Search Results (122)

Cognitive decline is a global public health challenge, yet the built environments where humans spend 90% of their time are only now being recognized as a means of preventive intervention. This paper presents a mechanistic framework describing how environmental and design features may influence hippocampal neuroplasticity, offering architects an evidence-based foundation for supporting brain health. We describe how eight environmental pathways, five activating features (design that promotes movement, enrichment, orientation features, daylight, views of nature) and three inhibiting features (air quality, noise, visual pattern stress) are hypothesized to converge on cAMP Response Element-Binding protein (CREB), a representative transcriptional integrator regulating Brain-Derived Neurotrophic Factor (BDNF) expression levels in the hippocampus. BDNF is a protein implicated in brain health outcomes including synaptic plasticity, neuronal survival, neurogenesis and cognitive function. Synthesizing evidence from neuroscience, exercise physiology, environmental psychology, toxicology, and visual neuroscience, we grade evidence strength for each pathway and identify the specific design variables involved. Evidence strength varies markedly across pathways: movement and enrichment rest on direct experimental and meta-analytic data, including human studies; air quality and noise rest on direct mechanistic evidence largely from animal and exposure studies; orientation features, daylight, and views of nature rest on indirect mechanistic inference; and visual pattern stress remains hypothesis-generating at the architectural scale. Enrichment and active design pathways show the strongest evidence for CREB activation, while noise, air quality, and non-natural visual patterns are associated with CREB inhibition. From this framework, we derive a consolidated set of design features organized by pathway, evidence strength, and temporal impact on brain health outcomes. These range from immediate synaptic plasticity to long-term neuroprotection. This mechanistic model offers a roadmap for a longer-term research program and outlines the formal structure required for future computational implementations. The framework can serve as a bridge connecting neuroscience to the emerging global movement on brain health that positions the built environment as an underutilized lever for supporting cognitive health across the lifespan. Full article

Severe mental disorders, including schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD), are leading causes of global disability, yet current treatments remain largely symptomatic and fail to alter disease trajectories. Converging evidence from genetics, longitudinal studies, and systems neuroscience supports a dimensional and transdiagnostic architecture of psychopathology, involving shared polygenic risk and overlapping neurodevelopmental and circuit-level alterations. Traditional approaches—such as post-mortem brain analysis, neuroimaging, and animal models—have delineated core molecular perturbations (e.g., dopaminergic, glutamatergic, and GABAergic dysfunction), as well as informed translational frameworks for mechanistic investigation, but remain constrained by restricted access to dynamic processes and incomplete recapitulation of human-specific biology. The advent of human-derived cellular models, particularly human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), has partially addressed these limitations, enabling the study of patient-specific neurodevelopment and synaptic function in vitro. Within this evolving landscape, the olfactory neuroepithelium (ONE) has emerged as an accessible source of neural progenitors, obtainable through minimally invasive procedures, providing a window into living human neurobiology. ONE-derived cells retain donor-specific genetic and epigenetic signatures while recapitulating disease-relevant phenotypes across major psychiatric disorders, including altered neurodevelopmental dynamics, synaptic gene expression, and inflammatory profiles. Here, we present a narrative review of the principal cellular and tissue models used in biological psychiatry, examining their respective strengths, limitations, and translational relevance across experimental contexts. By situating these approaches within a unified framework, we aim to clarify their complementarity, identify current gaps, and outline future directions, highlighting the emerging potential of ONE-based models to bridge genetic risk, cellular dysfunction, and clinical phenotype, thereby advancing precision psychiatry. Full article

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder caused by the interaction between genetic and environmental influences, potentially mediated by epigenetic mechanisms such as DNA methylation. Genome-wide DNA methylation profiling was performed using the Infinium MethylationEPIC v2.0 array on peripheral blood mononuclear cells (PBMCs) from 100 children with ASD and 50 typically developing controls. Differential methylation analyses were conducted by adjusting for age, sex, and estimated blood-cell-type composition as covariates. Functional enrichment, SFARI gene-overlap analysis, and cross-cohort validation were performed. We identified 3507 differentially methylated positions (DMPs) in the ASD cohort. Functional enrichment revealed pathways involved in neuronal signaling, synaptic activity, and immune regulation, suggesting coordinated neurodevelopmental and immune processes in ASD. Stratification by clinical severity demonstrated common and unique biological characteristics between the moderate and severe ASD groups. Furthermore, DMP-associated genes significantly overlapped with high-confidence ASD risk genes from the SFARI database and established transcriptomic signatures of neurodevelopmental disorders. Comparisons with independent post mortem brain tissue and peripheral blood datasets revealed partial overlap and directional concordance. However, the strength of concordance varied across datasets and was limited in the most directly comparable peripheral blood cohort. Our findings suggested that DNA methylation profiling of PBMCs provided peripheral epigenetic signatures and candidate loci for further validation in larger independent cohorts. Full article

Opioid analgesics are essential in the management of severe and chronic pain; however, their prolonged use is limited by the onset of analgesic tolerance and opioid-induced hyperalgesia (OIH). Recent studies increasingly implicate both synaptic functional and structural plasticity within nociceptive pathways as crucial mechanisms in OIH and tolerance. This review integrates current mechanistic understanding of how opioids alter synaptic transmission throughout the dorsal root ganglia (DRG), spinal dorsal horn, and supraspinal nociceptive networks. Peripherally, μ-opioid receptor (MOR) activation on TRPV1-positive nociceptors initiates presynaptic long-term potentiation (LTP), forming an early substrate for central sensitization. In the spinal dorsal horn, chronic opioid exposure drives NMDAR-dependent LTP, TRPC-mediated calcium influx, and actin cytoskeleton remodeling, leading to persistent increases in synaptic strength and excitatory connectivity. In supraspinal regions—including the ventral hippocampus, prefrontal cortex, and amygdala—opioids promote experience-dependent plasticity and predictive coding, which link environmental cues to reduced analgesic effectiveness. In addition to synaptic functional plasticity, opioid-induced synaptic structural plasticity within nociceptive pathways has been shown to underlie the long-term nature of opioid analgesic tolerance. Collectively, these data define a distributed network of opioid-responsive synapses whose pathological potentiation underpins the development of tolerance and hyperalgesia. Elucidating these mechanisms underlying OIH and tolerance paves the way for targeted therapeutic strategies that maintain analgesic efficacy while minimizing adverse synaptic remodeling and negative outcomes. Full article

Neural progenitor cell (NPC) transplantation is a promising strategy for spinal cord injury repair, as graft-derived neurons can integrate into host circuitry and promote functional recovery. While the brain-regional and dorsoventral identities of NPCs are known to influence graft composition and performance, the importance of axial (rostrocaudal) identity, specifically whether NPCs must be matched to the spinal level of injury, remains poorly understood. To address this, we compared outcomes following transplantation of NPCs isolated from the anterior embryonic spinal cord (A-NPCs) versus the posterior spinal cord (P-NPCs) in a mouse model of C5 cervical dorsal column injury. Following transplantation, NPCs retained their intrinsic molecular axial identities; P-NPC grafts maintained significantly higher expression of the lumbar-associated gene HoxC10 and possessed a higher proportion of Chx10-high V2a neurons compared to A-NPCs. Despite these maintained molecular differences, A-NPC and P-NPC grafts were indistinguishable in neuronal and glial density, axon outgrowth, and their ability to support host axon regeneration, including the corticospinal tract. Long-term behavioral testing and retrograde transsynaptic tracing revealed no significant differences between groups in the recovery of skilled pellet reaching, grip strength, or synaptic integration with host cervical motor circuitry. These findings demonstrate that although transplanted NPCs retain their molecular axial identity in the adult injured environment, this identity is not a primary determinant of anatomical integration or functional outcome. Our findings suggest a degree of plasticity in graft-host interactions and indicate that strict segment-matching is not essential for the efficacy of NPC-based therapies in spinal cord injury. Full article

Epileptogenesis is commonly defined by the emergence of spontaneous seizures after an initial insult; however, convergent experimental and clinical evidence indicates that the underlying disease process begins well before seizures become clinically detectable. During this pre-seizure phase, persistent molecular cascades remodel synaptic plasticity, circuit architecture, and glial–immune signaling. These processes are associated with trait-like alterations in cognition, affect, and behavior. Despite their clinical relevance, these neurobehavioral signatures remain poorly integrated into molecular models of epileptogenesis and are rarely considered as translational biomarkers of disease progression. This review synthesizes evidence linking core epileptogenic molecular cascades—maladaptive synaptic plasticity, glial–immune signaling, oxidative–metabolic stress, and activity-dependent gene regulation—to reproducible alterations in executive control, cognitive flexibility, emotional regulation, and motivational–social behavior. We outline an integrative framework in which these phenotypes are conceptualized as system-level readouts of progressive network reconfiguration rather than nonspecific “comorbidities” or mere consequences of recurrent seizures. Within this perspective, neurobehavioral markers can complement electrophysiological and molecular measures by capturing disease-relevant changes during windows when anti-epileptogenic interventions would be most effective. To increase mechanistic specificity, we provide representative pathway and gene-level anchors across epileptogenesis stages, a structured molecular-to-neurobehavioral mapping, and an operational biomarker panel specifying confounders and minimal controls. These anchors are included to ground the framework in experimentally documented molecular nodes with stage-dependent relevance; examples are representative rather than exhaustive, and evidence strength is indicated as preclinical mechanistic versus associative human observations. Finally, we discuss methodological requirements for biomarker validity (specificity, temporal anchoring, and cross-model consistency) and outline how integrating molecular and neurobehavioral trajectories may refine target discovery and improve the translation of anti-epileptogenic strategies. Conceptualizing epileptogenesis as a progressive disease process with measurable pre-seizure neurobehavioral signatures may broaden biomarker strategies beyond seizure occurrence and support the development of disease-modifying interventions. Full article

Orthobiologic treatments such as platelet-rich plasma and stem cell therapies are increasingly used to support the healing of tendons, ligaments, and joints. This perspective proposes applying periodization—a structured, progressive model borrowed from athletic training—to rehabilitation following orthobiologic interventions in order to improve functional outcomes. The framework is organized into sequential phases that align with biological stages of healing. Early phases emphasize pain control, inflammation management, and safe, controlled mobility. Rehabilitation then progresses toward gradually increasing load bearing and strength, and toward more specific exercises to promote tissue regeneration while reducing the risk of re-injury. In later phases (mesocycles), the model highlights the importance of neuroplastic adaptations for sustained functional recovery, including neurogenesis, synaptic plasticity, and functional remodeling to safer RTP for athletes. A key advantage of this approach is its adaptability: progression can be individualized according to a patient’s recovery trajectory and response to loading. By aligning rehabilitation progression with intrinsic healing processes and integrating physiological and neuromuscular goals, the proposed model aims to maximize regenerative potential across both athletic and non-athletic populations. Overall, this neuroplastic periodized approach offers a practical, evidence-informed structure to guide clinicians in delivering patient-centered regenerative rehabilitation and may help standardize care after orthobiologic procedures. Full article

Optical synaptic transistors employing polymer dielectrics have emerged as promising building blocks for neuromorphic computing due to their low power consumption and rich photo-induced memory behaviors. While extensive experimental studies have demonstrated various synaptic functions, a unified physical understanding of the coupled charge trapping and ionic polarization processes governing device dynamics remains incomplete. In this work, we develop a unified physical model to investigate optical synaptic behaviors in polymer-based transistors with oxide interlayers. The model explicitly describes the time-dependent evolution of photo-induced charge trapping at the semiconductor–dielectric interface and ionic polarization within the polymer dielectric, which jointly modulate the effective threshold voltage of the transistor channel. Based on this framework, key synaptic functions including excitatory postsynaptic current (EPSC), paired-pulse facilitation (PPF), and pulse-dependent potentiation are quantitatively reproduced. The model further reveals how dielectric structure and trapping strength govern the transition between short-term and long-term plasticity. This study provides a physically intuitive and experimentally relevant modeling framework for understanding optical synaptic transistors, offering guidance for the rational design and optimization of polymer-based neuromorphic devices. Although simplified, the proposed model captures the essential physics governing optical synaptic behaviors and provides a general framework applicable to a wide class of ion–electronic neuromorphic devices. Experimental measurements are used as physically motivated proxies to validate the multi-timescale structure of the model rather than direct numerical fitting. Full article

Neuronal synapses are the functional units of communication in the central nervous system. This review describes the molecular mechanisms regulating synaptic transmission, plasticity, and circuit refinement. At the presynaptic active zone, scaffolding proteins including bassoon, piccolo, RIMs, and munc13 organize vesicle priming and the localization of voltage-gated calcium channels. Neurotransmitter release is mediated by the SNARE complex, comprising syntaxin-1, SNAP25, and synaptobrevin, and triggered by the calcium sensor synaptotagmin-1. Following exocytosis, synaptic vesicles are recovered through clathrin-mediated, ultrafast, bulk, or kiss-and-run endocytic pathways. Postsynaptically, the postsynaptic density (PSD) serves as a protein hub where scaffolds such as PSD-95, shank, homer, and gephyrin anchor excitatory (AMPA, NMDA) and inhibitory (GABA-A, Glycine) receptors are observed. Synaptic strength is modified during long-term potentiation (LTP) and depression (LTD) through signaling cascades involving kinases like CaMKII, PKA, and PKC, or phosphatases such as PP1 and calcineurin. These pathways regulate receptor trafficking, Arc-mediated endocytosis, and actin-dependent remodeling of dendritic spines. Additionally, synapse formation and elimination are guided by cell adhesion molecules, including neurexins and neuroligins, and by microglial pruning via the complement cascade (C1q, C3) and “don’t eat me” signals like CD47. Molecular diversity is further expanded by alternative splicing and post-translational modifications. A unified model of synaptic homeostasis is required to understand the basis of neuropsychiatric and neurological disorders. Full article

Background: The three Synuclein family members (α-, β-, and γ-synuclein) are presynaptic proteins that regulate synaptic vesicle trafficking and thereby influence neurotransmitter release. Synucleins belong to a class of intrinsically disordered proteins and are prone to aggregation into pathological deposits, which may impair their physiological synaptic functions. Knockout (KO) mouse lines, commonly used to model synuclein depletion in the nervous system, reveal a range of phenotypes with different motor and behavioral deficits. However, given the high sequence homology and functional interplay among the three synucleins, the specific contribution of each family member to these phenotypes remains poorly understood. Objective: In this study, we conducted a comparative phenotypic analysis of γ-synuclein KO, α- and β-synuclein KO, and αβγ-synuclein KO mice. Methods: Mice were subjected to a battery of behavioral tests assessing motor activity and coordination, anxiety-like behavior, and spatial learning and memory. Synaptic vesicle proteins were analyzed in brain tissues using Western blotting. Results: We observed that knocking out γ-synuclein but not α- and β-synucleins reduces mouse lifespan and leads to sustained reduction in muscle strength implicating that γ-synuclein is essential for longevity and motor system function. Another consequence of γ-synuclein deficiency is altered anxiety-like behavior manifested as a diminished aversive response, while exploratory behavior and memory remain intact. The triple KO mice mirror γ-synuclein KO mice in some behavioral changes, including shortened lifespan, reduced muscle strength, and decreased anxiety-like behavior. However, the triple KO mice additionally exhibit hyperactivity, which is not present in the other groups. No changes in synaptic vesicle marker levels were detected, indicating that the observed motor and behavioral abnormalities are not attributable to impaired synaptic connectivity. Conclusions: Taken together, these findings demonstrate nonredundant functions of individual synuclein family members and highlight a distinct role of γ-synuclein in regulating motor performance and behavioral responses. Full article

Background and Objectives: Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by social communication deficits, restricted interests, and repetitive behaviors. At present, there is no pharmacological intervention that reliably targets the core symptoms of ASD; instead, medications are primarily used to manage associated or concurrent symptoms such as irritability, aggression, anxiety, attention difficulties, and sleep disturbances. This review summarizes the current evidence for pharmacological treatments in ASD, emphasizing how these interventions are used in a symptom-focused, adjunctive manner, and highlighting efficacy, mechanisms, limitations, and emerging therapeutic targets. Methods: A comprehensive literature review was conducted across PubMed, Cochrane Library, and Embase to identify clinical trials, systematic reviews, meta-analyses, and preclinical studies on pharmacological interventions for ASD. Seventy-seven references were integrated to reflect the current state of evidence. Results: Established pharmacological strategies include atypical antipsychotics for severe irritability and aggression, as well as antidepressants, stimulants and non-stimulant agents, mood stabilizers, and anxiolytics for selected comorbid symptoms, although efficacy is often modest and variable, and side effects can be significant. Adjunctive and investigational approaches targeting glutamatergic and GABAergic neurotransmission, monoaminergic systems, and neuroinflammatory and oxidative stress pathways show preliminary promise but remain experimental. Across all categories, pharmacological treatments are most effective when embedded in individualized, multimodal care plans that integrate behavioral, rehabilitative, and psychological interventions. Conclusions: This review maps pharmacologic strategies in ASD onto their underlying neurobiological mechanisms and clarifies how evidence strength differs across drug classes and symptom domains. Ongoing advances in genetics, synaptic and circuit-level neuroscience, and neuroimmune signaling are expected to yield more specific, mechanism-based pharmacological approaches for autistic behaviors, with the potential to improve long-term functioning and quality of life when combined with comprehensive psychosocial care. Full article

Background: Dystonia, the third most common movement disorder, is increasingly recognised as a network disorder with both motor and non-motor symptoms. Non-motor symptoms have been shown to be key determinants of quality of life in dystonia and include anxiety, depression, sleep disturbance, cognitive dysfunction and fatigue. Results: Emerging data suggests that dysfunction within cortico-striato-thalamo-cerebello-cortico circuits underpins both motor and non-motor symptoms. Genetic studies have highlighted shared gene clusters involved in synaptic function that are associated with both dystonia and psychiatric disorders. Neuroimaging studies reveal microstructural and functional alterations in patients with dystonia that correlate with non-motor symptoms. Discussion: Current research into both the pathophysiology and treatment of non-motor symptoms remains limited, heterogeneous and based on small sample sizes, which restricts the strength of the conclusions that can be drawn. Evidence for targeted therapies for non-motor symptoms is scarce. Conclusions: A greater understanding of the overlap between neural pathways underpinning motor and non-motor symptoms may provide a foundation for the development of novel pharmacological and non-pharmacological therapies. As understanding advances, treatment strategies will likely adopt a holistic model that integrates pharmacological options with non-pharmacological measures, including multi-disciplinary rehabilitation and supportive therapies. Full article

Chemical synaptic coupling is crucial in the nervous system. This paper establishes a chemical synaptic Chay neuronal coupling system using the Heaviside function and analyzes the equilibrium point’s type and stability based on the Jacobian matrix. Matcont simulation found that the Hopf bifurcation point transformed into a Bogdanov–Takens bifurcation point under the influence of chemical coupling strength, and a series of saddle-node bifurcation points are generated. The discharge time history of the system and the evolution of single-parameter bifurcation behavior were numerically simulated through a language and Matlab. The parameter matching results indicated that the chemical synaptic reversible potentials and synaptic thresholds were −15 mV and −35 mV, respectively. The bifurcation behavior and its changes under multi-parameter conditions were studied by using various numerical methods such as time series diagrams, bifurcation diagrams, and two-parameter diagrams. The similarity function identified key factors affecting synchrony in a chemical synaptic coupling system. Results indicate that synchrony primarily depends on chemical coupling strength, with other factors providing positive feedback to enhance it. The simulation of the spatiotemporal dynamics in a chemically synaptic coupled network of 2000 ring neurons revealed that altering the maximum conductance at local positions within the network can induce the generation of traveling waves. Strong coupling strengths ensure that the induced traveling waves propagate at greater velocities and can excite and awaken a larger number of neurons in a shorter time frame. The nonlinear properties of chemical synaptic neuronal system offer essential tools and foundations for studying neurobiology and brain dynamics. Full article

Background/Objectives: Previous multi-ethnic genome-wide association studies (GWAS) have identified the GALNT13 rs10196189 polymorphism as a potential genetic marker linked to sprint–power performance. However, its relevance in East Asian populations, particularly the Han Chinese, remains untested. This study aimed to replicate the association of rs10196189 with elite sprint–power athlete status in Han Chinese males and examine its potential influence on physical performance traits and tissue-specific gene regulation. Methods: A total of 188 healthy Han Chinese males (49 elite sprint–power athletes and 139 non-athletic controls) were genotyped using the TaqMan assay. Assessments included strength, sprint, jump, anaerobic power, DXA-derived body composition, and muscle ultrasound. Logistic regression and ROC analyses evaluated the predictive value of rs10196189. Linear regression models adjusted for age and BMI tested genotype–phenotype associations. Tissue expression and functional networks were analyzed using GTEx and HumanBase databases. Results: The G allele frequency was significantly higher in athletes (12.2%) than in controls (5.4%, p = 0.042). Dominant and additive models effectively predicted athlete status (OR = 2.53–2.58, p < 0.05). Although most traits showed no significant associations post-correction, medial gastrocnemius thickness showed a nominal association (β = 0.371, p = 0.011). Functional analyses revealed high GALNT13 expression in brain tissue and co-expression networks enriched in synaptic signaling and glycosylation pathways. Conclusions: This is the first study to validate the association of GALNT13 rs10196189 with elite athletic status in Han Chinese males. Findings provide novel population-specific evidence and propose tissue-specific glycosylation and neural mechanisms as pathways linking this variant to sprint–power phenotypes. Full article

One major challenge in cellular neuroscience is to elucidate how the accurate alignment of presynaptic release sites with postsynaptic densely clustered ligand-gated ion channels at chemical synapses is achieved upon synapse assembly. The clustering of neurotransmitter receptors at postsynaptic sites is a key moment of synaptogenesis and determinant for effective synaptic transmission. The number of the ionotropic neurotransmitter receptors at these postsynaptic sites of both excitatory and inhibitory synapses is variable and is regulated by different mechanisms, thus allowing the modulation of synaptic strength, which is essential to tune neuronal network activity. Several well-regulated processes seem to be involved, including lateral diffusion within the plasma membrane and local anchoring as well as receptor endocytosis and recycling. The molecular mechanisms implicated are numerous and were reviewed recently in great detail. The role of pre-synaptically released neurotransmitters within the complex regulatory apparatus organizing the postsynaptic site underneath presynaptic terminals is not completely understood, even less for inhibitory synapses. In this mini review article, we focus on this aspect of synapse formation, summarizing and contrasting findings on the functional role of the neurotransmitters glycine and γ-aminobutyric acid (GABA) for initiation of postsynaptic receptor clustering and regulation of Cl⁻ channel receptor numbers at inhibitory synapses gathered over the last two decades. Full article