Full article

Hexavalent chromium [Cr(VI)] is the toxic form of chromium often used in industry for its hardness, bright colors, and anticorrosive properties. Cr(VI) is a known human lung carcinogen, making its inhalation an occupational hazard. Growing evidence emphasizes the neurotoxic potential of Cr(VI), though it is not linked to brain cancers. Few studies consider neurotoxicity in chromate workers, reporting impaired olfactory discrimination and an increased risk of death from mental health disorders. A major factor limiting translation of most rodent Cr(VI) studies to human populations has to do with vitamin C, which can reduce the toxic Cr(VI) to non-toxic Cr(III). Rats and mice synthesize vitamin C and are likely more resistant to Cr(VI) than humans. Here, we considered Cr(VI) neurotoxicity in guinea pigs (Cavia porcellus), which do not endogenously synthesize vitamin C. We exposed Hartley guinea pigs (both sexes) to occupationally relevant concentrations of Cr(VI) via oropharyngeal aspiration weekly for 90 days. We observed behavioral effects in the open field assay, elevated plus maze, Y-maze, and novel object recognition test during weeks 9–12 of exposure. After euthanasia, we assessed Cr accumulation and essential metal dyshomeostasis in the hippocampus. We observed significantly increased hippocampal Cr accumulation in females, while males exhibited essential metal dyshomeostasis. Full article

Background: Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition with limited treatment efficacy. Alternating current electroacupuncture (AC-EA) represents a novel neuromodulatory approach, though its mechanisms—particularly its influence on the gut–brain axis—remain underexplored. Methods: We investigated the neurobehavioral and microbiological effects of AC-EA in a rat model of PTSD induced by single prolonged stress. Animals received AC-EA at Baihui (GV20) and Mingmen (GV4) acupoints with varying parameters (0.5 mA/20 Hz, 1 mA/20 Hz, and 1 mA/2 Hz). Behavioral tests (open field test, elevated plus maze), histopathological assessments, immunofluorescence for TLR4, and 16S rRNA sequencing of gut microbiota were performed. Results: AC-EA at 1 mA/2 Hz significantly improved exploratory behavior and reduced anxiety-like responses (p < 0.05). This regimen also restored neuronal integrity in the hippocampus and cortex and reversed PTSD-induced gut dysbiosis, enriching beneficial genera such as Ligilactobacillus. Furthermore, AC-EA downregulated hepatic TLR4 expression, indicating suppression of neuroinflammatory signaling. Conclusions: Our findings demonstrate that AC-EA exerts neuromodulatory and microbiota-rebalancing effects via the gut–brain axis, highlighting its potential as a non-invasive therapeutic strategy for PTSD and related brain health disorders. Full article

Growing evidence highlights the links between diabetic neuropathy (DNP), gut dysbiosis, mitochondrial dysfunction and neuroinflammation in colon and bone microstructure deterioration. Geranylgeraniol (GG) shows neuroprotective and osteoprotective capacity. Our study examines GG’s effects on pain-associated behaviors, glucose homeostasis, gut microbiota, mitochondrial homeostasis, and bone microstructure in DNP rats. We randomly assigned 27 male Sprague Dawley rats to three groups (n = 8–10/group): a control group (regular low-fat diet), a DNP group (high-fat diet + a single dose of 35 mg/kg streptozotocin), and a GG-treated DNP group (a single dose of 35 mg/kg streptozotocin + GG at 800 mg/kg in diet) for 6 weeks. Nocifensive response was assessed via the von Frey test and an open field test, and the elevated plus maze was used to assess anxio-depressive behaviors. The mRNA expression levels of tight junction protein, mitochondrial homeostasis, and neuroinflammation were measured in the colon using qRT-PCR. We collected fecal samples for microbiota composition analysis with 16S rRNA gene sequencing and analyzed by QIIME 2. All other data were analyzed via one-way ANOVA followed by post hoc Tukey’s multiple comparison. p < 0.05 was defined as statistical significance. Our study showed GG’s ability to mitigate mechanical hypersensitivity and anxio-depressive behavior in rats with DNP. GG supplementation did not improve glucose homeostasis (i.e., glucose intolerance, insulin sensitivity, pancreatic β-cell dysfunction) and bone microstructure. GG increased alpha-diversity without changing microbial abundance. DNP rats exhibited elevated Clostridium sensu stricto and reduced Eubacterium coprostanoligenes, Lachnospiraceae, Oscillospiraceae, and Peptococcaceae compared with controls. GG did not reverse DNP-induced gut dysbiosis but increased colonic claudin-3 (tight junction), MFN1 (mitochondria fusion), and TFAM (mitochondria biogenesis), while reducing FIS1 (mitochondria fission), GFAP (glial activation), P62 and PINK1 (mitophagy), and TNFα (inflammation). Functionally, GG reduced pain behaviors, improved intestinal integrity and mitochondrial homeostasis, increased alpha-diversity, and suppressed neuroinflammation, but did not improve glucose homeostasis or bone microstructure in obese DNP rats. Full article

Acquiring new experiences, especially in adolescence, shapes behavioral responses to life’s challenges. The absence of novelty-related experiences in laboratory rats raises concerns about their behavioral development and the reproducibility of research. This study examined changes in behavioral responses to novelty from early and late adolescence to adulthood, as well as the long-term effects of prior novelty exposure. To assess maturational differences, seven early adolescent, nine late adolescent, and seven adult male Wistar Han rats were tested once in a behavioral battery consisting of the novel arena, novel object exploration, light/dark box, and elevated plus maze. To evaluate the influence of prior experience, early and late adolescent groups were retested once more in adulthood. Late adolescents showed consistent patterns across spatial tasks, displaying increased anxiety-like behavior and reduced exploratory and risk-assessment activity. Early adolescents exhibited variable behaviors, resembling adult or late adolescent profiles depending on the task. Novelty exposure during adolescence produced subtle long-term effects, including reduced discomfort in mildly aversive environments, while late adolescent experience increased thigmotaxis in adulthood. Overall, adolescent responses to novelty were influenced more by spatial than nonspatial environmental features. These findings highlight stage-specific sensitivity to novelty, the influence of adolescent experience, and the potential reuse of experienced animals. Full article

The standardization of husbandry in animal studies for drug development aims to minimize variability and enhance inter-laboratory comparability. Rats are a commonly used species in such studies. This standardization yields housing conditions that do not reflect the natural environment of rats, raising animal welfare concerns and prompting discussions about whether such conditions might also influence physiological or behavioral outcomes, thereby potentially affecting the translatability of study results. In this study, we compared a two-level, enriched colony cage housing groups of ten Sprague-Dawley rats with conventional pair-housed Type IV cages over 28 days, asking whether social and physical complexity alters parameters relevant to early drug development and safety assessment. These included body weight, food and water intake, behavior (open field, elevated plus maze), hematology, clinical chemistry, blood gases, gross pathology, organ weights, histopathology, and IgG levels. Differences in key measures between housing conditions were minimal: Hematology showed time-restricted shifts. On study day 28, immunoglobulin G concentrations were higher in conventionally housed animals, though values were comparable and within the normal range. Behavioral tests revealed notable but limited differences between housing conditions, mainly involving locomotor activity. Clinical chemistry and blood gases were largely unchanged. Body weight, food and water intake, and pathology parameters were comparable. Together, these findings demonstrate that enriched colony housing can be implemented as a refinement strategy without compromising the integrity of key study endpoints relevant to early drug development and safety assessment. Full article

Objective: Neuronal growth regulator 1 (Negr1) is a GPI-anchored neuronal cell adhesion molecule of the IgLON superfamily associated with multiple psychiatric disorders. This study aimed to investigate behavioral and molecular adaptations to social isolation (SI) stress in Negr1-deficient (Negr1^−/−) mice. Methods: Male and female Negr1^−/− and wild-type (Wt) mice (n = 10 per group) were exposed to two weeks of SI or group housing (Ctl). Behavioral assays assessed exploratory and anxiety-like behavior. Gene expression analyses in the prefrontal cortex and hippocampus were performed using RT-qPCR, focusing on GABAergic, neurotrophic, and IgLON family genes. Results: SI-induced weight loss in Negr1^−/− mice compared to Wt was evident in both sexes but more pronounced in males. Behaviorally, SI Wt males showed stress-induced hyperactivity compared to Ctl Wt, whereas SI Negr1^−/− males exhibited blunted exploratory behavior relative to SI Wt in the open field test (OFT). Negr1^−/− females showed reduced exploration in the elevated plus maze (EPM), suggesting increased anxiety. Hippocampal Pvalb was downregulated in SI Negr1^−/− mice of both sexes compared to Wts, with a stronger decrease in males, indicating heightened male vulnerability in GABAergic interneuron function. In males, SI reduced hippocampal Bdnf in both genotypes, whereas Ntrk2 (TrkB) upregulation occurred only in Negr1^−/− mice, suggesting a genotype-specific compensatory response. Hippocampal expression of Fgfr2 and IgLON members (Ntm1a/1b, Lsamp1a/1b) was increased in SI Negr1^−/− males compared to SI Wt, with minimal changes in females. Conclusions: Negr1 deficiency leads to sex-specific behavioral and molecular adaptations to social isolation stress, highlighting the role of Negr1 in modulating neurotrophic and GABAergic signaling pathways under adverse environmental conditions. Full article

Chronic stress alters hypothalamic–pituitary–adrenal (HPA) axis function, affecting corticosterone regulation and adaptive responses. Understanding individual variability in stress adaptation requires identifying distinct HPA axis response patterns. Here, we assessed HPA axis sensitivity in male C57BL6 mice exposed to 30 days of chronic social defeat stress (CSDS). Negative feedback integrity was evaluated using the dexamethasone suppression test (DST), with corticosterone measured after saline or low-dose dexamethasone administration at days 10 and 30. Behavioral testing (open field, elevated plus maze, social interaction test, partition, social defeat, forced swimming test, sucrose preference test) and qPCR analysis of HPA-axis-related genes in the hypothalamus (Crh, Crhr1, Crhbp, Fkbp5, Nr3c1), pituitary (Pomc, Crhr1, Nr3c1, Nr3c2), and adrenal glands (Cyp11a1, Cyp11b1, Hsd11b1, Mc2r, Star, Fkbp5, Nr3c1) were performed. K-means cluster analysis identified three distinct response profiles differing in baseline and dexamethasone-suppressed corticosterone levels. Clusters also exhibited differences in behavioral phenotypes and HPA axis gene expression. Cluster 1 showed low basal corticosterone and an abnormal dexamethasone suppression response, without significant Crh or Crhbp dysregulation in the hypothalamus. Cluster 2 exhibited elevated basal corticosterone, a blunted dexamethasone response, anhedonia, and reduced immobility in the forced swim test; increased Crh and reduced Fkbp5 suggested enhanced glucocorticoid receptor sensitivity and sustained hypercortisolemia. Cluster 3, characterized by normal basal corticosterone and normal dexamethasone response, displayed upregulation of Crh and Crhbp, consistent with balanced and potentially adaptive HPA axis regulation under chronic stress. These results demonstrate that corticosterone response heterogeneity reflects distinct adaptive trajectories under chronic stress. Identifying behavioral and molecular markers of these strategies may advance understanding of stress vulnerability and resilience mechanisms, with implications for stress-related disorders. Full article

Background: Echinacea purpurea (L.) Moench (EP) and Onopordum acanthium (L.) (OA) are promising medicinal plants with diverse biological activities but there is no information on the effects of their combinations. To harness the therapeutic potential of both while minimizing the risk of adverse effects, we prepared two combinations (CE1 and CE2) of EP and OA in ratios 1:1 and 3:1, respectively. Methods: Oxygen radical absorbance capacity (ORAC), hydroxyl radical absorbance capacity (HORAC), and an electrochemical assay were used to determine the antioxidant activity of the extracts in vitro. The anxiolytic and immunomodulatory properties were studied in rats. Animals were subjected to acute cold stress and anxiety-like behavior was evaluated by the elevated plus maze (EPM) and social interaction test (SIT). Serum IFN-γ, TNF-α and IL-10 levels were measured by ELISA. Results: CE2 demonstrated the highest antioxidant activity (1841.7 μmolTE/g by ORAC, 277.2 GAE/g by HORAC, and 39.6 by electrochemical method). Moreover CE2 produced anxiolytic-like effects—significantly increasing the open arms entries ratio (OAER; p < 0.001), open arms time ratio (OATR; p < 0.01) in the EPM, and prolonging the social interaction time (p < 0.05) versus the stressed control. OA increased OAER (p < 0.01) and OATR (p < 0.001), while EP increased only OAER (p < 0.01). CE1 showed no significant behavioral consequences. CE2 significantly reduced IFN-γ (p < 0.05), and IL-10 levels were elevated in OA and CE2 groups (p < 0.01). No significant changes in TNF-α levels were observed across groups. Conclusions: These findings indicate that CE2 and OA attenuate anxiety-like behavior and modulate the immune response primarily by stimulating IL-10 production. Full article

Background/Objectives: Baihe Dihuang Tang (BDT), a classical herbal formula from Zhang Zhongjing’s Han Dynasty work Jin Gui Yao Lue, is widely used to treat depressive disorder by nourishing Yin, clearing heat, and tonifying the heart and lungs. However, its pharmacological mechanisms remain unclear. This study aims to explore BDT’s antidepressant effects via MAOA-regulated serotonin (5-HT) metabolism and synaptic plasticity, supported by experimental validation, while using network pharmacology to predict MAOA-targeting active components. Methods: Active components and targets of BDT were screened using TCMSP, TCMID, and other databases, and then a component-target-pathway network was constructed. A chronic restraint stress (CRS)-induced depressive mouse model was established. Behavioral tests, including open field test (OFT), elevated plus maze (EPM), forced swimming test (FST) and tail suspension test (TST), were conducted to evaluate antidepressant effects. ELISA, qRT-PCR, and Western blot were employed to assess hippocampal 5-HT metabolism (MAOA, 5-HT/5-HIAA ratio) neurotrophic signaling (BDNF, TrkB) and synaptic plasticity-related proteins (PSD-95, SYN1). Results: BDT significantly reduced FST/TST immobility time and improved anxiety-like behaviors in OFT/EPM. BDT treatment downregulated MAOA expression, elevated hippocampal 5-HT/5-HIAA ratio, activated BDNF/TrkB pathway, and upregulated PSD-95/SYN1. Network pharmacology confirmed MAOA’s central role, identifying MAOA/serotonergic synapse modulation as BDT’s main mechanism and pinpointing Ferulic acid, Caffeate, Stigmasterol, (−)-nopinene, Eugenol, and cis-Anethol as MAOA-targeting bioactive components. Conclusions: BDT ameliorates depressive-like behaviors. This effect is mechanistically linked to suppression of MAOA-mediated 5-HT catabolism—a key validated target. This suppression elevates hippocampal 5-HT bioavailability, thereby activating BDNF/TrkB signaling and promoting synaptic plasticity. Network pharmacology confirmed MAOA as a primary target and identified specific modulatory bioactive components. Full article

Background: Aromatic plants like peppermint (Mentha x piperita, Lamiaceae) have a long tradition of use. Most of the plant material is used to produce herbal drugs and for the isolation of essential oils. However, since essential oils are present in very small amounts, the largest proportion of plants remains unused. Objectives: The aims of this study were the analysis of chemical, biochemical, antimicrobial, and pharmacological properties of peppermint waste material extracts (derived from stems, post-distillation waste, and deodorized leaves) in comparison with the officially prepared extract. Results: The obtained results revealed that the investigated peppermint waste extracts (PWEs) are a rich source of phenolic compounds, where rosmarinic acid was determined as the dominant one (7.05–21.19 mg/g d.e.). Antioxidant potential and hepatoprotective effect of PWE were comparable with the official extract, where the most active ones were those prepared by treating the deodorized leaves with both 45% and 75% ethanol. In addition, PWE exhibited notable antimicrobial and anticholinesterase activity. Results of pharmacological studies on experimental animals showed that peppermint extracts (official and those made from deodorized leaves) did not interfere with the effect of the tested drugs, midazolam and fluoxetine. The examined extracts neither exerted an influence on motor coordination nor acted as antidepressants. Results of the elevated plus maze test indicated that PWE affected the activity of the central nervous system. Conclusions: PWEs represent a significant source of phenolic compounds, especially rosmarinic acid, and they can be used in the pharmaceutical industry to produce various herbal products and in the food industry as natural additives. Full article

Aggression among group-housed male laboratory mice poses significant challenges for animal welfare and scientific outcomes. Semiochemicals, such as mammalian appeasing pheromones, have shown potential in modulating social behaviors in various species. This study aimed to evaluate the effects of a synthetic Common Trunk (CT) of mammalian appeasing pheromone on social behavior, aggression, and welfare indicators in adult male mice. Specific Pathogen Free (SPF) male RjOrl:SWISS mice (8–12 weeks old) were housed in open-top cages and exposed via environmental passive diffusion to either a 2% synthetic CT pheromone formulation or a placebo (excipient only). Behavioral tests included the Elevated Plus Maze (EPM) and the Resident–Intruder (RI) test. Clinical welfare assessments and hematobiochemical analyses were also performed. Behavioral testing revealed minimal differences between groups, except for—in animals exposed to the CT—significantly fewer unsupported rearings, both in number (p = 0.0284) and duration (p = 0.0184), suggesting reduced vigilance (EPM Test) and shorter upright posture durations (p = 0.0031), a behavior linked to social signaling during conflict (RI test). Welfare assessments and risk-based analyses indicated that mice exposed to the CT of the appeasing pheromone displayed more agonistic but less violent confrontations, with fewer visible lesions. The protective effect was most pronounced during early group housing of unfamiliar adult males, with significantly fewer injuries in treated mice during the first (p = 0.0215) and second week (p = 0.0329). Treated mice also showed higher serotonin levels (p = 0.0295), suggesting reduced aggressiveness in line with observed behavioral outcomes. Exposure to the CT appeared to improve social dynamics and reduce escalation of aggression in male mice, supporting its potential as a refinement tool in laboratory housing practices. Full article

Cardiovascular disorders and the medications used to treat them can affect physiological patterns of behavior. The aim of the present study was to determine whether the dual inhibition of neprilysin and angiotensin II—sacubitril/valsartan (ARNI) can modify anxiety-like behavior in male spontaneously hypertensive rats (SHR). We compared ARNI with two other drugs in the portfolio of heart failure treatment, captopril and ivabradine. Six groups (n = 13) of 12-week-old rats were treated for six weeks: control (Wistar rats), control + ARNI, SHR, SHR + ARNI, SHR + captopril, and SHR + ivabradine. The elevated plus maze test, the open field test, and the light–dark box test were used to determine anxiety-like behavior. SHRs exhibited higher systolic blood pressure (SBP), heart rate (HR), left ventricular weight (LVW), and hydroxyproline concentration (LVHP) but displayed a reduced level of anxiety-like behavior in comparison to controls. ARNI reduced SBP, HR, and LVW but had no significant effect on the level of anxiety in SHR, and similar results were achieved by captopril and ivabradine. Additionally, correlation analysis indicated that anxiety-like behavior in Wistar rats or SHR, either with or without cardiovascular therapy, was independent of SBP, HR, LVW, or LVHP. The level of anxiety-like behavior can, therefore, be considered part of the inherent neurobehavioral traits unrelated to fundamental hemodynamic or structural cardiovascular parameters. Full article