Search Results (282)

Spinal cord injury (SCI) induces persistent locomotor deficits that are closely associated with maladaptive structural plasticity of spinal neuronal circuits. Although motor rehabilitation improves functional outcomes, the cellular substrates underlying rehabilitation-induced recovery remain incompletely understood, particularly in relation to activity-dependent neuromodulation strategies. Here, we investigated how treadmill-based motor training (TMT) and its combination with bioluminescent optogenetic (BL-OG) stimulation of Hb9 (homebox 9)-positive motoneurons and excitatory interneurons selectively modulate microarchitectural plasticity in the injured rat spinal cord. At the level of gross locomotor assessment, Basso, Beattie and Bresnahan (BBB) scores were comparable between the BL-OG and SCI+TMT groups. Although no statistically significant differences in the total score in rung ladder were observed at 28 days post-injury, animals in the BL-OG group showed a tendency toward a higher ratio of successful hindlimb placements, indicating improved step accuracy. BL-OG stimulation was associated with a slightly greater attenuation of SCI-induced spine abnormalities compared to TMT alone, with significant differences between the experimental groups detected specifically in laminae VIII and IX. These lamina-specific alterations in dendritic integration and dendritic spine composition were accompanied by preservation of wisteria floribunda agglutinin WFA-positive perineuronal net (PNN) architecture. Against this background, reduced glypican-4 (GPC-4) expression and attenuated WFA/GPC-4 colocalization were observed in the SCI+BL-OG group relative to SCI in laminae VII–IX, consistent with activity-dependent modulation of PNN-associated synaptic organization in Hb9-positive neuronal populations. Together, these findings indicate that motor rehabilitation and bioluminescent optogenetic stimulation engage distinct but partially overlapping mechanisms of activity-dependent microarchitectural remodeling, preferentially targeting synaptic and perineuronal net-associated substrates rather than inducing large-scale circuit reorganization. Further studies are warranted to elucidate the mechanisms underlying these distinct plasticity profiles. Full article

Alzheimer’s disease (AD), the leading cause of global dementia, is a multifactorial process that goes beyond the accumulation of β-amyloid (Aβ) plaques and tau protein tangles, including glia cell-mediated neuroinflammation, vascular dysfunction, metabolic alterations, and synaptic loss. Its complex etiology also involves oxidative stress and mitochondrial dysfunction. Multiple neurotransmitter systems involved in the pathogenesis and the various cognitive and non-cognitive symptoms of AD are thus altered. The cholinergic system, historically the first to be associated with AD, suffers early degeneration and loss of neurons/receptors, correlating with cognitive impairment. The glutamatergic system, the main excitatory system, exhibits excitotoxicity due to increased extracellular glutamate and alterations in NMDA/AMPA receptor distribution, exacerbating neuronal damage. The GABAergic system, the main inhibitor, shows alterations in parvalbumin-positive interneurons, leading to hyperexcitability and dysfunction of neuronal networks. Monoaminergic systems (serotonergic, dopaminergic and noradrenergic) undergo early degeneration in key nuclei such as the raphe and locus coeruleus, contributing to the apathy, depression and sleep disturbances characteristic of AD. Other less explored systems, such as histaminergic and purinergic, are also crucial in cognitive modulation and neuroinflammation. The endocannabinoid system acts as a master modulator with neuroprotective and anti-inflammatory effects. These systems do not operate in isolation; their complex interactions generate pathological circuits that amplify neuronal dysfunction. The limited efficacy of current therapies, which are primarily symptomatic, highlights the need for multimodal approaches that may transform AD treatment toward personalized and more effective interventions. Full article

Cognitive impairment in schizophrenia remains insufficiently addressed by existing treatments. Current FDA-approved therapies primarily modulate neurotransmitter systems, resulting in incomplete symptom control and substantial adverse effects. There is therefore a critical need for therapeutic strategies that more directly address the intracellular signaling mechanisms underlying synaptic dysfunction and cognitive deficits in schizophrenia. Protein phosphatases represent an essential but historically underexplored class of signaling enzymes that regulate phosphorylation-dependent control of synaptic receptor trafficking, plasticity, and neuronal circuit function. Although multiple phosphatases have been implicated in schizophrenia through genetic, post-mortem, and functional studies, their therapeutic targeting has been limited by challenges related to selectivity, cellular permeability, and pleiotropy. Here, we review the etiology of schizophrenia and limitations of current pharmacological approaches, synthesize evidence linking specific protein phosphatases to schizophrenia pathophysiology, and discuss emerging strategies, including allosteric modulation and targeted protein degradation, that may enable selective intervention in phosphatase-driven signaling pathways. We highlight the striatal-enriched tyrosine phosphatase STEP (PTPN5) as a case study illustrating how selective phosphatase modulation can restore synaptic signaling in schizophrenia-relevant models. Full article

The coronavirus disease 2019 (COVID-19) pandemic has been associated with a wide range of neurological complications, among which persistent cognitive impairment and memory deficits are increasingly recognized as key symptoms of the post-acute sequelae of SARS-CoV-2 infection (PASC or long COVID). Although clinical and epidemiological studies have documented these symptoms across diverse patient populations, the underlying neurobiological mechanisms remain incompletely understood. Growing evidence from human studies, neuropathological analyses, and experimental models indicates that neuroimmune and inflammatory processes plays a central role in COVID-19-associated cognitive dysfunction. As the brain’s resident immune cells, microglia are vital for synaptic health, neuroplasticity, and memory, yet these processes may be compromised after SARS-CoV-2 infection. Systemic inflammation, blood–brain barrier (BBB) disruption, endothelial injury, and cytokine signaling can induce sustained microglial activation and priming, leading to inflammasome activation, complement-mediated synaptic remodeling, oxidative stress, and impaired hippocampal neurogenesis. These processes collectively disrupt neural circuits involved in learning and memory and may underlie the persistent “brain fog” reported by COVID-19 survivors. This review synthesizes clinical, biomarker, neuroimaging, and mechanistic evidence linking SARS-CoV-2 infection to microglia-mediated neuroinflammation and memory impairment. In contrast to prior reviews that broadly describe neuroinflammation in COVID-19, we integrate multidimensional evidence into a microglia-centric immunovascular framework that highlights converging pathogenic pathways underlying cognitive symptoms. We further discuss emerging biomarkers of glial activation and evaluate current and prospective therapeutic strategies targeting microglial and neuroimmune pathways. Understanding the role of microglial dysregulation in post-COVID cognitive impairment may facilitate the development of targeted interventions to mitigate long-term neurological consequences of COVID-19. 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

Perinatal brain injury (PBI) is a leading cause of long-term neurological deficits in newborns, yet effective therapies are limited. At the cellular level, PBI involves hypoxic–ischemic stress, neuroinflammation, oxidative damage, excitotoxicity, and disrupted neurovascular and glial development. Traditional animal models and 2D cultures cannot fully capture the spatiotemporal complexity of the developing human brain, highlighting the need for more physiologically relevant systems. Human brain organoids have emerged as advanced three-dimensional models that recapitulate region-specific cytoarchitecture, neuronal and glial differentiation, and early circuit formation. They enable modeling of hypoxic–ischemic and inflammatory insults, allowing for the study of injury-induced changes in neurogenesis, gliogenesis, synaptic development, and cell interactions. Organoids facilitate identification of molecular pathways involved in injury and repair, supporting therapeutic target discovery. Using patient-derived induced pluripotent stem cells, organoids also allow personalized pharmacogenomic studies to assess genotype-dependent drug responses and toxicity. Despite limitations such as variability, lack of vascularization and immune components, and ethical considerations, brain organoids offer a promising platform to bridge developmental neurobiology and translational therapeutics, paving the way for targeted and individualized interventions in PBI. Full article

Alpha-synuclein (αSyn) is one of the most abundant proteins in the nervous system and is currently associated with devastating synucleinopathies, yet its biology extends far beyond this. In this review, we suggest that αSyn-driven disease emerges within specific neural circuits through the combined effects of cell-type-specific roles, subcellular environments, post-translational modifications (PTMs), and co-pathology. These interacting and additive dimensions, rather than αSyn alone, generate the pathological diversity, shaping whether pathology manifests as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), or mixed dementia phenotypes. We integrate recent advances on the physiological roles of αSyn in neurons and glia (astrocytes, oligodendrocytes, and microglia), its compartment-dependent (e.g., synaptic and nuclear) functions, and the molecular transitions (e.g., mediated by pS129) that convert functional assemblies into pathogenic conformers. Building on this foundation, we outline mechanisms through which these factors contribute to disease-specific vulnerability, progression, and clinical heterogeneity. Finally, we highlight how this multidimensional perspective on αSyn biology can inform the development of next-generation biomarkers that support precision therapies across distinct disorders. Full article

Locus coeruleus (LC) noradrenergic neurons project their axons to the cerebellar cortex and modulate cerebellar circuit function via distinct adrenergic receptor (AR) subtypes. The present study investigated the mechanism by which optogenetic activation of LC noradrenergic neurons modulates facial stimulation-evoked long-term synaptic plasticity at cerebellar mossy fiber-granule cell (MF-GrC) synapses in urethane-anesthetized DBH-Cre mice. Blockade of GABA_A receptors, 20 Hz facial stimulation induced MF-GrC long-term potentiation (LTP) in the control group, and this LTP was impaired by optogenetic activation of LC noradrenergic neurons via α2-ARs. Meanwhile, facial stimulation induced LTP of glutamate sensor fluorescence in the granular layer, which was abolished by chemogenetic activation of LC noradrenergic neurons. Following NMDA receptor blockade, optogenetic activation of LC noradrenergic neurons triggered facial stimulation-induced MF-GrC long-term depression (LTD) via α2A-ARs. Optogenetically activated LC noradrenergic neuron-induced MF-GrC LTD was abolished by protein kinase A (PKA) inhibition but not by protein kinase C inhibition. Immunofluorescence results revealed abundant α2A-AR expression in the granular layer, with particularly high levels in glomeruli, and no colocalization with the glutamate sensor. These results indicate that optogenetic activation of LC noradrenergic neurons impairs facial stimulation-induced MF-GrC LTP by triggering presynaptic LTD via the α2A-AR/PKA signaling cascade. Full article

Background and Objectives: Autism spectrum disorder (ASD) is a prevalent and largely idiopathic developmental disorder with relatively widespread etiology. Currently, there are no validated diagnostic or screening biomarkers for ASD, besides addressing the associated comorbidities. ASD is primarily diagnosed based on behavioral, motor, and cognitive characteristics. Until recently, although the cerebellum was particularly implicated in motor control, it was under-researched for its potential role in the development of ASD. However, cerebellar circuitry is altered in ASD, impacting its brain interconnections, affecting brain development, as well as social and behavioral outcomes associated with ASD. Methods: We reviewed the potential role of the cerebellum in ASD, particularly how its dysfunction during development or its early postnatal injury may impact on the maturation of other connected circuits and play a role in the development of core ASD symptoms. Results: Based on the literature, we addressed cerebellar changes that may alter synaptic pruning, immune cells’ function, neurotransmitters, blood–brain barrier permeability, and potential signaling pathways involved in ASD, and how these changes may interplay to contribute to ASD pathophysiology. Conclusions: Further research is needed to understand these interactions that may provide novel therapeutic options specifically targeted at the cerebellum. Full article

This paper presents a compact floating memtranstor (MT) emulator, a memory element characterized by a direct φ–q relationship, realized without analog multipliers or complex circuitry. The proposed design employs only two active blocks—a voltage differential transconductance amplifier (VDTA) and a voltage differential current conveyor (VDCC)—along with three grounded capacitors and a single grounded electronically tunable resistor. The emulator accurately reproduces the fundamental φ–q dynamics, exhibiting origin-crossing pinched hysteresis loops under sinusoidal excitation, and operates at a low supply voltage of ±0.9 V. Electronic tunability is achieved via bias-controlled transconductance modulation, enabling flexible adaptation across excitation frequencies and operating conditions. Validation is performed through analytical modeling, Monte Carlo simulations, temperature sensitivity analysis, and full LTspice post-layout simulations using a 180 nm CMOS process. The full-custom layout occupies 2529.49 μm², with robust performance confirmed under parasitic and process variations. Adaptive learning simulations demonstrate the emulator’s artificial synaptic plasticity, highlighting its suitability for neuromorphic computing, chaos-based circuits, and nonlinear dynamical systems. The compact, low-power, and multiplier-free architecture establishes the proposed MT emulator as a practical platform for emerging analog memory-centric applications. To validate the feasibility of the proposed solution, experimental tests are performed using commercially available components. Full article

Neurological injury induces widespread neuroplastic changes that extend well beyond focal structural damage, altering synaptic function, circuit dynamics, and large-scale network organization. While these processes provide the biological substrate for recovery, they can also drive the stabilization of maladaptive network states that constrain long-term functional improvement. Traditional neurorehabilitation has largely emphasized compensation and task practice, often without explicitly targeting the neural dynamics that underlie persistent disability. In this Opinion, we propose that contemporary rehabilitation technologies, including robotics, virtual reality, and neuromodulation, should be conceptualized as mechanistically grounded interventions that actively perturb neural networks and interact with the pathobiology of post-injury reorganization. Drawing on advances in systems and network neuroscience, we examine key molecular, synaptic, and network-level mechanisms that govern adaptive and maladaptive plasticity, and discuss how these technologies modulate error processing, sensory context, and excitability landscapes to reshape recovery trajectories. We argue that when interventions are appropriately structured, timed, and combined within adaptive and closed-loop frameworks, technology-assisted rehabilitation can move beyond compensation and toward principled modulation of neuroplasticity, aligning therapeutic innovation with the biological rules that govern recovery. This perspective highlights the need for network-informed biomarkers and longitudinal approaches to translate technological advances into durable functional gains. Full article

Late-life depression is a prevalent and debilitating disorder. It differs significantly from depression in younger adults and often co-occurs with cognitive decline and increased physical frailty. This narrative review explores the role of accelerated biological ageing in late-life depression. We examine evidence linking three interconnected processes, namely telomere attrition, mitochondrial dysfunction and cellular senescence, to the pathophysiology of late-life depression. Excessive attrition of telomeres may serve as a biomarker of accumulated stress and cellular ageing. Mitochondrial dysfunction not only reduces energy production but also promotes oxidative stress and inflammation that increase neuroinflammatory pathways and synaptic loss. Increased cellular senescence further induces senescence-associated secretory phenotype factors that drive chronic inflammation and neuronal loss. Together, these processes create a cycle of cellular stress, persistent inflammation and damage to brain circuits involved in late-life depression. We additionally highlight potential limitations in current findings and propose a roadmap for future research to better elucidate the mechanistic dysfunction of late-life depression. These include the need for evaluation in long-term prospective cohort studies, improved tools to better correlate blood-based markers with changes in disease-relevant brain tissues and regions, and trials that test treatment and lifestyle modifications that are targeted at ageing biomarkers. Full article

The endocannabinoid system is a ubiquitous neuromodulatory network that links internal physiological state to neural circuit function across the brain. While its roles in memory, reward, pain, and motor control are well established, its contribution to olfactory processing has only recently gained attention. This review synthesizes the current knowledge on the anatomical, cellular, and functional interactions between the endocannabinoid system and the olfactory pathway, from the olfactory epithelium and main olfactory bulb to higher order cortical targets. We highlight how endocannabinoid signaling, primarily via cannabinoid receptor type 1 (CB1), shapes synaptic transmission within olfactory bulb microcircuits, modulates centrifugal feedback, and adjusts sensory gain in a state-dependent manner, particularly in relation to hunger, feeding behavior, stress, and reward. In addition, we review evidence that the endocannabinoid system regulates olfactory neurodevelopment and adult neurogenesis by influencing neural stem cell proliferation, migration, and integration into existing circuits. Emerging links between endocannabinoid signaling, olfactory dysfunction, neuropsychiatric disease, metabolic disorders, and neurodegeneration underscore the translational relevance of this system. We also discuss methodological challenges inherent to studying endocannabinoid signaling and outline future directions, including circuit-specific targeting and intranasal delivery strategies. Together, these findings position the olfactory system as a powerful and accessible model for understanding how endocannabinoids couple internal state to perception and behavior, with important implications for therapeutic development. Full article

Background: Obsessive–compulsive disorder (OCD) is a heterogeneous psychiatric condition with substantial heritability. Early genetic studies were often underpowered and produced limited reproducibility, but recent large-scale genomic and multi-omic approaches are beginning to elucidate the genetic architecture of OCD. Objectives: This review aims to synthesise current evidence from recent genomic and epigenomic studies on OCD and their implications for molecular pathways of pathogenesis, including endophenotypes. Methods: We reviewed peer-reviewed literature and preprints published in recent years, focusing on multiple genetic approaches, including genome-wide association studies (GWAS), whole exome sequencing (WES), whole genome sequencing (WGS), and methylome-wide association studies (MWAS). We then integrated the results with endophenotypic evidence at the biochemical, physiological, structural, functional, and executive/cognitive levels. Results: Recent large-scale genomic studies provide strong evidence of a highly polygenic contribution from common variants, while rare coding and structural variants also contribute measurably, with enriched signals in pathways relevant to neurodevelopment and, in some cohorts, early-onset presentations. Epigenomic studies have moved from scattered findings to more replicable methylation patterns, including loci influenced by nearby genetic variation and indications of sex-dependent effects. Although convergence at the single-gene level remains limited, cross-study and cross-omics signals increasingly point to biological domains involving synaptic organisation and plasticity, neurological development and chromatin regulation, immune/stress pathways, and cellular homeostasis. Conclusions: The biology of OCD risk is best represented by an integrative model combining polygenic load, contributions from rare variants, and regulatory (epigenetic) mechanisms that influence intermediate phenotypes at the circuit and cognitive levels. The current findings are not yet clinically applicable for individual diagnosis; however, they may inform future multidisciplinary research frameworks and, in the longer term, contribute to the development of more personalised approaches in OCD. Full article

Monosynaptic reflexes (MSRs) elicited by constant-intensity group I afferent stimulation exhibit marked amplitude variability, commonly attributed to stochastic presynaptic modulation and dynamic postsynaptic excitability. Here, we tested whether this variability could be attenuated using the Ott–Grebogi–Yorke (OGY) chaos–control algorithm, which stabilizes unstable periodic orbits in low-dimensional nonlinear systems. In spinalized, anesthetized cats, real-time implementation of the OGY method failed to reduce MSR amplitude variability, as quantified by the coefficient of variation, and the return map structure showed no evidence of orbit stabilization. These negative results contrast with successful applications of OGY control in physical systems, cardiac tissue, hippocampal slices, and stochastic neuronal models. We interpret this failure in the context of the intense, ongoing synaptic bombardment characteristic of dorsal horn circuitry, which likely obscures or destroys the low-dimensional geometric structure required for OGY-based control. Our findings delineate a fundamental limit to classical chaos–control algorithms in intact neural circuits and highlight the need for control strategies explicitly robust to high dimensionality and physiological noise. Full article