Biology and Life Sciences

Abstract: Background: Autism spectrum disorder (ASD) affects approximately 1-2% of children worldwide, yet its etiology remains incompletely understood. Emerging evidence suggests that offspring of parents with autoimmune diseases show elevated autism prevalence. Notably, children of parents with psoriasis (OR 1.59), type 1 diabetes (OR 1.49-2.36), and rheumatoid arthritis (OR 1.51) demonstrate particularly strong associations.Hypothesis: I propose that autism may be conceptualized as an immune-metabolic disorder in which multiple pro-inflammatory cytokines—including TNF-α, IL-6, IL-1β, and IFN-γ—act through distinct molecular pathways yet converge on a common endpoint of mitochondrial dysfunction and cerebral energy deficiency. This convergence implies that it is the cumulative prenatal inflammatory burden, rather than any single cytokine, that drives the energy deficit. The resulting energy shortage may impair three critical processes: (1) synaptic pruning during neurodevelopment, (2) real-time social cognition including gaze processing and emotion recognition, and (3) protein synthesis of critical synaptic scaffolding molecules.The proposed mechanism is a chronic low-grade pro-inflammatory cytokine state—clinically silent, yet biologically consequential—arising from inherited inflammatory susceptibility and/or direct fetal exposure to elevated maternal inflammatory signaling during pregnancy. Unlike high-grade inflammatory states in which maternal and fetal survival are acutely threatened, low-grade cytokine elevations may proceed without conspicuous symptoms or detectable clinical signs, particularly when chronic. Although seemingly quiet, such a state may be insufficient to endanger maternal or fetal survival, yet sufficient to disrupt fetal brain bioenergetics during sensitive gestational windows—producing neonates who appear outwardly healthy at term while their neurodevelopmental trajectories have already been altered.I further propose that the well-documented "firstborn effect" in autism reflects maternal immune maladaptation during primigravid pregnancies. Additionally, for cases without parental autoimmune history, a speculative secondary mechanism is proposed: mitonuclear immune conflict, where paternal immune genes may partially recognize maternal mitochondria as non-self, generating endogenous pro-inflammatory signaling.Implications: This framework may provide an integrative account of disparate observations about autism pathophysiology and suggests that pro-inflammatory immune pathways and mitochondrial protection strategies merit further investigation for potential risk modification, particularly in pregnancies identified as high-risk through parental autoimmune or inflammatory disease. If supported by sufficient subsequent evidence, prenatal cytokine monitoring and corresponding clinical management—currently not part of routine obstetric care—may merit consideration by the medical community as a candidate strategy for autism risk reduction.

Abstract: Background/Objectives: The oscillatory dynamics underlying stage-specific processing in working memory (WM) remain incompletely characterized, particularly under varying memory loads. We examined load-dependent modulation of theta (4-7 Hz), lower alpha (8-10 Hz), and upper alpha (11-13 Hz) absolute power during encoding, maintenance, and retrieval using quantitative EEG in a modified Sternberg task that temporally dissociates these stages. Methods: Forty-five healthy young adults performed trials with memory sets of three, five, or six uppercase consonants followed by a lowercase probe. EEG data were analyzed using cluster-based permutation testing, and brain-behavior relationships were assessed using regression models. Results: Fronto-central theta power increased with memory load and was significantly higher during retrieval than during encoding or maintenance. Greater theta power during retrieval predicted faster reaction times in the three-letter condition. Alpha oscillations showed robust stage effects. Lower alpha power was higher during maintenance than retrieval across loads and exhibited a load effect during maintenance (three > six letters) in occipital regions. Upper alpha power was consistently maximal during maintenance across all loads, involving bilateral fronto-central, parietal, and occipital regions. Critically, under moderate load (five letters), higher upper alpha power predicted a greater probability of correct responses across task stages. Conclusion: These findings demonstrate a functional dissociation between oscillatory bands across temporally separated WM stages: theta activity was retrieval-dominant and associated with response speed, whereas alpha, particularly upper alpha, was maintenance-dominant and supported accuracy under increased mnemonic demand.

Abstract: Predictive processing (PP) accounts often characterize post-traumatic stress disorder (PTSD) and depression as maladaptive and epistemically distorting, due to wide divergences between brain generated top-down models and bottom-up sensory inputs. This review questions that characterization. First, trauma survivors with PTSD or depression may lessen risk by overestimating threats, with hypervigilance sustaining a desirable gap between anticipated problems and harms that would otherwise occur. Second, PP psychiatric frameworks prescribe how trauma survivors ought to assess matters yet give limited justification, introducing tacit normative assumptions into neurocomputational models. This repeats in certain PP assessments of schizophrenia and psychosis, which presuppose Western concepts of self as normative neurocognitive ideals. Third, PP accounts claim that cognition evolved primarily for action, not veridical representation; but their notion of prediction error can tacitly invoke the concept of veridical representation. Fourth, PP defenders have asserted that depressive slow-downs follow from maladaptive brain-based regulatory models. However, physiological problems may instead make activity strenuous, such that slowing down is adaptive. This position advanced in this review is that atypical mental outlooks need not be epistemically distorted, and that mismatches between anticipatory models and outcomes—when they occur—can sometimes index adaptive success rather than failure.

Abstract: Glioblastoma multiforme (GBM) is a rare, hostile malignant brain cancer with no etiology or antidote. Current treatment options include the usual cancer therapies such as chemotherapy, radiation, and sometimes surgical intervention; however, these are often met with a poor prognosis due to the intimate and delicate location of GBM, in addition to killing the healthy cells in the brain. Originating from the rapid proliferation of glial cells, GBM can be located anywhere in the brain, from the cerebral hemispheres to the ventricles to the brainstem. Stem cells, located in various niches of the body systems, are specialized cells that can differentiate into specific body cells, including the brain. There are numerous subcategories and categories within them, such as pluripotent stem cells, cancer stem cells, neural stem cells, mesenchymal stem cells, etc. Due to their ability to differentiate into specific cells without killing the healthy cells in the surrounding environment, stem cells have been the target of various disease therapies, including cancer. Specifically, cancer stem cells, neural stem cells, and mesenchymal stem cells have been explored in targeting the GBM cells in the brain due to their promising effects in the cancer cells’ transcriptional factors, activation and inactivation of specific pathways, gene mutations, and recognizing certain cancer markers. The future of GBM will require a greater depth of investigation and a deeper understanding of stem cell mechanisms and their effects on the surrounding environment.

Abstract: This study investigates the nuclear distribution of phosphorylated tau (AT100) in the frontal cortex and cerebellum of 12 cetaceans stranded along the Galician coast (NW Spain). Using Bayesian beta regression, we identified a strong positive correlation between aging and tau phosphorylation, with posterior probabilities of 85.5% in the cortex and 89.5% in the cerebellum. This age-associated increase suggests a systemic and coordinated regulation of tau as the brain matures. We propose that the translocation of tau to the nucleus could act as a nuclear shield against cumulative oxidative stress, a process potentially intensified by the intermittent hypoxia characteristic of diving in these mammals. Furthermore, the elevated AT100 levels observed in adults and in a case of cerebral necrosis reinforce its protective role and its potential as a marker for neuronal distress. While this exploratory pilot study is limited by sample size (n=12), the Bayesian analysis confirms biological consistency across the species analyzed. These findings establish a baseline for understanding neuroprotection in cetaceans, suggesting that tau phosphorylation is a key evolutionary mechanism for preserving neuronal genomic integrity under extreme physiological conditions.

Abstract: Terminal glial cells (TGCs) are integral components of cutaneous end-organ com-plexes (CEOCs) and have traditionally been regarded as structural and trophic elements. However, increasing evidence suggests their involvement in mechanosensation and mechanotransduction. This study aimed to investigate the expression of mechanosensitive ion channel-related proteins in TGCs and axons of human Meissner and Pacinian cor-puscles from glabrous skin at different anatomical sites. Using immunohistochemistry and immunofluorescence, we analysed the distri-bution of ASICs, ENaC subunits, PIEZO channels, and TRP family members. Axonal terminals showed widespread expression of these proteins, including PIEZO1/2, ASIC2, TRPC6, and TRPV4, consistent with their role in mechanotransduction. In contrast, TGCs displayed a more restricted and heterogeneous profile. ASIC2 and TRPV4 were con-sistently detected in Meissner corpuscles, whereas PIEZO1/2 and TRPA1 showed site-dependent expression. In Pacinian corpuscles, TGCs were positive for ASIC2, PIE-ZO2, TRPA1, and TRPV4. Notably, TRPA1 expression in TGCs is reported here for the first time. These findings support the idea that TGCs may modulate mechanosensory input, although their functional role remains to be elucidated.

Abstract: Hereditary cerebellar ataxias are progressive neurodegenerative disorders for which diseasemodifying treatments are still lacking. Although these conditions have traditionally been studied from a neuron-centered perspective, evidence from several ataxia models indicates that changes in the cerebellar immune microenvironment can arise before overt neuronal loss and may contribute to early circuit dysfunction. This review examines hereditary cerebellar ataxias through the lens of early neuroimmune regulation, with particular attention to the region-specific properties of cerebellar microglia and their roles in synaptic refinement and circuit homeostasis. We also discuss zebrafish as a useful experimental system for this question, because they combine in vivo imaging, genetic manipulation, and scalable functional assays in an intact vertebrate model. In this context, flavonoids—and especially naringenin—are considered not as immediate therapeutic candidates, but as experimental tools to investigate how modulation of inflammatory balance affects disease-relevant phenotypes in vivo. By integrating genetic ataxia models with dynamic neuroimmune readouts, zebrafish-based approaches can help identify early windows in which neuroimmune signalling influences cerebellar vulnerability and can guide subsequent validation in mammalian systems.

Abstract: Background: Neuropathic pain (NP), a debilitating condition from nervous system le-sions, is poorly managed by current therapies. The cingulate cortex is crucial for affec-tive pain processing, yet a comprehensive spatiotemporal understanding of its molec-ular changes in NP is lacking. Methods: This study performed RNA sequencing to pro-file transcriptomic alterations in the anterior cingulate (ACC) and midcingulate (MCC) cortices of mice at two and four weeks after spared nerve injury. Bioinformatics anal-yses, including differential expression, functional enrichment, weighted gene co-expression network analysis, and protein-protein interaction (PPI) network con-struction, were employed. Results: We identified widespread, time-dependent tran-scriptional dysregulation in both regions, with differentially expressed genes increas-ing over time. Analyses confirmed central roles for synaptic plasticity and neuroin-flammatory pathways. Importantly, we uncovered significant dysregulation in prote-ostasis and mitochondrial function pathways, mechanisms shared with neurodegen-erative diseases. PPI analysis identified stage-specific hub genes (e.g., early interfer-on-stimulated genes and late ribosomal proteins in ACC; persistent extracellular ma-trix components in MCC). Conclusions: This study provides a detailed transcriptomic atlas of the cingulate cortex in NP, reinforcing known mechanisms while elucidating novel dysregulation in protein homeostasis and mitochondrial pathways. The findings highlight convergent pathophysiology with neurodegeneration and offer a new theo-retical framework with potential therapeutic targets for chronic NP.

Abstract: Alzheimer’s Disease (AD), the most prevalent form of dementia, is pathologically defined by extracellular beta-amyloid (Aβ) plaques and intraneuronal neurofibrillary tangles (NFTs), accompanied by chronic neuroinflammation. Recent advances in single-cell RNA sequencing (scRNA-seq/snRNA-seq) and spatial transcriptomics have provided unprecedented resolution for dissecting the cellular and molecular landscape of neuroinflammation in AD. While scRNA-seq enables high-throughput profiling of cellular heterogeneity across brain regions, spatial transcriptomics preserves tissue architecture to map cell-type-specific gene expression within anatomical contexts. This review synthesizes the neuroinflammatory mechanisms of AD, outlines the technical evolution and comparative capabilities of single-cell and spatial omics platforms, including resolution, throughput, and compatibility with multiple sample types, and critically evaluates findings from studies in both animal models and human brain tissues. These approaches have revealed state-specific transformations in microglia and astrocytes, including shifts in transcriptional programs, metabolic reprogramming, and pro-inflammatory polarization across disease stages. Notably, spatial transcriptomic analyses demonstrate pronounced regional heterogeneity: periplaque microenvironments exhibit distinct immune cell compositions and gene expression signatures. Collectively, these omics technologies are redefining the cellular basis of AD progression and hold transformative potential for the discovery of early diagnostic biomarkers and precision therapeutic targets.

Abstract: Epilepsy is increasingly understood as a disorder of neural circuit hyperexcitability arising from disruptions in the balance between excitatory glutamatergic and inhibitory GABAergic signaling. In many forms of epilepsy, recurrent seizures are associated with excessive glutamate release and calcium influx, along with inflammatory signaling, oxidative stress, and maladaptive changes in synaptic transmission. These processes can further destabilize vulnerable networks, particularly within hippocampal and cortical circuits. Endogenous mechanisms that normally constrain hyperexcitability—including endocannabinoid signaling through CB1 receptors—may become insufficient or dysregulated in chronic epilepsy, creating conditions that favor recurrent seizure generation. Here, we propose that multi-phytocompound combinations may influence neural balance in epilepsy by engaging several molecular systems that regulate neuronal excitability and seizure threshold. Cannabinoids and terpenes derived from Cannabis sativa interact with diverse molecular targets implicated in epilepsy, including CB1 receptors, GPR55, transient receptor potential (TRP) channels, GABAA receptors, voltage-gated ion channels, glycine and serotonergic receptors, as well as endocannabinoid metabolic pathways. Through these convergent mechanisms, phytocannabinoids and terpenes may influence excitatory and inhibitory signaling, limit excitotoxic processes, and modulate pathways associated with neuroinflammation and oxidative stress. Within this context, we outline a theoretical multi-compound approach composed of a dozen cannabinoids and terpenes selected for their potential synergy and interactions with pathways implicated in seizure generation, synaptic transmission, and neuroprotection, yielding testable predictions for future experimental and clinical investigation. This perspective provides a systems-level model for understanding how coordinated, multi-target modulation of neural signaling pathways may influence circuit stability in epilepsy and offers a foundation for future experimental validation of multi-compound strategies.

Abstract:

Background: There is a critical need for effective therapeutics for Alzheimer’s. Personalized, precision medicine approaches represent a potentially effective strategy, and proof-of-concept trials have provided supportive data. Objective: To determine whether a precision medicine approach to Alzheimer’s at the mild cognitive impairment or early dementia stage is effective in a randomized controlled clinical trial. Methods: Seventy-three patients with mild cognitive impairment or early dementia were evaluated for biochemical, microbiological, genetic, epigenetic, and imaging parameters associated with cognitive decline, then assigned randomly to a precision medicine approach or standard of care treatment. Results: Statistically significant effects of the precision medicine approach were observed for overall neurocognitive functioning (d=1.12; 95% CI, 0.56-1.66; p<0.001), memory (d=0.94; 95% CI, 0.40-1.46; p<0.001), executive function (d=0.89; 95% CI, 0.35-1.43; p=0.001), processing speed (d=0.67; 95% CI, 0.14-1.19; p=0.012), self-reported cognitive symptom severity (d=-1.05; 95% CI, -1.60, -0.49, p<0.001), and partner-reported cognitive symptom severity (d=1.26; 95% CI, 0.70-1.81; p<0.001), with MoCA scores showing a trend to improvement (p=0.154). Furthermore, overall health was enhanced, with improvements in blood pressure, body mass index, glycemic index, lipid profiles, and methylation status. Treatment effect size on overall cognitive function exceeded previous trials, being 2-3 times larger than effects of lifestyle interventions and 4-7-times larger than those of anti-amyloid therapies. Conclusion: A personalized, precision medicine approach represents an effective treatment for patients with mild cognitive impairment or early-stage dementia. This treatment improves cognition and overall health rather than simply retarding decline, without significant negative side effects such as brain edema, microhemorrhage, or atrophy.

Abstract: Autism is characterized by differences in cognition, behavior, and information processing that are often linked to alterations in neural circuit function. Synaptic plasticity—particularly long-term potentiation (LTP) and long-term depression (LTD)—plays a central role in learning, memory, and the adaptive updating of neural circuits. Here, we propose a mechanistic model in which a shift toward excessive synaptic strengthening, coupled with disrupted synaptic weakening, may contribute to core features associated with autism. Heightened plasticity in hippocampal–cortical, striatal, and cerebellar circuits may bias neural systems toward the persistent reactivation of previously formed activity patterns, limiting the flexible encoding of new information. Such dynamics could manifest as reduced cognitive flexibility, repetitive behaviors, and differences in language and social function. At the same time, similar mechanisms may, in certain contexts, support enhanced cognitive abilities, including exceptional memory and pattern recognition, suggesting that maladaptive persistence and enhanced function may arise from shared underlying processes. This perspective integrates findings from electrophysiological, genetic, and behavioral studies and proposes that autism may involve a shift in synaptic learning rules toward disproportionate stabilization of neural activity. It generates testable predictions regarding circuit-level plasticity and highlights potential strategies for modulating these processes to restore a balance between stability and flexibility in neural systems.

Abstract: Background: Hypoxic-ischaemic brain injury, (HIBI), is a major contributor to neurological deficits following stroke. Understanding what happens to the smallest functional and structural unit of the central nervous system in the face of oxygen and nutrient deprivation is essential to fully comprehend the pathogenesis of diseases and disorders that are associated with HIBI, as well as serve as a tool for initial screening of potential therapeutics and identification of diagnostic markers. Aim: The aim of this study was to develop a robust in vitro model for mechanistic investigation of the effect of HIBI on neurons. Method: This study details and validates a comprehensive protocol for modelling HIBI using differentiated SH-SY5Y neuroblastoma cells (Neuron-Like Cells, NLCs). First, we optimized the differentiation process and confirmed the maturity and purity of NLCs via standard molecular markers. The NLCs exhibited functional excitotoxicity, demonstrating a graded cell death response to N-methyl-D-aspartate (NMDA), validating their functional utility. To simulate HIBI, we initially optimized the oxygen-glucose deprivation (OGD) component using graded concentrations of CoCl2 (0.125mM to 2mM) in glucose-free media. The validated NLCs were then subjected to the refined OGD protocol (1mM CoCl₂ in glucose-free media) for 3 hours, followed by various periods of reoxygenation (1h, 3h, 6h, 12h, 18h, and 24h). Result: Bulk RNA-sequencing analysis revealed a critical temporal pattern in the transcriptional response to injury. Specifically, majority of the injury-related gene expression, including heat shock proteins, stress markers, and cell death were significantly (p<0.05) upgraded at the third hour of reoxygenation, peaked dramatically at the 6th hour, and then rapidly subsided to levels often higher than the baseline at 24 hours. Surprisingly, RNAseq revealed the emergence of transforming growth factor-beta 1 (TGF-β1), a known regulator of glia-scarring, as an upstream regulator after 6 h of reoxygenation. Analysis of the supernatant revealed a corresponding translational pattern, where cell death was most significant after 24 h reoxygenation, whereas the secretion inflammatory cytokine TNF-α, and neuroprotective biomolecules, β-NGF, BDNF, and VEGF increased as reoxygenation time increased. Conclusion: This study reveals the existence of a narrow transient transcriptional cascade, highlighting a critical window for initial damage and cellular response. It also establishes a highly reproducible NLC-based HIBI model and provides a comprehensive transcriptomic blueprint of the immediate and sub-acute neuronal response, pointing toward known and novel upstream regulators of the injury cascade for future therapeutic targeting.

Abstract: Background: Reaction time (RT) is a fundamental measure of information processing speed in cognitive neuroscience and is influenced by both structural and functional brain properties. While prior studies have independently linked white matter microstructure and EEG alpha oscillations to cognitive performance, their joint contribution to distinct aspects of RT remains unclear. This study aims to investigate whether multimodal data can dissociate neural systems underlying cognitive and motor components of processing speed. Methods: We analyzed diffusion tensor imaging, resting-state EEG alpha peak frequency, demographic variables, and behavioral RT measures from a Go/No-Go paradigm in 24 healthy adults from the Cuban Human Brain Mapping Project. Behavioral metrics included the mean, standard deviation and skewness of reaction times for simple and complex tasks. Sparse multiple canonical correlation analysis was applied to identify multi-variate associations across modalities. Results: Two significant latent dimensions were identified (p< 0.05). The first dimension linked bilateral association tracts (SLF, IFOF, UNC) with complex RT performance, reflecting higher-order cognitive processing. The second dimension associated motor and interhemispheric tracts (CGC, CST, ILF, forceps major and minor) with intra-individual asymmetric variability (skewness) across tasks, indicating a motor-execution consistency system. EEG alpha peak frequency did not significantly contribute to either dimension. Sex showed strong associations with both components. Conclusions: Distinct white matter networks support separable cognitive and motor aspects of processing speed, while resting-state alpha frequency does not independently explain behavioral variability. These findings highlight the importance of multimodal and multivariate approaches for understanding and potentially disentangling complex brain–behavior relationships.

Abstract: Autism spectrum disorder (ASD) is highly heterogeneous in symptom onset and severity, comorbidities, and treatment responsiveness, challenging a single “brain-centered” pathogenic model. Increasing evidence indicates that a subset of individuals with ASD exhibits prominent peripheral physiological alterations, including gastrointestinal (GI) dysfunction, gut microbial dysbiosis, immune imbalance, oxidative stress, and mito-chondrial/energy metabolic vulnerability. In this context, gut-derived metabo-lites—particularly short-chain fatty acids (SCFAs)—have emerged as plausible modula-tors of the neurodevelopmental milieu through the expanded gut–immune–metabolic–brain axis. This review synthesizes: (i) SCFA biogenesis and core physiological functions (GPCR-mediated signaling and epigenetic regulation), (ii) context- and developmental stage–dependent bidirectional effects shaped by dose, exposure duration, and tissue spec-ificity, (iii) the clinical heterogeneity of reported microbiome and SCFA alterations in ASD, and (iv) propionate as a frequently discussed candidate signal and the interpretive boundaries of preclinical evidence. Human studies show inconsistent directions and magnitudes of SCFA changes (increases, decreases, or no differences), driven by major sources of variability such as sample type (stool vs. blood, reflecting distinct physiological layers), GI symptom stratification, diet and medication/antibiotic exposure, and non-standardized analytical pipelines and reporting units. Accordingly, SCFAs should not be treated as universal ASD biomarkers; rather, they are better interpreted as con-text-dependent signals that may become salient under specific clinical-biological condi-tions. Building on this premise, we propose the conceptual framework of “metabolic ASD,” defined as a subtype in which peripheral metabolic–immune perturbations plausibly contribute to neurodevelopmental vulnerability. To avoid premature causal claims, we outline design requirements for future research, including developmentally informed lon-gitudinal cohorts, rigorous phenotypic stratification, standardized metabolomics, and multi-layer endpoints integrating barrier integrity, systemic inflammation, and metabolic stress. Ultimately, metabolic ASD should be positioned as a testable precision-medicine research frame rather than a universal etiological model.

Abstract: Background/Objectives: The hippocampus exhibits marked functional heterogeneity along its dorsoventral axis, with dorsal regions primarily supporting cognitive and spatial processing and ventral regions linked to emotional and stress-related functions. This functional gradient is shaped by intrinsic circuit properties and neuromodulatory systems, including the endocannabinoid system, whose cannabinoid type 1 (CB₁) receptors are abundantly expressed in the hippocampus. Sharp wave–ripple (SWR) complexes are highly organized network events that depend on precise excitation/inhibition balance and are essential for hippocampal information processing. The present study aimed to determine whether cannabinoid receptor activation or modulation influences SWRs and associated neuronal activity along the dorsoventral axis of the hippocampus. Methods: Extracellular field potentials and multiunit activity were recorded from the stratum pyramidale of the CA1 region in acute hippocampal slices obtained from dorsal and ventral segments. Spontaneous SWRs were analyzed under control conditions and following application of the CB₁ receptor agonists ACEA and WIN55,212-2, the cannabinoid compound cannabidiol (CBD), and the GIRK channel blocker tertiapin-Q. SWR incidence, waveform characteristics, and multiunit activity were quantified and compared between hippocampal segments. CB1 receptor expression was assessed in dorsal and ventral CA3 using Western blot analysis. Results: Baseline recordings revealed pronounced dorsoventral differences in SWR dynamics, with ventral hippocampus exhibiting higher SWR rates, larger amplitudes, and enhanced neuronal recruitment compared to dorsal hippocampus. In contrast, activation of CB₁ receptors by ACEA and WIN55,212-2, as well as application of CBD, did not significantly alter SWR occurrence, waveform properties, or associated multiunit activity in either hippocampal segment. Similarly, blockade of GIRK channels produced only limited effects, restricted to modulation of ripple power, and did not reveal a latent sensitivity of SWRs to cannabinoid receptor activation. Notably, CB1 receptor expression in the CA3 region was comparable between dorsal and ventral hippocampus. Conclusions: These findings demonstrate that spontaneous SWRs in hippocampal slices are robust to acute cannabinoid modulation despite strong CB₁ receptor expression. The intrinsic dorsoventral organization of hippocampal network dynamics persists under cannabinoid receptor activation, indicating that SWR generation is primarily based on local circuit properties rather than fast endocannabinoid signaling. This resistance has important implications for understanding how cannabinoids influence hippocampal function in vivo, suggesting that their cognitive and behavioral effects are likely mediated through modulation of large-scale network interactions rather than direct disruption of intrinsic SWR-generating mechanisms.

Abstract: Background: Auditory oddball paradigms are widely used to investigate neural responses to deviant stimuli and attentional processing. However, different paradigms involve deviant stimuli with varying levels of stimulus relevance, and the corresponding neural responses have rarely been directly compared within a unified experimental framework. The aim of this study was to compare neural responses elicited by three variants of the auditory oddball paradigm that differ in the type of deviant stimuli: tone, reversed speech, and self-name deviants. Methods: Electroencephalography (EEG) data were recorded from 38 healthy participants while they performed three paradigm variants. Event-related potentials (ERPs) were analyzed to examine neural responses to deviant stimuli. In addition, cortical activation patterns were identified via source reconstruction, and classification analyses were conducted to assess the discriminability of neural responses across the three variants. Results: ERP results revealed that the self-name paradigm elicited the most robust neural signatures, characterized by a significant P300 amplitude (3.95 μV) and prominent MMN (-6.39 μV). Crucially, source-space analysis revealed a graded expansion of cortical recruitment: acoustic deviance (tone) and structural reanalysis (reversed speech) were associated with 7 and 6 significant clusters, respectively, primarily in the auditory and fronto-cingulate cortices, whereas the self-name paradigm engaged 12 significant clusters spanning a distributed salience–self network (including the insula and posterior cingulate cortex). Classification analyses mirrored these findings: the self-name paradigm consistently yielding the highest neural separability (~80% accuracy) and greater robustness to interindividual variability, particularly when the EEGNet architecture was used. Conclusions: These findings demonstrate that self-referential auditory stimuli elicit stronger and more discriminable neural responses than other auditory deviant stimuli in the oddball paradigm. These results provide a comparative perspective on how different dimensions of auditory relevance modulate neural processing and may inform the design of effective auditory paradigms for cognitive neuroscience and related translational applications.

Abstract: Multiple Sclerosis (MS), a chronic, immune-mediated disease of the central nervous system (CNS) is typified by leukocyte infiltration into CNS, inflammation, demyelination, and neurodegeneration. Risk factors include genetic predispositions involving HLA-DR15 and various single nucleotide polymorphisms affecting T cell function. Early signs such as blurred/double vision, numbness, fatigue, and balance coordination, are later accompanied by cognitive as well as bladder and bowel dysfunction. Genetic models of neuroinflammation have helped development of drugs with significant effects on progression and relapse rate of MS. Nonetheless, MS continues to pose major challenges as the pathological mechanisms remain unclear. Recent studies highlight the crucial role of quality and organization of cytoskeletal proteins in maintaining complex cellular functions such as neuronal excitability and neuroinflammation. Understanding how changes in these proteins impact demyelination is key to drug development for MS. Systems biology, an interdisciplinary field of study posits that complex interactions within biological systems contribute to the inflammatory processes and suggests that Cav-1, an integral membrane protein of caveolae with crucial role in cell signaling may provide a novel target in MS. Herein, we examine potential genetic influences on Cav-1 and its role in inflammation and demyelination in relation to MS. Specifically, its roles in oxidative stress, inflammation, blood brain barrier (BBB) integrity, and autophagy are discussed. Nonetheless, we conclude that translational aspect of Cav-1 and hence its specific therapeutic targeting in MS requires further exploration.

Abstract: Autism spectrum conditions have been associated with alterations in synaptic transmission and excitatory–inhibitory balance across distributed neural circuits. Converging evidence from genetic, electrophysiological, and animal models suggests that dysregulated activity-dependent synaptic plasticity—particularly altered long-term potentiation or long-term depression within hippocampal-cortical, cortico-striatal, and cerebellar networks—may contribute to reduced cognitive flexibility, repetitive behaviors, and difficulties in social and communicative adaptation. From this perspective, core behavioral features of autism may reflect circuit-level persistence of previously-formed neural patterns and altered updating of new information, rather than global neural dysfunction. Here we propose that modulating activity-dependent plasticity and excitatory–inhibitory dynamics may represent a plausible strategy for supporting cognitive flexibility in autism. Cannabinoids and terpenes derived from Cannabis sativa interact with multiple neural signaling systems—including CB1 receptors, GPR55, TRP channels, voltage-gated ion channels, serotonergic pathways, and endocannabinoid metabolism—that are known to influence synaptic transmission and plasticity. By engaging these convergent mechanisms, interactions among multiple botanical compounds may influence circuit-level excitability and synaptic plasticity processes implicated in autism. We consider multi-target phytocompound interactions with neural signaling pathways implicated in autism, particularly those regulating synaptic plasticity and excitatory–inhibitory balance. Within this framework, cannabinoid–terpene interactions may influence circuit-level dynamics underlying cognitive flexibility.

Abstract: Kynurenine pathway (KP) of trytophan metabolism is emerging as a key regulator of immune response, neuroinflammation, and neurodegenration. Tryptophan derived metabolites influence multiple processes including excitotoxicty, oxidative stress, mitochondrial dysfunction, and protein aggregation which are underlying mechanisms in major neurological disorders. The dysregulation of the KP leads to an imbalance between neuroprotective metabolites such as kynurenic acid and neurotoxic metabolites including quinolinic acid and 3-hydroxykyrunine, contributing to neuronal dysfunction and disease progression. This imbalance is associated with chronic proteinopathies such as Alzeihmer‘s disease and Parkinson‘s disease, where persistent neuroinflammation and excitotoxicty sustain the activation of KP and subsequent neurodegenaration. Importantly, KP activation is not only limited to chronic conditions but also occurs in acute neurological insults such as heatstroke, where impaired thermoregulation contributes to systemic inflammatory responses, oxidative stress, and disruption of the blood-brain barrier. Consequently, this facilitates the influx of peripheral kyrunine into the brain and its conversion into neuroactive metabolites, linking peripheral immune activation and neuronal injury. These findings highlight KP as mechanistic bridge between acute and chronic neuropathological processes. In addition, the KP involvement in NAD⁺ production links immune activation and cellular energy metabolism, subsequently increasing neuronal vulnerability, particularly under stress. Emerging evidence further support the potential of KP metabolites as diagnostic biomarkers for disease progression and severity, as well as possible therapeutic targets. Targeting key enzymes within the KP may offer novel strategies to reduce neurotoxicity, and restore metabolic balance which subsequently improves clinical outcomes.