Abstract:

Spinal interneurons constitute the computational core of spinal circuitry, integrating excitatory and inhibitory inputs to generate the rhythmic patterns that drive locomotor, postural, and autonomic control. Their developmental logic, molecular diversity, and adaptive plasticity make them central determinants of functional recovery after spinal cord injury. Yet most regenerative strategies continue to emphasize cellular replacement rather than the restoration of the computational integrity of spinal networks. In this review, we reframe spinal repair as the reconstitution of circuit computation. We synthesize current insights into how embryonic patterning programs defined by SHH, Wnt, and BMP gradients, refined by Notch and retinoic acid signaling, and consolidated by axon guidance cues, establish interneuron diversity, connectivity, and network symmetry that together encode the logic of motor coordination. Spinal cord injury disrupts this developmental logic, fragmenting excitatory and inhibitory balance and desynchronizing rhythmic modules, while residual circuits retain latent capacity for resynchronization through plasticity and neuromodulation. Building upon this developmental and computational continuum, we propose the Patient Specific Interneuron Precision Model (PIPM), a closed loop framework that links patient specific biological states including progenitor competence, morphogen sensitivity, and metabolic tone to circuit level computation and recovery potential. By bridging molecular, physiological, and clinical insights, the PIPM establishes a systems logic that unifies biological competence with circuit recovery, positioning interneuron computation as the conceptual foundation for precision spinal cord regeneration.

Abstract: Neural coding means the representation of external stimuli and/or behavioral processes in the electrical activity of nerve cells. In recent years, many facts have been revealed that indicate the need to generate oscillations for such a representation in a normal brain. The hippocampus and its directly related structures (dentate gyrus, subiculum, and entorhinal cortex) generate many types of field rhythmic activity, the main of which are theta (~4-12 Hz), beta (~15-30 Hz), gamma (~25-100 Hz), and ripple oscillations (~120-500 Hz). With the participation of oscillatory activity generated in these frequency bands, both spatial and non-spatial information (temporal, auditory, olfactory, tactile, gustatory, etc.) is represented in the brain. It has been found that oscillations underlie many critical brain functions such as learning and memorization. However, a fundamental question remains to be fully resolved: what specific role do different types of oscillations generated in the hippocampal system play in cognitive functions (in particular, in encoding information), and what are the mechanisms of their participation in these functions? This paper is devoted to a review of the literature data on the role of oscillatory processes in encoding signals entering the brain both from the external environment and from the body itself. The issues of the participation of oscillations in the memorization and reproduction of stored information are also discussed. The main focus is on examining oscillatory activity directly in the hippocampus; the material obtained from the study of structures belonging to the hippocampal system and some neocortical regions are also evaluated.

Abstract: Neuromechanobiology has emerged as a multidisciplinary field at the interface of neu-roscience and mechanobiology, aiming to elucidate how mechanical forces influence the development, organization, and function of the nervous system. This review offers a comprehensive overview of the historical evolution of the discipline, its molecular and biophysical foundations, and the experimental strategies employed to investigate it. Recent advances have revealed the pivotal roles of substrate stiffness, mechanical sig-naling, and force transduction in neural stem proliferation, axon guidance, synapse formation, and neural circuit maturation. All these effects originate at the molecular level and extend to the mesoscopic scale. Disrupted mechanotransduction has been increas-ingly implicated in neurodevelopmental disorders and neurodegenerative diseases, underscoring its clinical relevance. Key unresolved questions and future directions are also highlighted, with emphasis on the need for integrative approaches to decipher the complex interplay between mechanical forces and neural function.

Abstract: This dataset provides synchronized multimodal behavioral measurements from 36 mice across four experimental groups: wild-type and rTg4510 tauopathy mice, each tested with or without doxycycline-mediated suppression of mutant tau expression. At six months of age, all animals underwent three standardized behavioral paradigms: home-cage monitoring, ten-day trace eyeblink conditioning, and contextual fear conditioning. Individual-level data include locomotor activity, rearing duration, conditioned response metrics, eyelid closure latencies, and contextual freezing percentages. All measurements are linked by unique mouse identifiers, enabling cross-task analyses without preprocessing or imputation. The dataset is accompanied by a complete data dictionary, processing workflow diagram, and validation analyses demonstrating cross-paradigm correlations. Cross-task associations are illustrated in main figures, with additional early-phase acquisition and temporal processing correlations provided in supplementary appendices. Provided in open CSV format with detailed metadata, this resource supports behavioral phenotyping, machine learning applications, and investigations of learning mechanisms in tauopathy models.

Abstract: Excitable neurons are intrinsically capable of firing action potentials, yet a state of hyperexcitability is prevented in the central nervous system by powerful GABAergic inhibition. For this inhibition to be effective, it must occur before excitatory signals can initiate runaway activity, implying the existence of a proactive control system. To test for such proactive inhibition, we used Ca²⁺ imaging and patch-clamp recording to measure how hippocampal neurons respond to depolarization and glutamatergic agonists. In mature hippocampal cultures (14 DIV) and acute brain slices from two-month-old rats, neurons exhibited non-simultaneous responses to various excitatory stimuli, including KCl, NH4Cl, forskolin, domoic acid, and glutamate. We observed that the Ca²⁺ rise occurred significantly earlier in GABAergic neurons than in glutamatergic neurons. This delay in glutamatergic neurons was abolished by GABA(A) receptor inhibitors, suggesting a mechanism of preliminary GABA release. We further found that these early-responding GABAergic neurons express calcium-permeable kainate and AMPA receptors (CP-KARs and CP-AMPARs). Application of domoic acid induced an immediate Ca²⁺ increase in neurons expressing these receptors, but a delayed response in others. Crucially, when domoic acid was applied in the presence of the AMPA receptor inhibitors NBQX or GYKI-52466, the response delay in glutamatergic neurons was significantly prolonged. This confirms that CP-KARs on GABAergic neurons are responsible for the delayed excitation of glutamatergic neurons. In hippocampal slices from two-month-old rats, depolarization with 50 mM KCl revealed two distinct neuronal populations based on their calcium dynamics: a majority group (presumably glutamatergic) exhibited fluctuating Ca²⁺ signals, while a minority (presumably GABAergic) showed a steady, advancing increase in [Ca²⁺]i. This distinction was reinforced by the application of domoic acid. The "advancing-response" neurons reacted to domoic acid with a similar prompt increase, whereas the "fluctuating-response" neurons displayed an even more delayed and fluctuating reaction (80 s delay). Therefore, we identify a subgroup of hippocampal neurons—in both slices and cultures—that respond to depolarization and domoic acid with an early [Ca²⁺]i signal. Consistent with our data from cultures, we conclude these early-responding neurons are GABAergic. Their early GABA release directly explains the delayed Ca²⁺ response observed in glutamatergic neurons. We propose that this proactive mechanism, mediated by CP-KARs on GABAergic neurons, is a primary means of protecting the network from hyperexcitation. Furthermore, the activity of these CP-KAR-expressing neurons is itself regulated by GABAergic neurons containing CP-AMPARs.

Abstract:

Multiple sclerosis (MS) pathogenesis involves not only immune-mediated myelin injury but also glial responses. We examined how three charge isomers of myelin basic protein (MBP)—native (C1), phosphorylated (C4), and citrullinated (C8)—modulate rat astrocytes. Cytokines were quantified and grouped (pro/anti-inflammatory, chemotactic, neurotrophic, angiogenic, tissue remodeling), and regulatory markers assessed. C1 strongly upregulated the lipid-sensing receptor LXR, and reduced global DNA methylation; C4 moderately enhanced LXR; C8 failed to activate LXR or alter methylation. Functionally, C1 attenuated IL-1β, IL-6 and GM-CSF while increasing IL-10 and certain chemokines. C4 elicited an intermediate pattern, inducing CX3CL1 (fractalkine), CCL20, VEGF-A and TIMP-1 with minor effects on classical cytokines. In contrast, C8 triggered a robust pro-inflammatory phenotype, increasing IL-1α/β, TNF-α and GM-CSF, with higher IL-10, fractalkine, CCL20, VEGF-A and TIMP-1. All isomers suppressed IFN-γ, IL-4 and CNTF. These data indicate that MBP post-translational modifications drive distinct astrocyte phenotypes through integrated cytokine, metabolic and epigenetic pathways: C1 favours immune regulation and repair, C4 blends inflammatory and reparative cues, and C8 amplifies neuroinflammation. Understanding how modified MBP shapes astrocyte behaviour provides mechanistic insight into lesion evolution in MS and suggests astrocyte-directed strategies to modulate neuroinflammation and promote remyelination.

Abstract:

Existing animal models of post-traumatic stress disorder (PTSD) are often methodologically complex and produce variable outcomes. The aim of this study was to develop a modified PTSD model that accurately recapitulates the clinical progression of the disorder incorporating both behavioral features and objective physiological parameters. We utilized a modified Single Prolonged Stress with Subsequent Stress (SPS&S) protocol, supplemented by a stress reminder phase (without re-exposure to primary stressors) and an evaluation of stress response extinction. Eighty Wistar rats were subjected to the stress protocol, followed by comprehensive behavioral, hematological (leukocytes, hemoglobin, hematocrit), and hormonal (corticosterone, ACTH) assessments 4-5 weeks post-stress. The model produced a PTSD-like phenotype in 25% of animals, characterized by persistent alterations in the investigated biomarkers. The PTSD group exhibited sustained behavioral impairments (increased anxiety), hematological changes (neutrophilic leukocytosis), and endocrine dysregulation (decreased corticosterone, ACTH, and epinephrine). This modified SPS&S model demonstrates validity for studying the long-term consequences of stress, with PTSD markers remaining stable throughout the 28-day observation period.

Abstract: Background/Objectives: Schizophrenia is a highly heritable psychiatric disorder that affects approximately 1% of the global population. Genome-wide association studies (GWAS) have mapped most schizophrenia risk variants to noncoding regions, highlighting the role of regulatory processes and noncoding RNAs in schizophrenia pathology. Despite this, and schizophrenia’s association with 5-hydroxytryptamine (serotonin) system dysfunction, HTR5A-AS1, a long noncoding RNA (lncRNA) antisense to the serotonin receptor (HTR, 5-hydroxytryptamine receptor) gene HTR5A, remains virtually unstudied. This study provides the first systematic characterization of HTR5A-AS1, validating its transcript structure and investigating its genetic associations, expression dynamics, developmental regulation, and potential synaptic and GABAergic functions in schizophrenia. Methods: Transcriptome-wide association study (TWAS) summary statistics were integrated with postmortem RNA sequencing (RNA-seq), BrainSpan developmental transcriptomes, UCSC Genome Browser annotations, and functional prediction tools. These complementary approaches enabled validation of the transcript’s structure, quantification of regional and developmental expression, and assessment of potential molecular functions. Results: HTR5A-AS1 showed significant TWAS associations with schizophrenia in the hippocampus and dorsolateral prefrontal cortex (dlPFC). In postmortem schizophrenia donor tissue, expression was significantly reduced in the hippocampus, with a non-significant but directionally similar decrease in the dlPFC; sex-stratified analyses revealed that hippocampal reductions were strongest in male donors. Parallel analyses showed modest hippocampal downregulation of the paired receptor gene HTR5A, again driven primarily by males. Developmental transcriptomes revealed region-specific developmental trajectories, with steep increases during adolescence, aligning with the age range of typical schizophrenia onset. HTR5A-AS1 was strongly co-expressed with HTR5A, and functional predictions implicated involvement in synaptic and GABAergic signaling, consistent with cortico-hippocampal circuit disruption in schizophrenia. Conclusions: These findings provide the first evidence that HTR5A-AS1 is a bona fide antisense transcript with developmental and synaptic roles that may contribute to schizophrenia risk. Future single-cell and functional perturbation studies are needed to test causality and define mechanisms of regulation.

Abstract: The endocannabinoid system is expressed in brain centers involved in a wide variety of functions which makes it an ideal target for disease therapy and prevention. Unlike major excitatory and inhibitory neurotransmitters such as glutamate and GABA, en-dogenously produced cannabinoids have been shown to play a complimentary role as neuromodulators by acting as gain regulators of neural signals. The endocannabinoid system consists of cannabinoid receptors, CB1R and CB2R, and endogenously generat-ed lipid-based neurotransmitters, 2-AG (2-arachidonoylglycerol) and anandamide, the endocannabinoids. In the central nervous system, these signaling molecules are re-leased from postsynaptic cells in an on-demand manner. This retrograde transmission from post- to presynaptic neurons and the binding of endocannabinoids onto the pre-synaptic CB1 receptors modulates the magnitude of release of glutamate and GABA, either enhanced or inhibited, depending on the brain area under study. Research has focused on the role of the endocannabinoid system in the limbic system such as the hippocampus and amygdala. Research is increasing regarding the role that endocan-nabinoids play in other brain centers such as the olfactory system with particular em-phasis on the role of the endocannabinoid system in neural networks of the main ol-factory bulb. This review aims to bring together research within the overlap of the ol-factory system and the endocannabinoid system. By better understanding the unique neuromodulator and neurodevelopmental role of endocannabinoids in the brain, in-sight into understanding how to mitigate disease states that result from aberrant re-lease of glutamate and GABA such as stroke, epilepsy, and schizophrenia is expected to be gained.

Abstract: Microtubules are cylindrical protein polymers that organize the cytoskeleton and play essential roles in intracellular transport, cell division, and possibly cognition. Their highly ordered, quasi-crystalline lattice of tubulin dimers, notably tryptophan residues, endows them with a rich topological and arithmetic structure, making them natural candidates for supporting coherent excitations at optical and terahertz frequencies. The Penrose-Hameroff Orch OR theory proposes that such coherences could couple to gravitationally induced state reduction, forming the quantum substrate of conscious events. Although controversial, recent analyses of dipolar coupling, stochastic resonance, and structured noise in biological media suggest that microtubular assemblies may indeed host transient quantum correlations that persist over biologically relevant timescales. In this work, we build upon two complementary approaches: the parametric resonance model of Nishiyama et al. and our arithmetic–geometric framework, both recently developed in Quantum Reports. We unify these perspectives by describing microtubules as rectangular lattices governed by the imaginary quadratic field Q(i), within which nonlinear dipolar oscillations undergo stochastic parametric amplification. Quantization of the resonant modes follows Gaussian norms N = p² + q², linking the optical and geometric properties of microtubules to the arithmetic structure of Q(i). We further connect these discrete resonances to the derivative of the elliptic L–function, L′(E, 1), which acts as an arithmetic free energy and defines the scaling between modular invariants and measurable biological ratios. In the appended adelic extension, this framework is shown to merge naturally with the Bost–Connes and Connes–Marcolli systems, where the norm character on the ideles couples to the Hecke character of an elliptic curve to form a unified adelic partition function. The resulting arithmetic–elliptic resonance model provides a coherent bridge between number theory, topological quantum phases, and biological structure, suggesting that consciousness, as envisioned in the Orch OR theory, may emerge from resonant processes organized by deep arithmetic symmetries of space, time, and matter.

Abstract: Mitochondrial dysfunction and impaired mitophagy are hallmark features of Parkinson’s disease (PD), especially in patients with mutations in the PINK1 gene. Peroxiredoxin 6 (Prx6) is a bifunctional antioxidant enzyme known for its protective roles under oxidative stress, but its effects on mitochondrial dynamics and mitophagy remain poorly understood. In this study, we investigated the impact of recombinant Prx6 on mitochondrial function, reactive oxygen species (ROS) production, and mitophagy in both wild-type (WT) and PINK1-mutant fibroblasts. We further assessed the expression of genes related to mitochondrial quality control in neuroblastoma SH-SY5Y cells.Prx6 treatment significantly reduced ROS production and preserved mitochondrial membrane potential under oxidative stress in both WT and PINK1-mutant fibroblasts. It enhanced basal mitophagy but dampened excessive mitophagic activation induced by H₂O₂. In SH-SY5Y cells, Prx6 upregulated multiple genes associated with mitochondrial fission/fusion (drp1, mfn2), mitophagy (parkin, pink1, optn), and cell survival (bcl2, nrf2).Our findings suggest that Prx6 promotes mitochondrial homeostasis and cellular resilience in PINK1-deficient conditions by modulating oxidative stress responses and mitophagy-related pathways. These results highlight the potential of Prx6 as a therapeutic candidate for PD and other neurodegenerative disorders involving mitochondrial dysfunction.

Abstract: Epilepsy is a neurological disorder characterized by a long-lasting predisposition to recurrently generate unprovoked seizures. Epilepsy affected over 70 million people worldwide, with approximately one third suffering from pharmacoreisitant seizures. Currently, the clinic antiseizure drugs have not the efficacy in alteration of epilepto-genesis. Adenosine, as an endogenous anticonvulsant, inhibits the development of ep-ilepsy via interaction with the molecular epileptogenic network on several levels: i) Activation of A1 receptor inhibits glutamate release via presynaptic inhibition, and hyperpolarize the synaptic potentials in post-synaptic neurons. ii) A2A receptor on as-trocyte interacts with glutamate transporter GLT-1, controlling glial glutamate homeo-stasis. iii) Activation of A3 receptor inhibits GABA transporter type 1 -mediated GABA uptake. iv) Adenosine kinase (ADK) is highlighted as a pathological hallmark of epi-lepsy. The short isoform adenosine kinase (ADK-S) in the cytoplasm of astrocytes, controls the extracellular levels of adenosine and hence adenosine receptor-mediated mechanisms. The long isoform of adenosine kinase (ADK-L) in the nucleus of astrocytes and a subset of neurons, modulates adenosine receptor independent epigenetic mech-anisms. In the present review, we focus on some of the most recent and exciting pro-gresses including mechanisms, evaluation biomarkers for epilepsy as well as therapy aim to modify the progression of epilepsy.

Abstract:

According to the World Health Organisation (WHO), conditions linked to the brain account for 28% of the social burden of all diseases, the largest sector, surpassing cancer and cardiovascular disease (CVD). Our incomplete understanding of human neurodegeneration biology is at the center of the devastating impacts it brings on our societies. A fundamental translational effect in those therapies is evident in that none have succeeded in registration-sized clinical trials. The outcome are coexisting therapies that remain largely palliative, managing symptoms or slowing decline but not providing hope for a reversal or cure. Increasing evidence has positioned the gut-brain axis (GBA) as a key modulator of neurodegeneration hallmarks, often inducing or progressing disorders such as Alzheimer’s, Parkinson’s and Multiple Sclerosis. Traditional research tools fail to recapitulate the accurate physiology of organ systems in humans, leading to the development of organoid technologies and organ-on-a-chip platforms. This literature review comprehensively analyses efforts to model neurodegenerative disorders through in vitro models, evaluating advancements in intestinal, cerebral, GBA, blood-brain barrier and other multi-organ systems. Further, the paper ties back to the known pathophysiology of such diseases and the GBA’s influence to evaluate limitations of current disease modelling approaches, offering future directions that enable applications in drug discovery. These technologies mark a transformative shift in methods to understand both the mechanistic causation and therapeutic strategies for previously incurable diseases, expanding the possibilities to improve the lives of millions of diagnosed patients.

Abstract: Rett syndrome (RTT), an X-linked neurodevelopmental disorder predominantly arising from de novo MECP2 mutations, manifests with psychomotor regression, stereotypic hand movements, gait apraxia, and expressive aphasia, driven by dosage-sensitive epigenetic dysregulation via MeCP2's methyl-CpG-binding domain (MBD) and transcriptional repression domain (TRD). Isoform-specific expression (MeCP2-E1 neuronal predominance) and X-chromosome inactivation mosaicism underpin phenotypic variability, with missense (R133C, T158M) and nonsense (R168X, R255X) variants correlating to severity gradients. Multisystem pathophysiology encompasses brainstem-mediated respiratory dysrhythmias, QTc prolongation via ion channel perturbations, enteric hypomotility, osteopenic fractures, and mitochondrial bioenergetic deficits, exacerbated by glial-neuronal crosstalk and oxidative stress. Preclinical platforms, including Mecp2-null rodents, patient-derived iPSCs, and cerebral organoids, elucidate synaptic hyperexcitability, dendritic arborization deficits, and reversibility upon Mecp2 reactivation. Therapeutic modalities span supportive multidisciplinary interventions, FDA-approved trofinetide (IGF-1 analog modulating neurotrophic cascades), AAV-mediated gene replacement (NGN-401, TSHA-102 with miRARE autoregulation), ASOs for dosage normalization, and emerging PPAR-γ agonists targeting metabolic homeostasis. Prioritized research agendas emphasize validated biomarkers (BDNF/IGF-1 axes, miRNA signatures), combinatorial regimens, and equitable global access to mitigate caregiver burden and phenotypic heterogeneity.

Abstract: This paper argues that the moment-to-moment content of phenomenal consciousness is identical to whichever neural or mnemonic representation is, at that instant, transiently the most accessible given the system’s causal history and current embedding context. Building on Tulving’s distinction between availability and accessibility, together with empirical work on working-memory constraints, attentional blink, priming, and neuromodulation, we argue that the “stream of consciousness” (James, 1890) is a serial, determined sequence of state transitions governed by relative accessibility. A broader claim is advanced: the stream of consciousness is not an accidental by-product of slower adaptive processes but the real-time continuation of the same abstract dynamic that operates across evolutionary, developmental, and cultural timescales, only here unfolding at psychological speed. The account is deterministic (or near-deterministic) at the psychological level, reframes the hard problem of consciousness as a tractable question about accessibility mechanisms, and remains neutral on low-level physical indeterminism. It is compatible with major neuroscientific findings and generates contrasting predictions about priming effects, mind-wandering sequences, conscious transitions under neuromodulation, and clinical disruptions of conscious seriality.

Abstract:

Sporadic Alzheimer’s disease (AD) is associated with numerous risk factors, yet its precise cause remains unclear. Here, we describe a novel framework for AD pathogenesis, whereby diverse risk factors converge on neuromodulatory subcortical systems to confer AD risk or resilience. Neuromodulatory projection neurons are uniquely fragile due to their large size, sparse myelination, and high basal metabolic demands. We propose that the increased prevalence of AD in older adult populations likely reflects a universal weakness within these projection systems, which is increasingly exposed as cellular transport and maintenance mechanisms deteriorate with age. The key insight of this ‘neuromodulatory fragility framework’ is that neuromodulatory system dysfunction is sufficient to explain both tau hyperphosphorylation and b-amyloid (Ab) plaque formation, the two pathological hallmarks of AD. We therefore predict that strengthening or preserving the endogenous functions of these systems in midlife represents the most effective strategy for preventing AD.

Abstract:

In pathological conditions, elevated activity of connexin and pannexin hemichannels facilitates Adenosine triphosphate (ATP) efflux and Ca²⁺ influx, activating metabolic pathways of neuroinflammation. While a small insult could result in a protective inflammatory response, more intense and/or prolonged insults induce cell death, causing tissue dysfunction. In the brain, different stressors elevate glucocorticoid (GC) levels that are sensed by mast cells and microglia, and this response persists for a long time, causing continuous inflammasome activation and release of IL-1β and IL-18. These proinflammatory cytokines, together with those released by mast cells, activate astrocytes and oligodendrocytes, which in turn release glutamate and ATP, and altogether reduce neuronal functionality and survival. The extent of neuroinflammation also depends on host features that result in different degrees of alterations during brain ontogeny, consequently changing the brain cytoarchitecture and leading to spectrums of behavioral diseases. Selective hemichannel blockers have been recently discovered and shown to reduce neuroinflammation, as well as neuronal suffering and symptoms linked to adult models of depression and epilepsy. These blockers can serve as tools to dissect the role of neuroinflammation in behavioral diseases. Early treatment during brain ontogeny could reduce detrimental impacts on the brain cytoarchitecture, inducing behavioral alterations elicited in adulthood.

Abstract: 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 neuromuscular 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.

Abstract:

Cell motility—the dynamic process encompassing migration, adhesion modulation, cytoskeletal remodeling, and extracellular matrix (ECM) interactions—is fundamental to ocular homeostasis. In glaucoma, disrupted motility of trabecular meshwork (TM) and Schlemm’s canal (SC) cells contributes to impaired aqueous humor outflow and elevated intraocular pressure (IOP), while reactive motility of optic nerve head (ONH) glial cells promotes fibrosis and neurodegeneration. Mechanistically, TM/SC motility is regulated by Rho GTPase and ROCK signaling, focal adhesion dynamics, and ECM interactions, while glial cells respond to mechanical stress and cytokines such as TGF-β2. Cytoskeletal alterations, ECM stiffening, and endothelial–mesenchymal transition (EndMT) contribute to glaucomatous damage by reducing normal cell motility and tissue remodeling capacity. Aberrant motility at the ONH, including heterogeneous astrocytic reactivity, leads to lamina cribrosa remodeling and retinal ganglion cell degeneration. Therapeutically, ROCK inhibitors improve TM/SC motility and outflow, suppress EndMT, and may confer neuroprotection. Stem cell–based strategies and modulation of TGF-β2 or mechanotransduction pathways represent emerging approaches to restore physiological motility and regenerative potential. Despite promising advances, challenges remain in ensuring targeted, durable, and safe modulation of cellular dynamics. Understanding and therapeutically harnessing cell motility offers a unifying framework to address both pressure-dependent and neurodegenerative mechanisms in glaucoma.

Abstract: This review examines convergent neurobiological mechanisms linking stress and drugs that drives stress-induced drug-related behaviors. It first outlines main theoretical frameworks explaining substance use disorders (SUDs), emphasizing vulnerability factors—particularly stressful life events—that increase addiction risk. The analysis integrates preclinical evidence demonstrating that chronic stress facilitates cross-sensitization to psychostimulants and accelerates drug self-administration, underscoring how stress and drugs converge on glutamatergic and dopaminergic transmission within the Nucleus Accumbens (NAc). Special attention is given to the glial cells, particularly microglia and astrocytes, in mediating stress-induced neuroimmune activation and glutamate dysregulation in the NAc. Three major themes related to microglia–astrocyte crosstalk are addressed: (i) the contribution of these glial cells to neuroimmune and glutamatergic alterations induced by stress; (ii) their role in synaptic and structural plasticity changes within the NAc; and (iii) the mechanisms by which stress and drug exposure reshape glial–neuronal communication, driving the comorbidity between stress and SUDs. A dedicated section focuses on key neuroimmune signaling pathways—particularly the TNF-α/NF-κB axis—and their involvement in stress-induced vulnerability to cocaine addiction. Finally, the review discusses preclinical evidence supporting the therapeutic potential of repurposed glutamate-modulating agents, as promising pharmacological candidates for treating comorbid stress and cocaine use disorder.