BACKGROUND:Although educational attainment influences both cognitive function and metabolic regulation, the biological mechanisms underlying this relationship remain unclear. This study investigated whether cerebrospinal fluid fibroblast growth factor 21 (CSF FGF21) mediates the association between educational attainment and cognitive function, and whether this pathway is moderated by the KLB rs17618244 genotype. METHODS:A total of 186 participants were included in this cross-sectional study. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA), and CSF FGF21 levels were measured. Genotyping of the KLB rs17618244 variant was performed using MassARRAY single nucleotide polymorphism genotyping technology. Mediation and moderated mediation analyses were conducted using the PROCESS macro. RESULTS:CSF FGF21 significantly mediated the association between educational attainment and cognitive function (β = 0.02, 95% CI: 0.0003 to 0.0526). Moderated mediation analysis further indicated that the KLB rs17618244 genotype significantly moderated this indirect pathway (Index = -0.05, 95% CI: -0.1219 to -0.0002). Specifically, the indirect protective effect of educational attainment on cognitive function through CSF FGF21 was significant only among AA/AG carriers (Effect = 0.05, 95% CI: 0.0060 to 0.1205), but not among GG carriers. CONCLUSION:In this cross-sectional study, CSF FGF21 statistically accounted for part of the association between educational attainment and cognitive function, particularly among KLB rs17618244 AA/AG carriers.
The normalization of ethanol consumption in Western societies represents a major public health concern, particularly when drinking begins during adolescence. The ketogenic diet (KD) has demonstrated therapeutic potential in various conditions, including substance use disorders. This, together with evidence showing that the diet does not significantly affect locomotor activity or aversive and spatial memory in adolescent male mice, makes it an interesting tool for addressing ethanol consumption during a critical developmental period: the transition from adolescence to young adulthood. However, the lack of evidence in females highlights an important gap in current research. This study aimed to evaluate the effects of a KD during adolescence on behavioral profile and ethanol consumption during young adulthood in female OF1 mice. In Experiment 1, behavioral profile was assessed after administration of a KD or control diet from postnatal day (PND) 25 to PND 48. Motor activity, anxiety-like behavior, memory, and learning were evaluated. In Experiment 2, ethanol consumption was assessed using the Drinking in the Dark and operant self-administration paradigms following dietary intervention from PND 39 to PND 82. The KD did not alter locomotion, anxiety-like behavior, or aversive memory, but enhanced hippocampus-dependent spatial memory. Molecular analyses revealed changes in gene expression, including Adora2a, Opmr1, Drd1, Cnr1, and Il-6. Additionally, KD significantly reduced ethanol consumption, which was associated with altered expression of Crhr1, Drd2, Adora2a, and Adora1. These findings support the potential of KD as a therapeutic strategy for reducing ethanol intake in females without negatively impacting behavioral development during adolescence.
Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are among the progressive disorders of the nervous system that are characterized by the gradual destruction of neurons, the accumulation of misfolded proteins, and the limited effective therapeutic options. In recent years, numerous lines of evidence have emphasized the important role of extracellular vesicles (EVs) in the formation and progression of these diseases. These vesicles are membrane-bound nanoscale structures that are secreted by almost all cell types and play a role in cell-cell communication through the transfer of molecules such as proteins, lipids, and nucleic acids. In neurodegenerative disorders, EVs can facilitate the transport and dissemination of disease-related proteins, including amyloid-β, tau, α-synuclein, mutant huntingtin, SOD1, and TDP-43, thus contributing to the spread of pathological processes in different parts of the nervous system. On the other hand, the ability of these vesicles to cross the blood-brain barrier and reflect molecular changes occurring in the central nervous system makes them valuable candidates for the development of minimally invasive biomarkers. This review reviews the biogenesis, classification, isolation methods, and molecular content of EVs, and analyzes their role in the pathogenesis, diagnosis, and treatment of the most important neurodegenerative diseases. Also, the importance of EV-associated proteins, RNAs, and lipids as emerging diagnostic biomarkers, as well as the therapeutic potential of natural and engineered vesicles as drug delivery systems and regulators of neuroinflammation and neurodegenerative processes, is discussed.
BACKGROUND:Stroke remains of the leading causes of mortality/long-term disability worldwide, with post-stroke seizures and secondary neuronal injury contributing to unfavorable outcomes. Levetiracetam (LEV), the widely used antiepileptic drug in clinical practice, has demonstrated neurobiological effects beyond seizure control in experimental models, raising interest in its potential role in stroke-related neuroprotection and neurological recovery. OBJECTIVE:To synthesize experimental and clinical evidence on LEV in stroke, focusing on (i) preclinical neuroprotective mechanisms and outcomes and (ii) clinical outcomes in stroke populations, particularly post-stroke seizure management and safety. METHODS:We conducted a narrative review informed by a comprehensive literature search of major biomedical databases (PubMed/MEDLINE, Scopus, Web of Science Core Collection, Embase, and Google Scholar) from 2001 to 2025, and eligible studies included preclinical stroke models evaluating LEV and clinical studies involving LEV use in stroke patients. Study selection and data extraction were performed using predefined criteria and risk of bias was further assessed using standardized tools. Due to heterogeneity in stroke models, patient populations, interventions, and outcomes, findings were synthesized narratively and summarized in structured tables. RESULTS:The preclinical literature suggests that LEV may reduce infarct volume and improve neurological outcomes in several ischemic and hemorrhagic stroke models. Reported mechanisms include modulation of neuroinflammatory signaling, attenuation of apoptosis, reduced oxidative stress, and preservation of blood-brain barrier integrity, although methodological limitations and incomplete reporting contribute to uncertainty across studies. In clinical studies, the most consistent evidence supports LEV use for post-stroke seizure treatment and prevention, with generally favorable tolerability compared with older antiepileptic drugs. However, direct clinical evidence supporting LEV as a neuroprotective therapy to improve stroke lesion outcomes or long-term functional recovery remains limited and indirect. CONCLUSIONS:Experimental data support biologically plausible neuroprotective effects of LEV in stroke models, while clinical evidence primarily supports its role in post-stroke seizure management and tolerability. The potential for LEV to modify stroke-related neurological injury in humans remains uncertain and requires well-designed clinical trials with stroke-specific neuroprotection endpoints.
With growing recognition that somatic symptoms constitute a clinically significant yet underexplored dimension of major depressive disorder (MDD), symptoms including sleep disturbances, gastrointestinal discomfort, pain, appetite changes, and fatigue have attracted increasing research attention. These symptoms are not only highly prevalent but are also closely associated with poor prognosis, treatment resistance, and elevated suicide risk. In this context, neuroimaging studies of the somatic manifestations of MDD have provided critical insights to advance precision diagnosis and individualized intervention. This review comprehensively integrates functional and structural neuroimaging findings on discrete somatic symptoms and somatic symptom clusters in MDD. It identifies the specific neural circuit abnormalities associated with individual symptom domains while elucidating shared pathophysiological mechanisms across symptom types, including disrupted interoceptive processing, pathological default mode network activity, and impaired sensory gating. On this basis, the review discusses the therapeutic and predictive implications of these findings and proposes future research directions oriented toward network-based brain-symptom mapping, transdiagnostic and longitudinal designs, and multimodal multilevel integration. By synthesizing existing evidence, this review provides a framework for understanding the neural substrates of somatic symptoms in MDD, developing somatic phenotype-based biomarkers and targeted neuromodulation therapies, and integrating systems-level neuroimaging into precision psychiatry to advance biologically informed diagnosis/treatment.
Patients with neuropathic pain also experience depression. Although they are treated with various therapies, the effectiveness of these medications is unclear. In the present study, the effect of buspirone on allodynia and depressive-like behavior caused by chronic constriction injury (CCI) of the sciatic nerve, as well as the role of opioid pathways, was investigated. Our findings showed that acute and sub-chronic administration of buspirone (0.3-10 mg/kg) attenuated the mechanical and cold allodynia induced by CCI. In addition, a moderate dose of buspirone (1 mg/kg), but not a high dose (10 mg/kg), reduced the depressive-like behavior induced by CCI. Furthermore, pretreatment with naloxone attenuated the effects of buspirone, whereas co-administration with an ineffective dose of morphine potentiated its action. Also, hippocampal μ-opioid receptor mRNA was decreased, whereas κ-opioid receptor mRNA was increased in CCI mice 14 days after surgery. However, repeated buspirone in CCI-mice mitigated the observed alteration in opioid receptors mRNA expression. In addition, unlike morphine, buspirone did not produce tolerance or withdrawal symptoms following repeated administration. Collectively, these data provide evidence that buspirone can effectively alleviate neuropathic pain and exerts antidepressant-like benefits, potentially through modulation of opioid receptors. Moreover, the effects of buspirone may also be associated with changes in mRNA expression of μ-and κ-opioid receptors in the hippocampus.
Manual asymmetries in goal-directed aiming have been linked to interhemispheric interactions, yet it remains unclear whether experimentally modulating hemispheric activity alters both motor behavior and interhemispheric functional coupling. We investigated how bilateral transcranial direct current stimulation (tDCS) targeting primary motor cortices modulates manual asymmetries and interhemispheric connectivity during aiming. Twelve healthy right-handed male adults completed a protocol comprising three sessions: dominant hemisphere inhibition (DHI; cathode over C3/anode over C4), non-dominant hemisphere inhibition (NDHI; cathode over C4/anode over C3), and sham stimulation. In each session, participants performed a goal-directed aiming task with both hands before and after 20 min of tDCS. Behavioral outcomes included reaction time, movement time, response time, spatial accuracy (radial error), kinematic (peak velocity; relative time to peak velocity), and online control indices (number of discontinuities and first submovement error). EEG was recorded continuously, and interhemispheric coupling between motor regions was quantified in the high-alpha band during preparation and execution phases. tDCS produced selective behavioral effects, including condition-dependent changes in reaction time and response-time asymmetry, modulation of relative time to peak velocity, and increased movement discontinuities under DHI compared with sham, while movement time and several accuracy metrics showed minimal change. Interhemispheric coupling during preparation was largely unchanged; however, during execution, a robust Condition × Hand interaction emerged, with NDHI increasing coherence changes and coherence asymmetry relative to DHI. These findings suggest that bilateral tDCS can differentially shape interhemispheric functional coupling during movement execution and modulate specific temporal/kinematic components of aiming, with limited impact on overall movement time and endpoint accuracy.
INTRODUCTION:Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline. Bovine lactoferrin (bLf) is an iron-binding protein with immunomodulatory effects both in the intestine and throughout the body. In this study, the potential therapeutic effects of bLf were evaluated using two different rat models that mimic key aspects of AD pathology. METHOD:Forty-two female Wistar albino rats (10-12 weeks old, weighing 200-250 g) were included in the study and randomly assigned to 7 groups of 6 rats each. The groups were: 1- Control, 2- Phosphate-buffered saline (PBS), 3- bLf, 4- Colchicine (COL) (for the TAU model), 5- Okadaic acid (OKA) (for the Aβ model), 6- COL + bLf, 7- OKA + bLf. Cognitive deficits were tested using the Morris Water Maze (MWM). Motor coordination and anxiety levels were assessed using the OFT. Following these assessments, cerebrospinal fluid (CSF), hippocampal tissue, serum, and whole blood samples were collected. Aβ, TAU, Ferritin, TAS, and TOS levels in these samples were measured using ELISA. For genetic modulation, the gene expression patterns of Fpn, Bax, Bcl-2, p38, FoxO, and GSK-3β were analyzed by quantitative Real-Time PCR (qRT-PCR). RESULTS:bLf reduced oxidative stress. Decreases in Aβ and TAU levels were observed in the hippocampus and CSF. Ferritin levels were relatively lower in the hippocampus, CSF, and serum. Fpn and Bcl-2 were downregulated in the hippocampus of AD models but upregulated after bLf treatment. Expression levels of Bax, p38, FoxO, and GSK-3β were also downregulated following bLf administration. CONCLUSION:These findings were consistent across both models. Overall, bLf holds promise as a therapeutic candidate capable of simultaneously targeting two key pathological features of AD.
Cognitive deficits are a major contributor to disability in numerous neuropsychiatric and neurodegenerative disorders, yet effective pharmacological treatments remain limited. Ferulic acid eicosyl ester (FAE-20), a natural constituent of the plant Rhodiola rosea, has previously been identified as an enhancer of simple forms of Pavlovian conditioning in flies, bees, and mice. Here, we investigated whether FAE-20 has further potential to enhance cognitive flexibility, working memory, or spatial learning in mice, and explored potential neurobiological mechanisms underlying such enhancement. Cognitive flexibility was assessed using the attentional set-shifting task (ASST). Subchronic FAE-20 treatment significantly improved ASST performance in both male and female young adult mice, indicating enhanced cognitive flexibility. In contrast, no effects were observed on spatial working memory, assessed by spontaneous alternations in the Y-maze, or on spatial learning in the Barnes maze in either young or aged mice. Notably, FAE-20 enabled spatial learning in the Barnes maze in a subgroup of aged mice that failed to learn the task under vehicle treatment. Histological analyses using c-Fos immunohistochemistry as a marker of neural activity and doublecortin expression and spine density as markers of hippocampal plasticity revealed sex-specific effects on components of the ascending arousal system. FAE-20 increased the activation of orexinergic neurons in the lateral hypothalamus of male mice, whereas it reduced the activity of cholinergic neurons in the laterodorsal tegmental nucleus of females. No effects were detected on hippocampal neurogenesis or dendritic spine density. These findings suggest that the cognitive effects of FAE-20 are selective, depending on the cognitive demands of the task and the baseline cognitive abilities of the animals, and may be mediated, at least in part, by modulation of arousal-related neural circuits.
Cerebral ischemia‑reperfusion (I/R) injury induces neuronal death via caspase-dependent apoptosis and parthanatos, a poly (ADP-ribose) polymerase 1 (PARP-1)/apoptosis-inducing factor (AIF)-mediated caspase-independent pathway. Simultaneous inhibition of these pathways may provide enhanced neuroprotection. N-Stearoyltyrosine (NsTyr), a synthetic analogue of the endocannabinoid anandamide (AEA), exhibits neuroprotective effects in various models, however, its efficacy and mechanism in middle cerebral artery occlusion (MCAO) remain unclear. Neuronal oxygen-glucose deprivation/ reoxygenation (OGD/R) and rat MCAO models were employed to evaluate the neuroprotection of NsTyr. Neuronal viability and apoptosis were assessed using MTT assay, flow cytometry, TUNEL staining, and Hoechst 33342 staining. The cognitive impairment was evaluated using the Morris water maze. Mitochondrial function and ultrastructure were eassessed by JC-1 assay and transmission electron microscopy (TEM). Expression levels of key apoptotic-related proteins were determined by immunoblotting. Intracellular NAD⁺ and ATP levels were measured to assess PARP-1 activity. NsTyr significantly improved neuronal survival, reduced apoptosis, and ameliorated cognitive deficits in both in vitro and in vivo models. Mechanistically, NsTyr preserved mitochondrial integrity, maintained the Bcl-2/Bax balance, suppressed cytochrome c release and caspase-3 activation, and inhibited nuclear translocation of AIF. Concurrently, NsTyr attenuated PARP-1 overactivation, preserved NAD⁺ and ATP levels, and thereby suppressed parthanatos. These findings demonstrate that NsTyr confers potent neuroprotection against I/R injury by dual inhibition of caspase-dependent apoptosis and PARP-1/AIF-mediated parthanatos through the maintenance of mitochondrial integrity, supporting its potential as a therapeutic candidate for ischemic stroke.
Systemic inflammation triggers a coordinated sickness response that includes behavioral suppression, anorexia, and thermoregulatory alterations, often viewed as a unified syndrome. However, increasing evidence suggests that distinct neural circuits govern different components of sickness behavior. Whether central endocannabinoid system (ECS) signaling differentially regulates behavioral and thermoregulatory responses during systemic inflammation remains unclear. We therefore investigated the role of central ECS signaling in specific sickness domains induced by lipopolysaccharide (LPS). Male Wistar rats received intracerebroventricular pretreatment with the CB1 receptor antagonist AM251, the endocannabinoid transport inhibitor VDM11, the CB1 agonist WIN55,212-2, or vehicle prior to intraperitoneal administration of LPS (1 mg/kg) or saline. Behavioral responses were assessed using the open field test, forced-swim test, and 24-h food intake. Core body temperature was continuously monitored by telemetry for 6 h, and thermal indices were calculated for hypothermia (0-2 h) and fever (3-6 h). LPS induced a robust sickness phenotype characterized by reduced locomotion, increased immobility, hypophagia, and a biphasic thermoregulatory response. Central ECS manipulations produced minimal effects on behavioral endpoints. In contrast, thermoregulation was selectively sensitive to ECS modulation: CB1 receptor blockade enhanced LPS-induced hypothermia and markedly reduced fever, whereas increasing endocannabinoid tone attenuated hypothermia without affecting fever. These findings demonstrate that central ECS signaling selectively modulates thermoregulatory, but not behavioral, components of the sickness response, supporting a modular organization of sickness behavior.
During recent years, researchers have extensively investigated various health issues associated with prenatal challenges and the subsequent outcomes emerging in the next generation. In this respect, prenatal exposure to infections is correlated with the development of cognitive deficits in offspring. There is evidence indicating that disturbance of maternal microbiota adversely affects the gut-brain axis, which in turn could compromise fetal development and cause persistent physiological defects. Previous studies have reported that Helicobacter pylori infection is correlated with cognitive decline; however, this issue has not been investigated in offspring. Therefore, we applied behavioral methods to reveal how maternal H. pylori infection could affect memory function using the Morris water maze and novel object recognition in male offspring. Then, the cellular mechanisms associated with H. pylori-induced effects were probed using specific biochemical measurements in hippocampal tissues. Results indicated that spatial and recognition memory is impaired in offspring born from mothers with a history of H. pylori infection, and this appears to be correlated with a disturbance of the balance among oxidative, inflammatory, serotonergic, and cholinergic profiles within the hippocampi. In addition, the mentioned H. pylori-related effects were found to be biochemically restored and behaviorally ameliorated by pharmacological inhibition of the monoamine oxidase enzyme, proposing a potential for amelioration of cognitive outcomes.
BACKGROUND:Gliomas are highly aggressive primary brain tumors with a dismal prognosis. Temozolomide (TMZ) serves as the first-line chemotherapeutic agent for glioma patients. However, the clinical efficacy of TMZ is severely limited by the inevitable development of acquired chemoresistance, which ultimately leads to tumor recurrence and treatment failure. Unraveling the molecular mechanisms underlying TMZ resistance is therefore critical for improving glioma prognosis. This study aimed to identify key genes driving TMZ resistance and explore their underlying mechanisms to provide novel therapeutic targets for overcoming this clinical challenge. METHODS:Differentially expressed genes (DEGs) between TMZ-resistant (LN229TR, U251TR, and U87TR) and TMZ-sensitive glioma cells were screened using GEO datasets. The intersecting DEGs were subjected to protein-protein interaction (PPI) network construction via the STRING database and visualized using Cytoscape software. Hub genes were identified by integrating the results from the Maximal Clique Centrality (MCC) and Density of Maximum Neighborhood Component (DMNC) algorithms. The expression patterns of candidate hub genes were validated in glioma cells, clinical tissues, and the Gene Expression Profiling Interactive Analysis (GEPIA) database. Functional assays, including cell counting kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine, colony formation, transwell, flow cytometry, and sphere formation assays, were performed to evaluate cell viability, proliferation, migration, apoptosis, and stem-like properties in vitro. Furthermore, a subcutaneous xenograft tumor model in mice was established to assess the in vivo therapeutic effects. RESULTS:A total of 320 intersecting DEGs were extracted from the three cell line groups, and interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) along with 2'-5'-oligoadenylate synthetase like (OASL) were ultimately identified as the core hub genes. IFIT3 was selected for further investigation due to its significant upregulation in both low-grade gliomas and glioblastoma compared to normal brain tissues. Consistently, IFIT3 expression was remarkably elevated in TMZ-resistant glioma tissues and cell lines (P < 0.05), which exhibited significantly higher half-maximal inhibitory concentration (IC50) values of TMZ than their sensitive counterparts (P < 0.05). Functionally, IFIT3 silencing significantly decreased the IC50 of TMZ (P < 0.05), suppressed cell proliferation (P < 0.05), migration (P < 0.05), and stem-like traits (P < 0.05), and induced apoptosis (P < 0.05) in resistant glioma cells. Conversely, ectopic IFIT3 expression exerted opposite effects on cell proliferation, migration, and stem-like traits and notably increased the ratios of phosphorylated phosphoinositide 3-kinase (PI3K) to total PI3K and phosphorylated AKT to total AKT (P < 0.05); however, these effects induced by IFIT3 overexpression were effectively reversed by the PI3K inhibitor LY294002 (P < 0.05). In vivo experiments demonstrated that knocking down IFIT3 expression remarkably reduced tumor volume and weight upon TMZ treatment, accompanied by decreased expression levels of IFIT3, nuclear proliferation marker (Ki-67), and phosphorylated AKT in tumor tissues (P < 0.05). CONCLUSION:IFIT3 overexpression conferred TMZ resistance and promoted multiple malignant phenotypes in gliomas by activating the PI3K/AKT signaling pathway. Clinically, targeting IFIT3 might effectively re-sensitize resistant gliomas to TMZ, thereby offering a novel and actionable strategy to overcome chemoresistance and improve clinical outcomes for glioma patients.
Risperidone is an atypical antipsychotic that exerts widespread effects on cognitive functioning. Antipsychotics are most often administered to individuals with schizophrenia, providing relief from positive symptoms primarily through antagonism of the D2 dopamine receptor. One behavior that is often abnormal in schizophrenia and is partially mediated by the D2 receptor is risky decision-making. Therefore, it is critical to understand how antipsychotics impact risky decision-making in healthy subjects to disentangle the influence of schizophrenia and antipsychotics. Here, the effects of risperidone were examined in rats trained in the Risky Decision-making Task (RDT), in which subjects choose between a small, safe reward and a large reward accompanied by escalating risk of mild footshock. Both daily and acute administration of low to medium doses of risperidone induced a female- specific decrease in choice of options associated that had previously been associated with risk, even when the risk was not present. High-dose risperidone reduced risky choice in both sexes, which likely reflected risk aversion in males and cognitive or motivational disruption in females. Moreover, daily risperidone caused a stark reduction in total trials completed and weight in female but not male rats. Shock threshold testing revealed that risperidone-driven avoidance of risky options was unrelated to altered shock sensitivity, but reduced responding on a progressive ratio schedule suggested that risperidone may reduce risky choice by attenuating appetitive motivation. These findings align with emerging evidence of increased sensitivity to cognitive effects of antipsychotics in females.
Obsessive-compulsive disorder (OCD) is a debilitating condition associated with repetitive behaviors and cognitive inflexibility, often linked to abnormalities in cortico-striato-thalamo cortical (CSTC) circuitry. Although the Slitrk5 knockout (Slitrk5-/-, KO) mouse has been proposed as an OCD-related model, it remains unclear how Slitrk5 deficiency influences adaptive decision making, task-related behavioral organization, and orbitofrontal-dorsomedial striatum (OFC-DMS) signaling during reversal learning.To address this, Slitrk5-/- and wild-type (WT) mice were examined using probabilistic reversal-learning paradigms combined with licking-behavior analyses, fiber photometry recordings optogenetic inhibition of OFC-DMS projections, and open-field assessment. Across paradigms, Slitrk5-/- mice displayed largely preserved reversal-learning performance and adapted to changing reward contingencies similarly to WT mice. However, genotype-dependent differences emerged in how licking behavior was organized across behavioral epochs and reward contingencies, indicating altered anticipatory, choice-related, and reward-associated responding during task performance.Fiber photometry recordings further identified altered OFC-striatal signaling in Slitrk5-/- mice across anticipatory and reward-associated behavioral periods. In contrast, optogenetic inhibition of OFC-DMS projections produced no detectable effects on reversal-learning performance or licking behavior. Open-field assessment revealed age-dependent alterations in locomotor and exploratory behavior together with progressive grooming-related lesion development.Together, these findings demonstrate selective alterations in task-related behavioral organization and OFC-striatal signaling despite preserved reversal-learning performance in Slitrk5-/- mice, highlighting the heterogeneous behavioral and neural expression associated with corticostriatal dysfunction across OCD-related phenotypes.
The tumor suppressor protein p53 is a known modulator of neurodegenerative disease (ND) processes. Although p53 expression is increased in the brains of patients with Alzheimer’s disease, Parkinson’s disease, and ischemic stroke, its role in mood disorders such as anxiety and depression remains unclear. To investigate the role of p53 in behavioral responses to chronic stress, we examined behavioral and molecular alterations in p53 knockout (p53-/-) mice and wild type mice. In p53-/- mice, increased vulnerability to chronic unpredictable mild stress (CUMS)-induced anxiety- and depression-like behaviors was observed following CUMS exposure. In parallel with these behavioral changes, BDNF expression was reduced, whereas glutamate levels were elevated in the prefrontal cortex of p53-/- mice. Increased calcium-associated staining and NMDAR2B expression were observed together with increased neuronal injury- and cell death-related markers. In primary cortical neurons derived from p53-/- mice, corticosterone treatment resulted in greater increases in glutamate levels, NMDAR2B expression compared to wild-type controls. Cell death markers (cleaved caspase-3, p-p38, p-JNK) were upregulated, while neuroprotective signals (BDNF, p-Akt, p-ERK, p-CREB) were suppressed in p53-/- mice, and corticosterone-treated primary neuronal cells from p53-/- mice. These findings indicate that p53 deficiency is associated with enhanced vulnerability to CUMS-induced anxiety- and depression-like behaviors and is accompanied by alterations in calcium handling, glutamate homeostasis, neuronal injury-related markers, and BDNF-associated neuroprotective signaling.
BACKGROUND:The ability to prioritize long-term goals over immediate rewards is a cornerstone of human self-regulation and life-course success. Emerging evidence suggests that axial postural orientation provides a continuous stream of proprioceptive feedback that modulates this temporal valuation process. Using the framework of grounded cognition, this study investigated whether inducing Forward Head Posture (FHP) influences the valuation processes underlying self-regulation and future-oriented choice. METHODS:Healthy young adults (N = 59) performed a Delay Discounting Task (DDT) and a control simple reaction time (SRT) task in one of two conditions: FHP or Neutral Head Posture (NHP). Choice behavior was modeled using Generalized Linear Mixed Models (GLMM) to isolate shifts in reward-valuation probability. RESULTS:Participants in the FHP condition showed a significantly higher probability of choosing smaller-sooner rewards compared to the NHP group (p = .004). The groups did not differ on SRT latency (p = .82), indicating that the FHP effect reflects a selective shift in executive decision-making rather than a general decline in processing capacity. CONCLUSION:These findings provide experimental evidence that the head-neck-torso relationship is a relevant variable in the functional architecture of self-regulation. Transient FHP appears to shift the organism toward an immediacy-biased state, suggesting that postural orientation is an integral component of the physiological processes that influence executive function. This has direct implications for neurorehabilitation and the study of behavioral self-control.
Visuospatial working memory (VSWM) is supported by distributed fronto-parietal networks and is critically dependent on coordinated neural oscillations, particularly in the theta band (4-8 Hz). Non-invasive neuromodulation via transcranial alternating current stimulation (tACS) has been proposed to enhance cognitive function by entraining these oscillations. The present study investigated the effects of theta-frequency (6 Hz) tACS applied over the left fronto-parietal network (F3/P3) on VSWM performance using the Corsi Block Tapping Task. In a within-subjects design, participants completed four sessions under in-phase, anti-phase, tRNS and no-stimulation conditions. Linear mixed-effects modeling indicated higher accuracy during both in-phase and anti-phase tACS relative to the no-stimulation condition, whereas the tRNS effect was not statistically significant. In the interaction model, the stimulation-related differences were most pronounced during the first session and attenuated thereafter. No stimulation-related effects were observed on response speed. The results suggest that frontoparietal theta tACS may modulate visuospatial working-memory accuracy, particularly during initial task exposure. However, the present findings do not demonstrate a selective behavioral advantage of anti-phase over in-phase stimulation.
