Propionic acid (PPA), a short-chain fatty acid produced by the gut microbiota, has been implicated in neurodevelopmental and neurological disorders, including autism. The PPA animal model is widely used to investigate mitochondrial dysfunction and associated cellular alterations; however, ultrastructural changes in mitochondrial quality-control pathways, particularly those involving mitochondria-derived vesicles, remain poorly characterized. In the present study, we investigated the effects of a single intraperitoneal injection of PPA on mitochondrial vesicular associations in neurons of the medial prefrontal cortex of adolescent male Wistar rats. Animals were randomly assigned to control (PBS, n = 5) and PPA-treated (175 mg/kg, n = 5) groups. Ten days after treatment, brain tissue was processed for transmission electron microscopy, followed by quantitative morphometric analysis of mitochondria associated with single- and double-membrane vesicular structures in neuronal perikarya, neuronal processes, and pre- and postsynaptic compartments. In control animals, mitochondria associated with single-membrane vesicular structures were more frequently observed than mitochondria associated with double-membrane vesicular structures across all analyzed compartments. PPA exposure produced compartment-specific alterations in these associations, characterized by a significant reduction in mitochondria associated with single-membrane vesicular structures in neuronal perikarya and synaptic compartments, together with an increased number of mitochondria associated with double-membrane vesicular structures in presynaptic terminals. Total mitochondrial number remained unchanged following PPA treatment. These findings demonstrate that PPA induces selective remodeling of mitochondrial-associated vesicular structures in the medial prefrontal cortex without affecting overall mitochondrial abundance. The observed alterations suggest that PPA influences mitochondrial quality-control pathways and reveal ultrastructural changes in mitochondrial vesicular trafficking as a previously underexplored feature of this model. Further studies combining ultrastructural, molecular, and functional approaches are required to determine the mechanisms underlying these changes and their relevance to neurodevelopmental disorders.
In the literature on language comprehension during concurrent scene viewing (i.e., the "visual world paradigm"), many studies tacitly assume that the more certain listeners are that an entity is being referred to, the more they gaze at it-and findings often appear to support this assumption. Here we directly test this assumption across two experiments that used identical linguistic materials and visual scenes but differed in task demands. In a task in which participants were instructed to act upon the referent of a pronoun, we observed the typical positive relationship between referential certainty and visual attention to the entity most likely to be the pronoun's referent. However, in a comprehension-only task (i.e., "look-and-listen"), greater referential certainty did not increase looks to the likely referent. Instead, referential certainty was positively related to looks to entities that were not potential referents. Thus, the relationship between referential certainty and visual attention depended on task context. These findings show that eye movements in the visual world paradigm do not necessarily shift to entities whose representations are currently active. Instead, the goals of the listener shape how visual attention is allocated during comprehension. Thus, it is important to consider task context when interpreting eye movements in the visual world paradigm. We speculate that the pattern observed in the comprehension-only task may arise because rather than focusing visual attention on entities that are already well-established in the discourse, listeners may direct their visual attention toward entities that they expect will be more informative given their goal of comprehending the language. We relate our findings to similar phenomena observed during reading, scene description and viewing, and in infants' gaze preferences, as well as to related effects in language production.
Managing agitation after traumatic brain injury (TBI) often involves antipsychotic drugs, despite evidence that dopamine D2 antagonists can impair recovery. Brexpiprazole, a third-generation APD with partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors, may provide a safer alternative. To test the hypothesis that brexpiprazole would not hinder recovery and might improve functional outcomes after TBI, anesthetized adult male rats received a controlled cortical impact or sham injury and were treated with brexpiprazole (0.5, 1, or 2 mg/kg, i.p.) or vehicle beginning 24 h post-injury for 21 days. Motor and cognitive performance were assessed during recovery, and cortical lesion volume was measured on day 21. Sham groups did not differ by treatment and were pooled. Relative to vehicle-treated TBI controls, brexpiprazole did not impair motor recovery at any dose. The 0.5 mg/kg dose improved spatial learning, while the 2 mg/kg dose reduced cortical lesion volume (p < 0.05). Memory retention in the 0.5 mg/kg group was comparable to sham controls. These findings demonstrate dose-specific behavioral and histological benefits of brexpiprazole following experimental TBI without detectable adverse effects on recovery. Although the mechanisms underlying these effects remain unclear, brexpiprazole warrants further investigation as a treatment option after TBI.
Female rugby is a collision sport involving contact events such as tackling, rucking, and scrumming, elevating the risk of sport-related concussion (SRC) and repetitive head acceleration events (rHAEs) in female adolescent athletes. Event-related potentials (ERPs) are neurophysiological markers, which can reflect SRC and rHAEs, however, preseason benchmark ERP characteristics in female adolescent rugby players remain poorly understood, particularly regarding age, concussion history, and Sport Concussion Assessment Tool (SCAT) outcomes. The primary aim was to examine associations between SCAT symptom severity score and ERP outcomes (N100, P300, N400 amplitude and latency) at preseason benchmark. The analyses of symptom number, subdomains, age, concussion history, and days since concussion were exploratory and uncorrected for multiple comparisons. Female adolescent rugby players (ages 15-18) from the 2025 Calgary high school spring season completed preseason ERP assessment. Symptom severity score was not significantly associated with any ERP outcome. In exploratory analyses, each one-unit increase in symptom number was associated with a 1.97 ms decrease in P300 latency (95% CI: -3.86, -0.09; p = 0.041). No significant associations were observed with N400 outcomes. Given the small sample size and lack of correction for multiple comparisons in exploratory analyses, these findings should be interpreted as preliminary and hypothesis-generating. Preseason P300 measures show exploratory associations with symptom burden in female adolescent rugby players. Establishing these benchmark characteristics is critical for interpreting post-concussion and post-season ERP changes in this high-risk population.
Neurological disorders, including ischaemic and haemorrhagic stroke, traumatic brain injury, and chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, represent a major global health burden. Despite diverse etiologies, these conditions share common pathological mechanisms driven by oxidative stress, neuroinflammation, mitochondrial dysfunction, iron dysregulation, and secondary neuronal injury. The nuclear factor erythroid 2-related factor 2 (Nrf2) signalling cascade and its downstream target heme oxygenase-1 (HO-1) are master regulators of cellular redox homeostasis. HO-1 plays a pivotal yet dichotomous role: its products biliverdin/bilirubin and carbon monoxide exert antioxidant, anti-inflammatory, and anti-apoptotic effects, whereas excessive HO-1 induction can exacerbate iron-mediated oxidative injury and ferroptosis through the release of redox-active ferrous iron. Rather than cataloguing protective studies, this review builds a contextual framework that specifies when HO-1 activation is protective versus detrimental, organised around three converging determinants: cell-type specificity, iron-handling capacity, and disease stage. We extend this framework to the often-overlooked dimensions of sex, age, and model heterogeneity, and use it to interrogate conflicting findings across the literature. We further dissect how Nrf2/HO-1 regulates ferroptosis through the GPX4-ACSL4-SLC7A11 axis, critically appraise the largely unexamined relationship between Nrf2 and the parallel FSP1/CoQ10, GCH1/BH4, and DHODH defence systems, and distil lessons from clinical trials of Nrf2 activators. The goal is an analytical account that identifies where the evidence is robust, where it is contradictory, and where the principal research gaps lie.
BACKGROUND:miR-1289 is dysregulated in various cancers, but its mechanism in glioblastoma (GBM) remains unclear. AIMS:This study sought to examine the association between miR-1289 expression and GBM patients' clinical prognosis, and its effect on GBM cell biological behaviors. METHODS:qRT-PCR was used to measure miR-1289 and EFNA5 expression. Kaplan-Meier (KM) survival analysis was used to assess the association of miR-1289 expression and patient survival probability, and a multivariate Cox regression model was utilized to assess its prognostic value. CCK-8 and Transwell assays were utilized to detect GBM cell migration, invasion, and proliferation. Potential target genes of miR-1289 were computationally predicted via an integrated approach using the miRDB database. The direct binding between miR-1289 and EFNA5 was experimentally validated via dual-luciferase reporter assays. RESULTS:miR-1289 was highly expressed in GBM. High miR-1289 expression in GBM correlated with notably shorter survival, and it served as a GBM prognostic marker. Downregulation of miR-1289 significantly inhibited GBM cells' malignant behaviors. Mechanistically, miR-1289 could directly target and regulate EFNA5, and their expressions were negatively correlated in GBM. Knockdown of EFNA5 reversed the tumor-suppressive effect induced by miR-1289 downregulation. CONCLUSIONS:miR-1289 has the potential to be a prognostic biomarker for GBM and promotes the malignant biological behaviors of GBM cells by targeting EFNA5.
RBFOX3 is a neuron-specific RNA-binding protein essential for maintaining brain circuit homeostasis and functional connectivity. Genetic disruptions in RBFOX3 are clinically linked to cognitive impairment, epilepsy, and sleep disorders. Although global Rbfox3 knockout (Rbfox3-/-) mouse models have established its necessity in hippocampus-dependent neuronal circuits and behaviors, the underlying hippocampal transcriptomic landscape and synaptic ultrastructure remain poorly understood. To address these gaps, we integrated hippocampal RNA-sequencing from Rbfox3-/- mice with high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation analysis. We identified 3,401 differentially expressed genes in the hippocampus of Rbfox3-/- mice, confirming 1,920 as candidate RBFOX3 targets. Gene Ontology enrichment analysis revealed that these candidate targets converge on pathways governing neuronal morphogenesis, synaptic transmission, dendritic development, and cognition. Furthermore, transmission electron microscopy of the hippocampal dentate gyrus revealed that while the overall presynaptic area remained unaltered, Rbfox3 deletion reduced presynaptic vesicle number, presynaptic mitochondria area, and postsynaptic density thickness. Collectively, our findings demonstrate that RBFOX3 acts as a critical regulator orchestrating the transcriptomic programs required for hippocampal structural and functional maturation, revealing that its loss compromises both the metabolic and structural architecture of the synapse.
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition involving interactions between genetic and environmental factors. Among environmental exposures, maternal nutrition has received increasing attention. This narrative review critically discusses preclinical evidence on maternal high-fat diet (HFD) exposure and autism-relevant behavioural domains in rodent offspring, focusing on social and anxiety-like behaviours and their underlying neurobiological mechanisms. Maternal HFD exposure was associated with alterations in sociability, social novelty, direct social interaction, aggression, and anxiety-like behaviour. These outcomes varied according to diet and control-diet composition, exposure window, maternal metabolic phenotype, offspring sex and age, species and strain, and behavioural paradigm. Despite significant evidence, the methodological heterogeneity between studies limits the generalisability of the findings and points to the need for standardisation of experimental protocols and further investigation of dimorphic differences and long-term impacts. Additionally, this review highlights the importance of considering contextual factors, such as variations in dietary composition and environmental conditions, which may modulate behavioural and neurochemical outcomes. Furthermore, the integration of interdisciplinary approaches and use of more refined models may improve our understanding of the underlying mechanisms. This review contributes to advancing knowledge regarding the impact of HFD during pregnancy on the neurodevelopment of the offspring.
While physical exercise (PE) acts as a modulator of memory acquisition, its influence on the persistence of consolidated fear memories remains paradoxical in the literature. This divergence suggests that PE can either strengthen or attenuate the original mnemonic trace, as this effect may be conditioned by the initial learning intensity and biological variables, such as sex. This study investigated how a 14-day treadmill PE protocol, initiated after memory consolidation, influences the persistence of contextual fear conditioning (CFC) memory acquired under different learning intensities (0.3 mA or 0.7 mA) in male and female Wistar rats. Memory was assessed at 24 h post-acquisition and then at 15 and 30 days after the start of the PE, using the percentage of freezing (passive defense strategy) and escape behavior (active defense strategy). Results demonstrated that PE had a sex-specific and intensity-dependent modulatory effect. In females, PE significantly reduced the freezing behavior in the 15-day test, specifically in the group that acquired high-intensity memory (0.7 mA). However, this reduction in freezing was accompanied by a significant increase in escape responses, indicating a shift in the defensive strategy. Conversely, PE did not modulate freezing or escape behavior in males at either intensity. Our findings suggest that 14 consecutive days of PE have the potential to attenuate the freezing but not escape behavior, specifically in females. These results reinforce the necessity of considering sex as a biological variable in this type of study and highlight the importance of including the analysis of active behavioral strategies, despite the more traditional one (freezing) in fear memory research.
Cancer patients often experience psychiatric dysfunctions, such as depressive symptoms, which have been shown to persist long after treatment. However, the underlying mechanisms remain elusive. In the present study, we evaluated tumor bearing-associated biological effects on behavior and brain function after cancer remission, using mice that underwent surgical resection of tumors formed following inoculation with colon 26, a murine colorectal cancer cell line. In tumor-resected mice, hippocampal Iba1-positive cells exhibited shortened process length until 14 days post-resection, consistent with the persistent social deficits. Furthermore, in the hippocampus of tumor-resected mice, the area ratio of CD68/Iba1 double-positive cells and the expression level of the Tnf gene were significantly increased. Antidepressant fluoxetine or the microglial modulator minocycline improved both the social deficits and the shortened process length of hippocampal Iba1-positive cells in tumor-resected mice. To clarify the relationship between microglia and neurons, their interactions with synapses were assessed. In the hippocampus of tumor-resected mice, an increased number of PSD-95-positive particles colocalized with Iba1-positive cells was observed, along with a decrease in the density of dendritic spines of hippocampal neurons; these changes were ameliorated by minocycline. These findings demonstrate that functional changes in hippocampal microglia and neuronal structural alterations are associated with social deficits persisting after tumor resection.
Corticosterone (CORT) modulates aversive memory through glucocorticoid receptor signaling. Although classical models emphasize intracellular receptors and transcriptional mechanisms, glucocorticoids can also produce rapid, non-genomic effects through membrane-associated signaling. The dorsomedial striatum (DMS) is critical for goal-directed learning, but its contribution to the extinction of aversive memory remains unclear. Here, we investigated whether membrane-associated glucocorticoid signaling in the DMS modulates inhibitory avoidance (IA) consolidation and extinction as a function of learning strength. Immediately after IA training, rats received bilateral intra-DMS infusions of corticosterone conjugated to bovine serum albumin (CORT-BSA), a membrane-impermeable ligand commonly used to activate membrane-associated glucocorticoid signaling. In a dose-response experiment, post-training intra-DMS CORT-BSA enhanced IA retention, with maximal efficacy at an intermediate dose, consistent with an inverted-U function. Using this effective dose, we then examined extinction across training intensities. CORT-BSA increased resistance to extinction after low-intensity training (0.5 mA), produced a transient effect after moderate training (1.0 mA), and facilitated extinction after intense training (3.0 mA). These findings suggest that rapid membrane-associated glucocorticoid signaling in the DMS modulates the persistence of aversive memory as a function of learning strength, extending current models of striatal involvement in extinction.
Background Sensory processing dysfunction is linked to emotional dysregulation and anxiety in humans. While tactile deprivation is known to impair dorsal hippocampal functions (spatial memory and learning), its impact on the cytoarchitecture of limbic regions central to emotional processing remains poorly understood. Methods: Adult CD-1 mice (postnatal day 50) underwent bilateral infraorbital nerve transection (Tactile Deprivation, TD) or sham surgery. Four weeks later, anxiety-like behavior was assessed using the Open Field (OFT), Elevated Plus Maze (EPM), and Light-Dark Transition tests. Neuronal cytoarchitecture was analyzed in the ventral hippocampal CA1, basolateral amygdala (BLA), and medial prefrontal cortex (mPFC) using Golgi-Cox staining and Sholl analysis. Results: TD induced sex-dependent dendritic remodeling across all regions. In ventral CA1, TD males showed reduced proximal dendritic complexity, while TD females exhibited decreased dendritic branching. In the BLA, TD males displayed soma hypertrophy and a distal shift in dendritic complexity. In the mPFC, TD females showed reduced higher-order branching, while TD males exhibited increased distal complexity. Behaviorally, TD reduced anxiety-like behaviors in a test- and sex-specific manner: males showed reduced anxiety in the OFT, whereas females showed greater reductions in the EPM and increased exploration in the Light-Dark Transition test. Sociability did not show differences. Conclusion: Tactile deprivation produces sex-specific cytoarchitectural reorganization in limbic circuits, which correlates with distinct alterations in anxiety-related behaviors. These findings elucidate the role of tactile experience in shaping emotional regulation in a sexually dimorphic manner.
Interpersonal neural coordination may vary across close-relationship contexts, yet direct comparisons between friendship and romantic relationships remain limited. This study used functional near-infrared spectroscopy (fNIRS) hyperscanning to compare inter-brain synchrony (IBS) between female-female friend dyads and heterosexual romantic dyads during cooperative coordination and shared emotional video viewing. Thirty dyads were initially recruited, and 13 dyads in each group were included in the final analyses. During the cooperative coordination task, female-female friend dyads showed greater IBS than heterosexual romantic dyads in the right inferior frontal gyrus (IFG). No significant main effect of block or dyad type × block interaction was observed. During the shared emotional video-viewing task, heterosexual romantic dyads showed greater IBS than female-female friend dyads in the middle frontal pole and right IFG. No significant between-group differences were observed in the corresponding behavioral measures, and IBS was not significantly associated with behavioral performance. These findings suggest that interpersonal neural coordination varies across close-relationship contexts and task settings. Rather than indicating categorical differences in cognitive or affective empathy, the observed IBS patterns may reflect context-dependent differences in the neural processes supporting cooperative coordination and shared emotional experiences. These findings should be interpreted cautiously given the modest sample size and the confounding of relationship type with dyadic sex composition.
Alzheimer's disease (AD) develops through interacting proteinopathic, metabolic, oxidative, and neuroimmune processes. Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation and failure of antioxidant defense systems. This review examines the bidirectional interface between ferroptosis and neuroinflammation in AD and distinguishes direct AD-related evidence from findings derived from experimental models and broader ferroptosis or inflammatory studies. Iron dyshomeostasis, impaired ferroportin-dependent iron export, lipid peroxidation, and reduced glutathione/GPX4-dependent protection may increase neuronal susceptibility to ferroptotic injury. In turn, oxidized lipids and danger-associated molecular patterns released from damaged neurons may activate microglia and astrocytes, engage inflammasome and complement signaling, and amplify inflammatory responses. Conversely, cytokine signaling, altered iron handling, and immune-cell redox and lipid remodeling may further increase ferroptotic vulnerability. We also compare ferroptosis-related markers and pathways in neurons, microglia, and astrocytes and discuss potential therapeutic approaches targeting iron metabolism, lipid peroxidation, GPX4 activity, system xc - function, NRF2-related antioxidant defense, neuroimmune signaling, and multitarget compounds. Although available evidence supports an association between ferroptosis-related processes and AD pathobiology, no single marker is sufficient to establish ferroptosis in human AD tissue. This limitation currently restricts the diagnostic and therapeutic interpretation of ferroptosis in AD.
Reactive astrocyte transitions are central to neurological disease, yet their long non-coding RNA (lncRNA) regulators remain poorly defined, and single-nucleus studies frequently treat nuclei rather than donors as replicates. This study analyses publicly available human single-nucleus RNA sequencing from four disorders using donors as the unit of inference throughout: Alzheimer's disease (AD; middle temporal gyrus, 88 donors), C9orf72-associated amyotrophic lateral sclerosis and ALS/frontotemporal dementia (ALS; frontal cortex), multiple sclerosis (MS; cortex and white matter), and major depressive disorder (MDD; amygdala). The public MDD release pools nuclei by condition, so that arm cannot support donor-level inference and is exploratory only. Covariate-adjusted pseudobulk analysis of 70,009 CE astrocytes, controlling for sex, age at death and assay chemistry, identified 1,019 down-regulated autosomal lncRNAs after sex-chromosome transcripts were removed. This signature was not attributable to astrocyte subtype composition, which did not differ between groups, and 99.9% of members remained down-regulated within the dominant homeostatic subtype alone. The signature replicated in an independent AD cohort (32 of 41 testable members concordant; resampling P < 0.0001). Testing it outside AD gave a directional result: it was concordant in the MS discovery cohort (P < 0.0001) but inconclusive in an independent MS cohort in which the transcripts lay near the detection floor, and it was reproducibly inverted in ALS, in the C9orf72 discovery cohort and in an independent motor-cortex cohort not restricted to C9orf72 carriers. The inversion survived negative controls for global normalisation and expression level. These astrocyte lncRNA changes are therefore disorder-specific rather than pan-neuroinflammatory.
Chronic unpredictable mild stress (CUMS) is known to negatively impact hippocampus-dependent memory performance. Environmental enrichment (EE) improves memory and neural architecture. Our study aimed to determine the effects of EE on memory performance and neuroinflammation in CUMS-treated rats. Thirty-two 3-month-old male Wistar-Albino rats were randomly assigned to four groups (n = 8): control, CUMS, CUMS + EE, and EE group. The CUMS procedure was performed in standard cages using random stressors, while the EE procedure was performed in literature-compliant cages for 21 days. Animals were subjected to Novel Object Recognition (NOR) and Morris Water Maze (MWM) tests to assess their memory performance. At the end of the experiment, hippocampus and prefrontal cortex (PFC) tissues were isolated, and ELISA and biochemical studies were performed. Levels of BDNF (Brain-Derived Neurotrophic Factor), TrkB (Tropomyosin Receptor Kinase-B), IL-1β (Interleukin-1β), IL-6 (Interleukin-6), NF-κB (Nuclear Factor-κB), and TNF-α (Tumor Necrosis Factor-alpha) were investigated in hippocampus and PFC tissues, along with plasma corticosterone levels and brain tissue levels of MDA (malondialdehyde) and GSH (reduced glutathione). Recognition memory assessed by the Novel Object Recognition test was impaired by CUMS and improved by environmental enrichment. Exposure to CUMS was associated with increased corticosterone, hippocampal IL-1β and IL-6 levels, decreased BDNF and TrkB levels, and impaired recognition memory. Environmental enrichment attenuated these alterations and improved recognition memory. These findings suggest that environmental enrichment may protect against stress-induced cognitive dysfunction and is associated with modulation of oxidative stress, selected inflammatory markers, and BDNF/TrkB signaling.
Annexin A1 (ANXA1) is a multifunctional regulatory protein involved in neuroinflammation and cellular homeostasis, but its role in amyotrophic lateral sclerosis (ALS) remains unclear. In this study, we investigated the relationship between ANXA1 and Hippo pathway signaling in ALS. Bioinformatic analysis of transcriptomic data from iPSC-derived motor neurons showed that ANXA1 expression was reduced in ALS and associated with apoptosis and Hippo pathway-related changes. Decreased ANXA1 expression was confirmed in hSOD1^G93A transgenic mice and NSC34 motor neuron-like cells. Phosphorylation levels of MST1/2, LATS1/2, and YAP1 were elevated, indicates activation of the Hippo pathway. Functional experiments showed that ANXA1 overexpression reduced Hippo pathway activation, enhanced cell viability, and decreased apoptosis, as increased Bcl-2 expression and reduced Bax and cleaved caspase-9 levels. In contrast, ANXA1 knockdown further activated Hippo pathway and aggravated apoptotic changes. These findings identify ANXA1 as an upstream regulator associated with Hippo pathway activation in ALS and suggest that the ANXA1/Hippo axis may represent a potential therapeutic target.
