Zebrafish larvae are increasingly used in behavioural pharmacology because of their translational relevance and suitability for anxiety- and stress-related studies. However, it remains unclear whether commonly used behavioural assays and molecular stress markers provide convergent evidence of anxiolytic-like drug activity. This study therefore aimed not to validate a single predictive screening platform, but to assess the concordance and interpretative value of behavioural and molecular endpoints in larval zebrafish anxiety-related drug screening. Reference compounds with established anxiolytic or antidepressant activity, including diazepam, amitriptyline, and fluoxetine, were used to anchor assay performance. TP003, a GABAergic modulator, and three serotonergic psychedelic compounds, DOI, 5-MeO-DMT, and psilocybin, were included to challenge the assays with pharmacologically diverse mechanisms relevant to stress- and anxiety-related responses. Diazepam showed the strongest cross-assay behavioural consistency compatible with an anxiolytic-like profile. However, this response was not accompanied by reduced cortisol levels or straightforward normalisation of stress-related gene expression. Amitriptyline reduced cortisol but produced only partial behavioural effects, whereas DOI affected selected behavioural preference endpoints and transcriptional markers without significantly reducing cortisol. Fluoxetine and 5-MeO-DMT altered locomotor activity in patterns requiring cautious interpretation, as reduced movement may reflect locomotor suppression or sedation rather than anxiolysis alone. These findings indicate that behavioural and molecular endpoints should not be treated as interchangeable measures of a single anxiety construct. Instead, combined behavioural and molecular assessment is most useful as a profiling framework to identify endpoint-dependent responses, detect sedative or nonspecific locomotor confounds, and support more cautious interpretation of putative anxiolytic-like effects in larval zebrafish.
Exploring the mechanism of Ding-Zhi-Xiao-Wan(DZXW) on disorders of sphingolipid metabolism in Alzheimer's disease(AD) through network pharmacology, molecular docking and animal experiments. The chemical constituents of DZXW were obtained via the TCMSP, with target prediction conducted using the SwissTargetPrediction database; the GeneCards database was consulted to identify targets associated with AD and sphingolipid metabolism disorders. The intersecting targets from these three databases underwent GO and KEGG enrichment analyses. Cytoscape was employed to construct networks and screen core components and targets for molecular docking validation. Animal experiments employed AD model mice, utilising the water maze, ELISA, qPCR, LC-MS, and Western blot to evaluate the effects of DZXW on behavioural, oxidative stress, inflammatory, apoptotic, and sphingolipid metabolism-related indicators. Network pharmacology identified 51 common targets, with enrichment analysis indicating their involvement in multiple pathways including signal transduction, apoptosis, and the phosphatidylinositol 3kinase/protein kinase B(PI3K/Akt) pathway. Molecular docking revealed that multiple components within DZXW(such as cerevisterol and isorhamnetin) interacted with targets including caspase 3(CASP3), mitogen-activated protein kinase 14(MAPK14), estrogen receptor 1(ESR1), and silent information regulator factor 2 related enzyme 1(SIRT1), with SIRT1 being particularly crucial. Animal studies indicate that DZXW enhances learning and memory capacity in AD mice, reduces ceramide levels, and inhibits oxidation factors [4-hydroxynonenal(4-HNE), 8-hydroxy-2'-deoxyguanosine(8-OHdG), nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4)] and inflammatory factors [tumour necrosis factor-α(TNF-α), interleukin(IL)-1β], downregulates CASP3, MAPK14, sphingomyelin phosphodiesterase 1-3(SMPD1-3), B cell chronic lymphocytic leukaemia/lymphoma-2(Bcl-2)-associated X protein(Bax), and increases IL-10, ESR1, mammalian target of rapamycin(mTOR), SIRT1, PI3K phosphorylation, Akt phosphorylation, and Bcl-2. In conclusion, DZXW may improve sphingolipid metabolism disorders in AD by inhibiting neuronal apoptosis and mitigating oxidative and inflammatory responses through the SIRT1/PI3K/Akt pathway.
Diabetic neuropathy (DN) is a multifactorial complication of diabetes mellitus driven by chronic hyperglycemia, insulin resistance, and disturbed metabolic homeostasis, leading to progressive injury of both the peripheral and central nervous systems. This study investigated whether L-serine supplementation could attenuate DN through dose-dependent metabolic and neuroprotective mechanisms in a high-fat diet (HFD) plus streptozotocin (STZ)-induced diabetic rat model. Male Wistar rats (n = 8 per group) were allocated to five groups: normal control (NC), diabetic control (DC), pioglitazone (PIO; 1.5 mg/kg/day), low-dose L-serine (S1; 200 mg/kg/day), and high-dose L-serine (S2; 400 mg/kg/day). After 60 days of oral gavage, behavioural testing, glucose and insulin profiling, HOMA-IR calculation, brain histopathology, nerve growth factor (NGF) immunohistochemistry, and LC-MS/MS-based proteomic analysis of cerebral tissue were performed. Diabetic rats exhibited marked hyperglycaemia (355.33 ± 4.72 mg/dL), hyperinsulinaemia, severe insulin resistance (HOMA-IR 16.8 ± 3.2; a 14-fold increase), impaired thermal nociception, motor dysfunction, and pronounced neuronal degeneration. L-serine supplementation significantly improved metabolic status: S1 reduced HOMA-IR by 77.4% and S2 by 87.5% relative to diabetic controls (p < 0.001). High-dose L-serine produced greater improvements in thermal sensitivity, motor coordination (rotarod latency 26.67 ± 1.52 s vs. 16.1 ± 0.85 s in DC; p < 0.05), and NGF expression (8.6-fold increase vs. DC). Histopathology confirmed attenuation of neuronal injury and gliosis in both treatment groups. Exploratory, group-level proteomic profiling identified dose-specific molecular signatures: S1 was predominantly associated with carbohydrate, lipid, and biosynthetic pathways, whereas S2 was associated with synaptic, neurotransmission-related, and proteostasis pathways. Within the constraints of an exploratory design-group-level pooled proteomics, analysis of cerebral rather than peripheral-nerve tissue, and only two doses-these findings indicate that L-serine attenuates the metabolic and behavioural features of experimental diabetic neuropathy and generates the testable hypothesis of dose-dependent neuro-metabolic remodelling. The proteomic signatures are hypothesis-generating and require orthogonal validation before any mechanistic or translational inference can be drawn.
M8OI is a cytotoxic methylimidazolium ionic liquid solvent through its binding to the ubiquinone binding site on complex I of the mitochondrial electron transport chain. Given the overlap in terms of toxic mechanism of action with the pesticide rotenone, the potential neurotoxic effects of M8OI were examined. In vitro, cytotoxicity and mitochondrial function were assessed in SH-SY5Y cells by measuring MTT reduction and oxygen consumption/extracellular acidification using a Seahorse analyser. SH-SY5Y cells were sensitised to M8OI toxicity by replacing medium glucose with galactose. Glucose protected the cells from M8OI toxicity, whereas galactose showed no clear dose-response protection. M8OI induced a dose-dependent reduction in oxygen consumption rate with a compensatory increase in extracellular acidification rate, consistent with inhibition of mitochondrial oxidative phosphorylation and a shift toward glycolysis. In vivo, rats were orally exposed via drinking water for 20 weeks and assessed using behavioural tests. In addition, the concentrations of M8OI and its metabolites were quantified by LC-MS in rat brain and other tissues. In rats, M8OI concentrations were ~30-fold higher in kidney than brain, and brain levels were at least 100-fold lower than the concentrations that affected SH-SY5Y cell viability in vitro. However, based on open field tests, M8OI exposure suppressed motor activity without any anxious behaviours. The cytotoxicity of M8OI in SH-SY5Y neuroblastoma cells was associated with metabolic mitochondrial dysfunction. However, the neurobehavioural changes observed in orally exposed rats occurred at significantly lower brain concentrations than would be predicted to lead to neural cell death. Nevertheless, direct comparisons between acute in vitro exposures and chronic in vivo outcomes should be interpreted cautiously.
Withania somnifera (L.) Dunal (Solanaceae) is used traditionally for anxiety; however, the activity of the distilled-water root extract and its major withanolide constituents remains incompletely characterised in larval zebrafish. To evaluate the anxiolytic-like effects of a distilled-water root extract and selected withanolides in a larval zebrafish model, and to explore predicted pharmacokinetic properties and putative pharmacodynamic targets of withanolide A using in silico methods. The root powder was extracted with distilled-water and marker compounds were quantified by UPLC-PDA/MS. Anxiolytic-like effects were evaluated in 5 dpf zebrafish larvae using continuous-light and light-dark transition assays, with locomotor activity and reverse-thigmotaxis as behavioural endpoints. Physicochemical and pharmacokinetic properties of withanolide A, withanone and withaferin A were predicted using SwissADME and PreADMET, and network pharmacology analysis was performed for withanolide A. Withaferin A and withanolide A were detected in the extract; withanone was not detected. The extract showed anxiolytic-like activity at 250 μg/mL by reducing dark-phase locomotor activity and increasing central-zone exploration, with effects comparable to 10 μM diazepam. Withanolide A was the most active pure compound, particularly at 100 μM, where it reduced thigmotaxis without suppressing locomotor activity. In silico profiling predicted favourable drug-likeness and intestinal absorption, but limited blood-brain barrier penetration. Network analysis identified 33 anxiety-related targets, including CRHR1, CYP3A4, NR3C1, GRM5, AR, MAOB and OPRM1. The findings support the ethnomedicinal use of W. somnifera for anxiety-related conditions and suggest that withanolide A may contribute to these anxiolytic-like effects through putative multi-target mechanisms.
Digital technology has rapidly transformed how people communicate, learn, and perform professional activities. While technological advancements have improved access to information, productivity, and global connectivity, excessive reliance on digital devices has raised concerns regarding cognitive and behavioral health. Emerging evidence suggests that prolonged screen exposure, constant multitasking, and dependence on digital aids may contribute to cognitive symptoms resembling dementia, including impaired attention, memory difficulties, reduced problem-solving ability, and emotional disengagement. This phenomenon, often described as "virtual dementia" or "digital dementia," has become an area of growing scientific and public health interest. Current evidence indicates that excessive digital technology use may alter neural circuits involved in cognition, particularly within the prefrontal cortex, hippocampus, and the Default Mode Network. These changes may manifest as digital amnesia, attentional fragmentation, mental fatigue, reduced social engagement, and emotional blunting. Adolescents and young adults appear especially vulnerable due to ongoing neurodevelopment, although many of these changes may be reversible with behavioral modification. Unlike neurodegenerative disorders such as Alzheimer's disease, virtual dementia is characterized by lifestyle-associated and potentially reversible cognitive dysfunction. At the same time, digital technologies also show therapeutic potential in cognitive monitoring, rehabilitation, and preventive interventions, highlighting their dual role in brain health. Virtual dementia represents a potentially reversible form of technology-associated cognitive impairment driven by maladaptive digital behaviours. Promoting digital hygiene, mindful technology use, cognitive training, and responsible technology policies may help protect cognitive health. Future longitudinal and mechanistic studies are needed to establish diagnostic criteria, clarify long-term neurological effects, and develop evidence-based prevention and intervention strategies.
Maternal immunisation allows the transfer of protective antibodies to the offspring, reducing the risk of severe infection during early life. While vaccination during pregnancy is clinically recommended, its long-term impact on neurodevelopment remains under investigation. Autism spectrum disorder (ASD) is a neurodevelopmental condition characterised by social and behavioural alterations. Here, we evaluated whether prenatal exposure to the COVID-19 mRNA BNT162b2 vaccine or influenza vaccine affects general and autism-related behavioural outcomes in juvenile (4 weeks) and adult (8 weeks) mouse offspring. We also assessed maternal and fetal immune responses by measuring cytokines, soluble P2X7 receptor, BDNF, CRP, and lipid peroxidation in maternal plasma and fetal brain tissue. Prenatal COVID-19 vaccination elicited a moderate maternal cytokine response (increased IL-6 and KC) without overt fetal brain inflammation. Mild, age- and sex-dependent behavioural changes were observed, including anxiety-related parameters in the elevated plus maze and altered locomotion in the open field at 4-8 weeks, however, no consistent or robust ASD-like behavioural phenotype emerged across ages. Fetal P2X7 receptor levels were elevated, while fetal CRP, BDNF, and TBARS remained unchanged. In adult offspring, BDNF was selectively reduced in the prefrontal cortex, whereas hippocampal BDNF and P2X7 receptor levels in both regions were unaffected. Although embryonic P2X7 receptor levels were transiently elevated following COVID-19 vaccination, these changes were not accompanied by fetal inflammation or persistent adult purinergic alterations. Prenatal influenza vaccination induced mild, age-dependent behavioural alterations, such as increased circling in juveniles and reduced sociability in females, without detectable maternal or fetal inflammatory responses or changes in fetal neurotrophic markers. In contrast, maternal poly(I:C) administration provoked robust systemic inflammation and pronounced fetal brain effects, including elevated cytokines, CRP, P2X7 receptor, and region-specific microglial density, accompanied by persistent reductions in adult BDNF expression. Overall, within the limits of this experimental design, prenatal COVID-19 vaccination did not produce long-lasting ASD-like phenotypes or widespread neurodevelopmental alterations, while influenza vaccination had limited and transient effects. These findings are consistent with the absence of widespread or persistent neurodevelopmental disruption in this experimental model, although further studies-including multiple doses, gestational timepoints, and cellular-level analyses-are warranted to fully elucidate mechanisms and long-term outcomes.
Diabetes mellitus is associated with cognitive impairment and neurodegenerative changes, partly through hyperglycaemia-driven neuroinflammation and disrupted neuronal signalling. Retatrutide, a triple GIP/GLP-1/glucagon receptor agonist, has shown strong metabolic efficacy, but its effects on diabetes-associated cognitive dysfunction remain unclear. The present study investigated whether Retatrutide attenuates learning- and memory-related impairments in a streptozotocin-induced, insulin-deficient diabetic rat model. Male Sprague-Dawley rats were allocated to four groups: control (C), streptozotocin-induced diabetic (STZ), streptozotocin-induced diabetic treated with Retatrutide (STZR), and Retatrutide alone (R). Diabetes was induced with streptozotocin, and spatial learning and memory were assessed using the Morris Water Maze and Passive Avoidance tests. Metabolic parameters were monitored, while hippocampal cytokine levels (IL-1β, TNF-α), BDNF, CREB, and AKT mRNA expression, Tau protein levels, and cortical and hippocampal histopathology were evaluated using biochemical, molecular, and histological methods. Streptozotocin-induced diabetes produced persistent hyperglycaemia, marked body weight loss, and impaired behavioural performance, particularly prolonged escape latencies in the Morris Water Maze and a selective short-term Passive Avoidance deficit. Retatrutide reduced blood glucose levels but did not prevent diabetes-associated weight loss. In behavioural testing, Retatrutide-treated diabetic rats showed preserved overall Morris Water Maze performance relative to untreated diabetic rats and a limited, task-dependent attenuation of short-term avoidance deficits rather than complete normalisation across all memory measures. These effects were accompanied by a significant reduction in hippocampal TNF-α, a non-significant trend toward lower IL-1β, and partial preservation of cortical and hippocampal cytoarchitecture. Retatrutide alone did not improve behavioural performance beyond control levels, although BDNF and CREB mRNA expression were increased in the non-diabetic Retatrutide group. These findings indicate that Retatrutide is associated with a partial attenuation of streptozotocin-induced behavioural and neuroinflammatory alterations in male rats. The observed effects are consistent with actions extending beyond glycaemic control alone, although direct central exposure of Retatrutide was not established in the present study. Further studies in insulin-resistant and type 2 diabetes-like models are needed to clarify the underlying mechanisms and translational relevance.
The increasing prevalence of nutrition-related diseases and the limited availability of convenient, metabolically safe, high-protein foods represent a pressing public health challenge. This study aimed to evaluate the effects of four composite animal-derived high-protein ingredients based on collagen enzymatic hydrolysates on physical endurance, feeding behaviour, carbohydrate metabolism, renal function, and behavioural parameters in rats. Four lyophilised collagen hydrolysate-based ingredients were developed using enzymatic biotransformation of bovine and porcine raw materials, combined with bovine whey protein concentrate, bovine meat trim hydrolysate, porcine blood plasma proteins, and an api-component (Samples 1-4; protein content 87-89%). Ninety male Wistar rats were randomised into one control group and four experimental groups (n = 20 per experimental group, n = 10 controls) and received test samples by intragastric gavage at 3000 mg/kg/day for 40 days. Physical endurance was assessed via a weighted forced swimming test (days 0, 30, and 40); behavioural status by open field, adhesive removal, and marble burying tests; and biochemical parameters (blood glucose, serum urea, creatinine, urinary protein, and GFR) at days 0 and 40. All experimental groups demonstrated a significant reduction in standard chow consumption (19-24%, p < 0.01) without affecting body weight gain. Physical endurance improved significantly in all groups relative to baseline, with the most pronounced effect in the Sample 3 group (+39% at day 40, p < 0.05). Blood glucose levels were significantly reduced across all groups (9-16%, p < 0.05). No adverse behavioural effects were observed. Biochemical markers indicated an adaptive rather than pathological renal response, with elevated GFR in three of four experimental groups (p < 0.05) and reduced proteinuria in the Sample 1 and Sample 3 groups. Forty-day administration of collagen hydrolysate-based protein complexes improved physical endurance and glucose metabolism, reduced food intake without compromising body weight, and did not impair renal function or behavioural status in healthy adult rats. These findings support the potential of such ingredients as functional food components, pending confirmation of long-term safety in extended studies.
Myelin, a multilamellar sheath produced by oligodendrocytes, ensures rapid electrical impulse conduction and maintains axonal integrity in the central nervous system (CNS). Demyelination, the loss or disruption of this protective sheath, is a key pathological consequence of traumatic brain injury (TBI) that exacerbates axonal injury and ultimately contributes to persistent cognitive and motor deficits. Currently, no therapies specifically target demyelination after TBI. Liver X receptors (LXRs) regulate lipid metabolism, cholesterol homeostasis, and inflammation in CNS cells. Activation of LXRs promotes oligodendrocyte maturation, enhances myelin gene expression, and facilitates remyelination. We hypothesized that GW3965, a synthetic LXR agonist, would enhance myelination and improved cognitive outcomes after TBI. C57BL/6 mice were subjected to mild TBI using a closed-head injury model and treated orally with GW3965 (10 mg·kg-1·day-1) starting 1 day post-injury for 3 weeks. Cognitive and behavioural performance was assessed using the modified Neurological Severity Score, open-field, novel object recognition, and Y-maze tests. On day 28 post-TBI, cortical tissues were analysed by immunofluorescence and a ProteinSimple® capillary-based immunoassay. TBI caused sustained neurological and cognitive impairments characterized by demyelination, axonal injury, and neuronal loss. GW3965 treatment significantly preserved mature oligodendrocytes and myelin, reduced axonal degeneration, and improved behavioural performance. This study provides novel insights into the role of LXR activation via GW3965 in mitigating TBI-induced demyelination and axonal injury, while preserving mature oligodendrocytes and cognitive and behavioural outcomes. These findings advance our understanding of brain repair mechanisms and highlight LXR activation as a promising therapeutic strategy for TBI-related neurological damage.
Autism is a multifactorial neurodevelopmental disorder characterized by social deficits, stereotypical behaviour, and neurotransmitter imbalance. This study evaluated the neuroprotective potential of Puerarin (PUN) and Magnesium Acetyl Taurate (MGAT) in a propionic acid (PPNA)-induced rat model of autism. PPNA was administered intracerebroventricularly for 11 consecutive days to induce autism-like features, followed by a 44-day treatment period with PUN (300 mg/kg, i.p.) and MGAT (500 mg/kg, p.o.). A comprehensive assessment was conducted, including behavioural analysis, biochemical and molecular evaluations, cerebrospinal fluid and plasma profiling, and histopathology. Treatment with PUN and MGAT, particularly in combination, improved behavioural outcomes, restored neurotransmitter balance, reduced neuroinflammation and apoptotic signaling, and attenuated activation of the glutaminase-glutamate/NMDAR and MAPK pathways (C-JNK, ERK1/2, P38 MAPK). Additionally, treatment increased magnesium levels and PSD-95 expression, indicating significant neuroprotection. These findings support the potential of PUN and MGAT as a multitarget therapeutic strategy for autism and warrant further translational investigation.
Neuroanatomy is widely recognised as one of the most challenging subjects in health professions education due to its complex three-dimensional structures and spatial relationships. Technology-enhanced learning has increasingly been incorporated into neuroanatomy education to facilitate learning. This review aimed to evaluate the effectiveness of technology-enhanced learning interventions in teaching practical neuroanatomy skills. This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Randomised controlled trials published between 2013 -2023 that evaluated technology-enhanced learning interventions in neuroanatomy education were included using a Rayann software. Nine studies met the eligibility criteria and were analysed using the modified Kirkpatrick model to assess educational outcomes. Learner's motivation and engagement (Kirkpatrick Level 1) were consistently high. for virtual reality,3D visualisation, and stereoscopic learning modules, with students reporting increased satisfaction, confidence, and perceived understanding. Augmented reality inventions demonstrated more valuable responses, often influenced by design, quality, and implementation. Improvements in objective learning outcomes (Kirkpatrick Level 2) were reported in several studies, particularly those employing 3D visualisation and virtual reality tools. However, these findings were not consistent across all interventions. Technology enhanced learning appeared particularly beneficial for supporting cognitive engagement and visuospatial understanding of complex neuroanatomical concepts. Considerable heterogeneity was observed across intervention types, pedagogical approaches, and outcome measures. Few studies evaluated behavioural changes (Kirkpatrick Level 3) or long term educational impact (Kirkpatrick level 4). Technology -enhanced learning, particularly 3D visualisation and virtual reality, shows promise as a complementary approach to neuroanatomy education by enhancing learner's engagement, motivation, confidence, and spatial understanding. While improvement in object knowledge, outcomes were reported in several studies, evidence of superiority over conventional teaching approaches remains inconsistent. The evidence base was restricted to randomised controlled trials and was driven from undergraduate medical student populations, which may limit the generalisability of the findings. Further high -quality longitudinal studies are needed to evaluate behavioural change, long-term knowledge retention, and educational impact.
Xylopic acid (XA) and the deacetyl derivative (dXA) have been shown to exhibit antidepressant activity in acute models of depression in mice. This study evaluated and compared the effect of the deacetyl derivative in a chronic restrain model of depression. In the first phase of the study, the synergistic potential of dXA was evaluated using the mouse tail suspension test (TST) and forced swim test (FST). In the second phase, mice were subjected to chronic restraint stress for 42 days, starting from day 0, in ventilated tubes (0800-1400 h). On day 42, stress-naïve and stressed mice were assessed using both the FST and TST to identify the more sensitive behavioural assay for subsequent evaluation of treatment effects. Stressed mice were then administered fluoxetine, XA, dXA, vehicle for 72 h or single acute dosing of combinations of fluoxetine with XA or dXA, followed by repeat behavioural testing 90 min after the last dose of either a single acute or a chronic dosing regimen. The interaction index (γ), together with the significantly lower ED50mix compared to the ED50add, for the dXA combinations, with fluoxetine, sertraline, imipramine and ketamine is indicative of synergistic effect. An 8-hourly dosing, for 72 h of XA (100 mg kg-1) and dXA (100 mg kg-1) in the acute models did not reverse the behavioural traits of chronic restrain. However, fluoxetine (30 mg kg-1), given 12 hourly for 72 h, and the acute administration of combinations of fluoxetine (100 mg kg-1) and dXA (100 mg kg-1) significantly reversed the duration of immobility. The present study demonstrates that deacetyl xylopic acid (dXA) exerts synergistic antidepressant-like effects with selective antidepressants and augments the antidepressant effects of fluoxetine in a mouse model of chronic restraint stress-induced depression. These findings suggest that dXA may represent a promising adjunctive agent for improving antidepressant efficacy, particularly in stress-related depressive disorders.
Tourette syndrome is a neuropsychiatric disorder whose physiopathology is still poorly understood. It involves alterations in the dopaminergic system within the cortico-basal ganglia-thalamo-cortical loops although several hypotheses from the literature implicate the glutamatergic system. Our objective was to study the activity of NMDA receptors (NMDARs) in vivo in patients with Tourette syndrome compared to healthy controls. PET imaging was used in patients with Tourette syndrome (n = 12) and healthy controls (n = 12) with a new radioligand, the [18F]-FNM, which binds to activated NMDARs. Clinical and behavioural assessments were also performed on patients to evaluate tics severity (YGTSS), obsessive-compulsive disorder (Y-BOCS), impulsivity (BIS-11) and anxio-depressive state (HAD). PET activity was compared between groups in different ROIs. Correlations were made between PET activity and clinical/behavioural scores in patients with Tourette syndrome. Significant differences in NMDAR activity were found between patients with Tourette syndrome and controls in the right and left ACC, the right caudate nucleus, the right olfactory cortex and the left paracentral lobule: patients with Tourette syndrome exhibited higher NMDAR activity in these ROIs. Moreover, this hyper-NMDAR activity in the ACC correlated positively and significantly with YGTSS scores in patients with Tourette syndrome. Patients with Tourette syndrome showed higher NMDAR activity in the ACC, caudate nucleus, paracentral lobule and olfactory cortex. This presumed hyper-glutamatergic activity may indicate a hyper-activation of the direct striatal pathway leading to the onset of tics, in addition to the supposed hypo-activation of the indirect striatal pathway related to hypo-GABAergic state reported in the literature. Tourette syndrome would therefore be associated with an imbalance between excitatory and inhibitory influences within the cortico-basal ganglia-thalamo-cortical circuit.
Highly Superior Autobiographical Memory (HSAM) is a rare condition characterised by an exceptional ability to recall personal past experiences in remarkable detail and with great accuracy. Although HSAM has been extensively documented in adults, the age at which it first manifests remains unknown. Here, we present the first documented case of HSAM in early adolescence. A 13-year-old boy (AA) underwent assessment using a newly developed personalised autobiographical memory test modelled on established adult HSAM screening procedures. AA's performance was then compared with that of six age-matched controls and his younger sister. Additional neuropsychological, cognitive, and behavioural assessments were administered to evaluate potential differences beyond autobiographical recall. AA achieved near-perfect accuracy in recalling public, school and personal life events, significantly outperforming all of the other participants, while exhibiting a typical cognitive and behavioural profile in all other areas, as well as obsessiveness/compulsiveness tendencies like those observed in several adults with HSAM. These findings show that HSAM can appear during early adolescence, before the age typically associated with the full development of autobiographical memory capacity (around 15-17 years old). The early manifestation of HSAM poses a challenge to classical models of memory development, suggesting an accelerated or atypical trajectory of autobiographical memory maturation. While presenting a novel, sensitive approach with the capacity to identify HSAM in its developmental stages, this study also provides novel insights into the development of exceptional forms of autobiographical memory.
Investigating the cognitive effects of sevoflurane exposure during early development is essential due to its potential long-term neurodevelopmental impacts. This investigation systematically explored the molecular basis of sevoflurane-induced cognitive impairment, with emphasis on m6A RNA modifications and ubiquitin-dependent proteostasis involving Mid1 and Syngap1. Using integrated approaches, including methylated RNA immunoprecipitation sequencing (MeRIP-seq), transcriptomic profiling, neurobehavioural testing and molecular analyses, 2091 m6A methylation sites were identified that were differentially regulated. Mechanistically, Mid1 was found to orchestrate Syngap1 degradation via the ubiquitin-proteasome pathway, establishing a direct link between protein stability control and cognitive outcomes. Behavioural phenotyping demonstrated that Mid1 suppression ameliorated learning and memory deficits in sevoflurane-exposed mice, which was corroborated by improved neuronal viability and attenuated apoptotic signalling in biochemical assays. Epigenetic regulation studies further revealed that the m6A eraser ALKBH5 and the reader YTHDF2 collaboratively modulate Mid1 mRNA stability, thereby contributing to neuropathological progression. Pathway analysis uncovered Mid1-Syngap1 axis-mediated dysregulation of MAPK signalling cascades, proposing this network as a potential therapeutic target. Collectively, the present findings delineated a novel m6A-ubiquitin regulatory circuit centred on Mid1 that drives sevoflurane-associated cognitive dysfunction, offering mechanistic insights for the development of neuroprotective interventions against anaesthesia-related neurotoxicity in paediatric and other at-risk populations.
We appreciate the interest of Joaquin et al in our recent study on the treatment persistence of ixekizumab in psoriatic arthritis. In response, we clarify that our study utilized prospectively collected real-world clinical data from a multicenter observational cohort, rather than administrative databases. We emphasize the importance of persistence, as assessed through the Drug Retention Rate (DRR), a validated measure in observational studies of biologic therapies. The DRR reflects a complex interplay of factors, including efficacy, safety, and patient choice, making it a valuable indicator of therapeutic performance. We agree that adherence is an interesting topic, but argue that its absence does not invalidate persistence data. Our study was designed to evaluate treatment persistence, not behavioural pharmacology. We believe that our methodological rigor, real-world design, and consistency with international literature make our data a reliable reference for understanding ixekizumab persistence in routine clinical pratice.
Avoidance behaviour, a core feature of the "Behavioural Immune System," minimizes exposure to pathogens but limits social and environmental engagement. For some individuals, the benefits of approaching attractive but risky stimuli may outweigh the costs of avoiding them. In spontaneously approaching (AP) mice, we identified the neuronal and immune correlates that contribute to individual differences in approach to positive yet potentially risky stimuli. AP mice displayed enhanced excitatory synaptic transmission and excitability in the pyramidal neurons of the medial prefrontal cortex (mPFC), a neuronal transcriptomic profile enriched for immune pathways, and an increased abundance of T lymphocytes in both the mPFC and peripheral blood. Microglia in AP mice exhibited a pro-inflammatory shift with reduced anti-inflammatory markers. Modulating lymphocyte trafficking with fingolimod abolished the approach phenotype and reduced cerebral T cells, whereas microglial inhibition with minocycline did not affect approach behaviour. These findings reveal that T-cell-associated immune modulation plays a critical role to maintain risk-oriented approach behaviour, suggesting a functional coupling between adaptive immunity and prefrontal circuits. We propose an "Approaching Immune System" that complements the classical Behavioural Immune System in regulating the flexibility of approach-avoidance behaviours. The findings provide ground-breaking insight into neuronal and immune circuits orchestrating adaptive behaviours, offering broad translational relevance for psychiatric, infectious, and chronic inflammatory disorders.
Opioid use disorder, particularly involving fentanyl, poses major challenges due to high relapse rates and limited effectiveness of pharmacotherapies. The kynurenine pathway has emerged as a target for addiction treatment through its modulation of glutamatergic and dopaminergic neurotransmission. This study investigates the effects of kynurenine 3-monooxygenase (KMO) inhibition on fentanyl self-administration in rats. Adult male rats received the KMO inhibitor, Ro 61-8048 during fentanyl self-administration. Responding was assessed across acquisition, maintenance, extinction and reinstatement. The involvement of nicotinic acetylcholine receptor α7 subunit (α7nAChR) was investigated using the positive allosteric modulator PNU-120596. Sucrose self-administration, locomotor activity and rotarod performance were also evaluated. Kynurenine pathway metabolites were quantified in plasma and nucleus accumbens using ultra-performance liquid chromatography-mass spectrometry. Ro 61-8048 reduced fentanyl intake and active lever responding across all addiction phases. These effects were associated with increased kynurenic acid (KYNA) levels and altered kynurenine pathway metabolite profiles. PNU-120596 did not prevent Ro 61-8048 effects, indicating an α7nAChR-independent mechanism. Although Ro 61-8048 reduced sucrose self-administration and spontaneous locomotor activity, it did not affect rotarod performance, progressive ratio breakpoints nor did it produce aversive behaviour suggesting that KMO inhibition modulates the reinforcing strength of both drug and natural rewards, rather than inducing general behavioural suppression. KMO inhibition with Ro 61-8048 robustly attenuates fentanyl-directed behaviour and affects kynurenine pathway metabolism beyond a shift towards KYNA production. These findings support KMO inhibition as a potential therapeutic strategy for opioid use disorder and warrant further investigation into its underlying mechanisms and translational potential.
Assisted reproductive technology influences the epigenetic landscape of offspring, but whether trigger-day pharmacotherapy affects epigenetics and neurodevelopment remains unclear. In a prospective birth cohort of 365 families, higher trigger-day human chorionic gonadotropin dose associates with reduced global DNA methylation in peripheral blood from offspring conceived assisted reproduction compared with naturally conceived children. In a cohort of 1333 singleton offspring, higher maternal human chorionic gonadotropin dose associates with increased risk of suboptimal neurodevelopment. In mice, transient human chorionic gonadotropin exposure impairs offspring neurocognitive behaviours, reduces hippocampal dorsal dentate gyrus neurogenesis, and downregulates euchromatic histone methyltransferase 1 expression with reduced methylation observed in oocytes. Microinjection of euchromatic histone lysine methyltransferase 1 mRNA into exposed zygotes restores neurogenesis and improves behavioural outcomes in offspring. These findings suggest potential epigenetic and neurodevelopmental risks of higher-dose human chorionic gonadotropin exposure and support optimized trigger protocols in assisted reproductive technology that balance treatment efficacy with long-term offspring health.