Fibromyalgia (FM) is a complex, chronic disorder characterized by widespread pain, fatigue, cognitive impairment, and sleep disturbances, and it is considered the second most prevalent rheumatic condition. Current pharmacological therapies are often associated with undesirable side effects, underscoring the need for safer, natural therapeutic alternatives. Moringa oleifera leaves are rich in nutrients and bioactive antioxidants and have demonstrated therapeutic potential in inflammatory and immune-related disorders. This study investigated the therapeutic effects of M. oleifera leaf extract in a reserpine-induced fibromyalgia model using multiple treatment groups of male mice. Behavioral, histological, and neurochemical assessments were conducted. Mice with reserpine-induced FM exhibited reduced body weight, decreased paw withdrawal threshold and thermal latency, diminished locomotor activity and grooming behavior, impaired spontaneous alternation, and prolonged immobility time. Histopathological examination revealed marked structural disruption of hippocampal tissue, accompanied by reduced serotonin levels and elevated concentrations of IL-1β, TNF-α, and NO compared with control animals. Treatment with M. oleifera significantly attenuated these alterations by improving behavioral performance, restoring hippocampal architecture, and normalizing serotonin levels and pro-inflammatory markers. These findings indicate that M. oleifera exerts a protective effect against reserpine-induced fibromyalgia, likely through modulation of serotonergic activity and suppression of inflammatory cytokine signaling pathways.

Targeted inhibition of microglial C5aR1 by PMX205 mitigates post-ischemic stroke neuroinflammation and promotes functional recovery.

Myocardial infarction (MI) induces brain injury. Myrtenol has antioxidant and anti-inflammatory effects. This study investigated the neuroprotective effect of myrtenol following myocardial infarction induced by isoproterenol (ISO) in male rats. This experimental study involved 36 male Wistar rats. They were divided into six groups. Rats received ISO (85mg/kg) for two days. Subsequently, they were treated with vehicle or myrtenol (5, 25, or 50mg/kg) once daily, one hour after the last ISO injection, for seven days. Behavioral tests (spontaneous alternation and passive avoidance) were conducted post-treatment. Hemodynamic parameters and serum troponin were assessed. Tissue samples (heart/brain tissue) underwent histopathological examination via H&E and Nissl staining methods. The activities of glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD), along with malondialdehyde (MDA) content and total antioxidant capacity (TAC) were measured in heart and brain tissue. Western blot analysis was used for the assessment of inflammatory (TNF and NF-κB), cell death (Bax, Bcl2, and Cleaved caspase-3), and nuclear factor erythroid-related factor-2 (Nrf2) markers in brain tissue. ISO significantly reduced latency time and spontaneous alternation compared to control (p < 0.001). Myrtenol improved these parameters at 25mg/kg (p < 0.01) and 50mg/kg (p < 0.001). Myrtenol also reduced MDA content, Bax, Cleaved caspase-3, TNF, and NF-κB protein expression and also increased Bcl2, and Nrf2 proteins, TAC level, SOD, GPx, and catalase enzyme activity in heart/brain tissues when compared to ISO group (p < 0.05). Myrtenol improved memory function and hemodynamic parameters. It decreases brain oxidative stress, inflammation and cell death markers, highlighting its potential as a therapeutic agent.

Long-lasting cognitive deficits after surgery in aged individuals, referred to as perioperative neurocognitive disorder (NCD), are a significant public health concern. Such postoperative cognitive deficits are dependent on the presence of microglia in the brain, which, when activated, trigger neuroinflammation. The objective of our study was to determine whether modulation of α5-GABAA receptors by the α5-positive allosteric modulator (α5-PAM), MP-III-022, would improve cognitive deficits after surgery. MP-III-022 (1 mg·kg-1·day-1 in the drinking water) was administered to mice 3 days prior to laparotomy and throughout the study. Chronologically aged mice (21-24 months old) and mice with ablation of dentate gyrus hilar somatostatin interneurons (4-5months old), a model for hippocampal ageing, were used. Cognitive functions were assessed using a battery of behavioural tests. Immunohistochemistry and Golgi staining were used to analyse microglial activation and dendritic spine density. In both types of mice, we found that laparotomy reduced the percentage of spontaneous alternations in the Y maze, novel object recognition, and contextual fear conditioning, while these deficits were attenuated with MP-III-022 treatment, indicating prevention or reversal of postoperative cognitive impairments. Laparotomy increased hippocampal microglial activation-associated measures and reduced dendritic spine density, and these changes were attenuated by MP-III-022 treatment. The α5-PAM, MP-III-022, essentially abolished laparotomy-induced cognitive deficits and structural alterations. Positive allosteric modulation of α5-GABAA receptors may represent a novel therapeutic strategy to prevent the development of perioperative neurocognitive deficits in aged individuals.

Ameliorative effect of AYUSH formulation against scopolamine induced learning and memory impairment in rat via attenuation of oxidative stress, neuroinflammation, acetylcholinesterase inhibition and Aβ plaques.

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder marked by inattention, impulsivity, and hyperactivity. Although the spontaneously hypertensive rat (SHR) is widely used to model ADHD, intra-strain behavioral heterogeneity and its neurobiological relevance remain insufficiently defined. We conducted a comprehensive multidomain behavioral assessment of male adolescent SHR and Wistar-Kyoto (WKY) rats spanning locomotion/exploration, anxiety- and risk-related behavior, compulsive-like activity, cognition, and sensorimotor gating. Across tasks, SHR rats exhibited increased impulsive and repetitive exploratory behaviors, context-dependent alterations in anxiety-related measures, reduced spontaneous alternation, and impaired prepulse inhibition. Exploratory factor analysis of 26 behavioral variables identified five interpretable latent dimensions, including exploratory-attentional engagement and impulsivity/disinhibition, and revealed substantial heterogeneity within the SHR population. Using WKY-referenced factor-score deviation, SHR were stratified into normative-range and combined-deviant subtypes. The combined-deviant subtype exhibited convergent circuit-level alterations, including reduced parvalbumin (PV)/glutamate decarboxylase 67 (GAD67)-associated inhibitory features and decreased synaptic marker signals in prelimbic and infralimbic medial prefrontal cortex, together with increased dopamine transporter expression (DAT) in the striatum without changes in tyrosine hydroxylase (TH). Complementary principal axis factoring, bootstrap resampling, and split-sample analyses supported the robustness of the factor structure. These findings link multidimensional behavioral subtypes in SHR to distinct prefrontal-striatal signatures, strengthening the translational utility of SHR-based ADHD research.

Nanoemulsions are increasingly recognized as effective carriers for delivering neuroprotective agents in the management of neurodegenerative conditions like Alzheimer's disease. Alzheimer's Disease (AD) is a chronic and progressive neurological disorder marked by memory impairment, cognitive dysfunction, oxidative damage, and degeneration of neurons. This study focuses on designing and evaluating a nanoemulsion-based drug delivery system combining Resveratrol and Ginkgo biloba to investigate their potential neuroprotective effects in a scopolamine- induced Alzheimer's model in Wistar rats. A total of nine water-in-oil nanoemulsion formulations (F1-F9) were developed using probe sonication and examined for various parameters, including droplet size, zeta potential, polydispersity index (PDI), entrapment efficiency, and in vitro drug release profiles. Among these, Formulation F2, containing 25 mg of Resveratrol and 25 mg of Ginkgo biloba, showed the most favourable characteristics, including a high entrapment efficiency of 90.13%, maximum drug release of 92.33%, a particle size of 92.83 nm, and a zeta potential of 30.75 mV, suggesting good stability of the formulation. For the in vivo evaluation, rats were divided into six groups: normal control, negative control (scopolamine-treated), standard treatment group (Diazepam 2 mg/kg), and three test groups with different formulations. Behavioural studies using the Y-maze demonstrated that the Test Group 1 (treated with F2 formulation) had significantly improved spontaneous alternation behaviour, indicating enhanced cognitive performance. Biochemical analysis showed reduced malondialdehyde (MDA) levels and increased glutathione (GSH) levels, suggesting potent antioxidant activity. Additionally, histopathological examination of brain tissue revealed that the F2-treated group showed reduced neuronal damage and better preservation of hippocampal structure. In rats treated with scopolamine, the optimized F2 nanoemulsion showed excellent physicochemical stability and markedly enhanced cognitive function. Strong antioxidant and neuroprotective effects of the combination formulation are indicated by decreased MDA levels, increased GSH levels, and intact hippocampus architecture. The Resveratrol-Ginkgo biloba nanoemulsion (F2) successfully reduced oxidative stress and cognitive impairment, indicating its potential as a treatment for early-stage Alzheimer's disease. Additional research is needed to confirm its therapeutic application.

Dietary factors play an important role in cognitive health during aging. Dark tea has shown potential cognitive benefits, but its key bioactive component and underlying mechanisms remain unclear. In a naturally aged C57BL/6J mouse model, instant dark tea (IDT) samples with different fermentation degrees were evaluated together with behavioral outcomes using composition–effect relationship analysis. This analysis identified theabrownin (TB) as the component most strongly associated with improved cognitive performance. Compared with aged controls, TB increased Y-maze spontaneous alternation from 51.91% to 71.59% and reduced escape latency on day 5 of the Morris water maze from 44.84 s to 26.59 s. In contrast, the corresponding TB-depleted fraction produced no comparable cognitive improvement. TB also alleviated hippocampal injury and neuroinflammation. Antibiotic treatment abolished the cognitive benefits of TB, whereas fecal microbiota transplantation partially restored them. Multi-omics analyses suggested that TB treatment was associated with gut microbiota remodeling and increased serum acetate and 3-hydroxybutyrate; both metabolites partially recapitulated these benefits. Together, these findings show that TB attenuates age-related cognitive decline in naturally aged mice and suggest that modulation of gut microbiota and metabolites may contribute to this effect, supporting its potential as a functional food ingredient for healthy brain aging.

Lactate restores PGC1α and BDNF expression rescuing cognitive impairments in a mouse model for schizophrenia.

Chemogenetic inhibition of developmentally-born hippocampal neurons but not loss of adult neurogenesis impairs spatial working memory in the rat.

Perivascular macrophages (PVMs) are increasingly recognized as key players in maintaining brain homeostasis, yet their role in maintaining neurovascular-metabolic homeostasis has not been fully explored. We hypothesized that PVM depletion compromises cerebrospinal fluid-interstitial fluid exchange through glymphatic system (GS) dysfunction, thereby exacerbating cortical hyperexcitability manifested as increased epilepsy susceptibility and seizure intensity. Using clodronate liposomes (CLOs), we achieved >85% PVM depletion in mice. Following pentylenetetrazole (PTZ) challenge, PVM-depleted mice exhibited anxiety-like behaviors (reduced center time, p < 0.05), impaired working memory (decreased spontaneous alternation, p < 0.05), and increased cortical hyperexcitability, including shorter seizure latency and elevated EEG total power (p < 0.05). Mechanistically, PVM loss led to dysregulation of extracellular matrix components (increased laminin and collagen IV), impairing perivascular space integrity and GS function (reduced CSF tracer clearance, p < 0.05). AQP4 inhibition with TGN-020 further exacerbated PTZ-induced EEG abnormalities (increased total power, p < 0.05). Analysis of human epileptic tissue confirmed elevated collagen IV deposition in the seizure focus (p < 0.05) and a trend toward increased PVM density (p = 0.0638). These results highlight PVMs as essential modulators of the glymphatic-metabolic axis, linking vascular health to brain excitability. Targeting the PVM-GS interface offers therapeutic potential for disorders involving vascular dysfunction and neuronal hyperexcitability.

Chaotic itinerancy—irregular switching among metastable collective states—provides a dynamical substrate for flexible social coordination, yet its mechanistic origin in multi-agent systems remains unclear. We present a multi-agent Active Inference model in which chaotic itinerancy emerges from Expected Free Energy minimisation without outcome-level social priors. Agents select actions to minimise Expected Free Energy while updating preferences through a precision-gated learning mechanism modulated by interpersonal trust. Hill-function nonlinearity in state transitions creates bistable “affordance landscapes” that gate behavioural mode switching. Simulations with small number of agents on an Erdos–Rényi trust network reveal spontaneous alternation among multiple metastable behavioural clusters, heavy-tailed dwell-time distributions, and sign-changing finite-time Lyapunov exponents—three hallmarks of chaotic itinerancy. Crucially, replacing Hill-function dynamics with linear transitions reduces the chaotic-itinerancy detection rate from 80% to 20%, demonstrating that nonlinear affordance structure is necessary for generating metastable switching. We further show that agents with simplified internal models of the world sustain richer itinerant dynamics as a group than “perfect-foresight” agents, suggesting that bounded rationality may be functionally advantageous for maintaining behavioural flexibility. These results establish active inference as a principled framework for modelling chaotic itinerancy in social systems and offer a computational account of trust-mediated collective transitions observed in theatre workshops and group dynamics.

Constitutive heterozygosity of Tbx1, a T-box transcription factor gene in the 22q11.2 deleted region, produces behavioral deficits and alters myelinated axon composition in the mouse fimbria. However, the cellular origins of these effects—and whether axon changes causally drive behavioral impairments—remain unclear. Prior data link Tbx1 heterozygosity to reduced oligodendrocyte precursor cell (OPC) markers in the fimbria in mice, raising the hypothesis that Tbx1 deficiency specifically in the oligodendrocyte lineage contributes to myelin and behavioral phenotypes. To test this hypothesis, we first showed via in vitro siRNA knockdown that Tbx1 regulates both OPCs and mature oligodendrocytes. We then generated conditional PdgfrαCre;Tbx1+/flox mice to initiate Tbx1 heterozygosity in OPCs. These mice exhibited Cre-mediated recombination in Pdgfrα-expressing brain regions and OPC progeny in the fimbria. At 1 month of age, male mutants displayed enhanced spontaneous alternation in the T-maze relative to wild-type littermates—an effect absent at 2 months. No differences appeared in neonatal ultrasonic vocalizations, social interaction, novel object approach, anxiety-like behavior (elevated plus maze), or open-field locomotion and thigmotaxis. Electron microscopic analysis demonstrated a compositional shift in myelinated axons within the fimbria of adult male mutants: increased numbers in the 300–800 nm diameter range and decreased numbers at ~ 1,200 nm and ~ 1,400 nm, with unchanged myelin thickness across diameters. These results demonstrate that Tbx1 heterozygosity in the oligodendrocyte lineage drives a selective shift toward smaller myelinated axons in the fimbria and a transient cognitive enhancement but does not recapitulate the full myelination abnormalities or the broader cognitive/social deficits observed in constitutive Tbx1 heterozygotes. Thus, Tbx1 function in non-oligodendrocyte lineage cells likely exerts non-cell-autonomous effects on myelination that contribute to neurodevelopmental behavioral impairments.

Long-term hippocampal alterations and cognitive impairment in a murine model of surgical sepsis.

Aim: This study evaluated the comparative effects of commonly consumed artificial and natural sweeteners on cognitive function, neurotransmitter-related enzyme activities, and oxidative stress status in the brains of Wistar rats to elucidate their potential neurotoxic or neuroprotective properties under sub-chronic dietary exposure. Methods: Seventy-two male Wistar rats were randomly assigned to twelve groups and fed composite biscuits formulated with sucrose (15% and 30%), aspartame (3.5% and 7.0%), date sugar (10% and 20%), erythritol (15% and 30%), or stevia (2.5% and 5.0%) for 21 days. Control groups received either a basal diet or plain wheat biscuits. Spatial working memory was assessed using the Y-Maze spontaneous alternation test. Hippocampal tissue was harvested to determine monoamine oxidase (MAO), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) activities, lipid peroxidation (TBARS, thiobarbituric acid-reactive substances), reactive oxygen species (ROS) production, and antioxidant enzyme activities (superoxide dismutase, catalase, glutathione-S-transferase (GST), and glutathione peroxidase). Results: Sucrose (15% and 30%) and aspartame (3.5% and 7.0%) significantly reduced spontaneous alternation performance, indicating impaired working memory. Both sucrose and aspartame dosages markedly elevated MAO, AChE, and BChE activities, increased TBARS and ROS levels, and suppressed antioxidant enzyme activities in the hippocampus. In contrast, diets containing date sugar and erythritol preserved cognitive performance and maintained neurochemical and redox homeostasis. Notably, stevia (5.0%) significantly reduced MAO and AChE activities, attenuated oxidative stress markers, and enhanced endogenous antioxidant defenses. Conclusions: Sub-chronic consumption of sucrose and aspartame induces hippocampal neurotransmitter dysregulation and oxidative stress, contributing to cognitive impairment, whereas natural sweeteners, particularly stevia and date sugar, exhibit neuroprotective effects. These findings support the preferential use of natural sweeteners as safer dietary alternatives for maintaining cognitive and neurochemical health.

This study aimed to investigate the potential of ononin in alleviating mild cognitive impairment (MCI) and to determine whether its effects depend on the functional recovery of neurons in the nucleus tractus solitarius (NTS). Four-month-old APP/PS1 mice were treated with 30-mg/kg ononin via oral gavage for 8 consecutive days. Cognitive behavior was assessed using the novel object recognition test, Y-maze test, and open field test. Cortical perfusion was measured by laser speckle contrast imaging. The activation of NTS neurons was detected using c-Fos immunofluorescence staining, while dendritic complexity and neuronal firing frequency were evaluated via Golgi staining and patch-clamp electrophysiology, respectively. Ononin treatment significantly improved the novel object recognition index and spontaneous alternation rate in the Y-maze test in APP/PS1 mice. It also enhanced cerebral blood flow perfusion and increased the number of c-Fos-positive cells in the NTS, hippocampal CA1 region, and cortex. Furthermore, ononin increased dendritic intersections and restored dendritic spine density in NTS neurons to normal levels, along with significantly elevating their firing frequency. Ononin may ameliorate MCI-like cognitive deficits in APP/PS1 mice by activating NTS neurons, restoring synaptic plasticity, and improving cerebral perfusion. These findings suggest that the NTS could serve as a potential target for early intervention in Alzheimer's disease.

Perinatal walnut-enriched diet partially rescues mitochondrial dysfunction, neuroinflammation, and behavioral deficits induced by developmental manganese exposure.

Synergistic effect of 5-HT4 receptor activation and phosphodiesterase type 7 inhibition on object recognition and working memory performances in adult mice.

Long-term proton pump inhibitor use is associated with cognitive and motor impairments and nutrient deficiencies. Whether these impairments result directly from proton pump inhibitors or indirectly from nutrient deficiencies remains unclear. Chronic pantoprazole treatment (0 or vehicle, 1, 10, or 100 mg/kg/day, by mouth, 38 days) was evaluated across tests of anxiety-like behavior, learning and memory behavior, and motor function and coordination in 4-month-old male C57BL/6 mice. Serum levels of holotranscobalamin and magnesium, as well as poly(A) RNA sequencing of brain tissue, were subsequently evaluated. Pantoprazole (100 mg/kg) reduced the percentage of spontaneous alternations in the Y-maze (P < .05 vs 0 and 1 mg/kg) and decreased the distance traveled in Rotarod testing (P < .05 vs vehicle), suggesting that it impaired short-term working memory behavior and motor coordination, respectively. All pantoprazole doses increased anxiety-like behavior in the open field (P < .05 vs vehicle). In novel (N) object recognition testing, pantoprazole (1 mg/kg) reduced the discrimination index at 24 hours (P < .05, vs vehicle), suggesting it impaired recognition memory behavior. Magnesium levels were similar across chronic pantoprazole groups. Holotranscobalamin, the bioavailable form of vitamin B12, was lower at 10 mg/kg pantoprazole (P < .05 vs vehicle). Poly(A) RNA sequencing identified 15 differentially expressed genes in hippocampus (10 upregulated and 5 downregulated) and 32 in FC (14 upregulated and 18 downregulated) with 100 mg/kg pantoprazole treatment compared to vehicle. There was no correspondence between behavioral changes and alterations in serum nutrient levels with the respective doses of pantoprazole. SIGNIFICANCE STATEMENT: Long-term proton pump inhibitor use may affect cognition, motor function, and nutrient status. This study examined the behavioral impact of chronic pantoprazole treatment in young male mice and whether declines in serum magnesium or holotranscobalamin levels could explain behavioral changes. Doses of chronic pantoprazole that altered behavior were not associated with declines in either nutrient.

SUCNR1-driven microglial polarization: Jiawei Xionggui decoction as a therapeutic strategy for Alzheimer's-related neuroinflammation.