Rodent cell culture models have long underpinned research into nociceptive signaling; however, their limited recapitulation of human nociceptor biology has created a translational gap in analgesic development. While primary human sensory neurons are relevant, their use is hampered by scarcity, ethical constraints, donor variability, and difficulties in long-term culture. Furthermore, conventional cultures lack the compartmentalization needed to study sensory neuron processes and fail to recapitulate the synaptic connectivity between sensory and spinal cord neurons, limiting their translational relevance. To address these limitations, we utilized a microfluidic platform enabling compartmentalized culture of human induced pluripotent stem cell (hiPSC) derived sensory neurons (hiPSC-SNs) to study the function of their processes. We also demonstrate the feasibility of microfluidic co-cultures of hiPSC-SN with human iPSC-derived cortical excitatory neurons (hiPSC-CNs) as a basis for future development of models for sensory-to-CNs communication circuit. Using optimized protocols, we maintained stable microfluidic cultures and confirmed expression of pain-relevant sodium channels (Nav1.7, Nav1.8) in hiPSC-SN in both mono- and co-culture configurations. Leveraging this compartmentalized platform, we demonstrate that pharmacological blockade of Nav1.7 and Nav1.8 inhibits signal propagation along sensory neuron processes. We also demonstrate that growth factors modulate excitability of these processes. This functional validation underscores the platform's capability to investigate signal transmission along human sensory processes and demonstrates its potential for modelling more complex cellular interactions. Thus, we present a human iPSC-based microfluidic culture model that enables detailed study of sensory neuron processes and assessment of analgesics targeting nociceptive transmission, offering a significant advance toward analgesic drug discovery.
Integrated information theory (IIT) makes two predictions about the role of inactive neurons in consciousness. According to the silent brain (SB) prediction, rendering all active neurons inactive ("silent") in the physical substrate of consciousness (the "main complex") does not eliminate the presence of consciousness, because the neurons are still able to spike. According to the disabled neuron (DN) prediction, rendering a subset of silent neurons in the main complex no longer able to spike ("disabled") can impact the qualitative character of experiences "nonconventionally" associated with those neurons. Bartlett (2022) argues that these predictions are untestable, because evidence for either prediction would imply that the testing conditions were not met. In this paper, we provide a detailed analysis of both silent neuron predictions, showing how they can in fact be tested. For the SB case, we clarify how a neural mechanism outside of the main complex can yield the required report of consciousness while maintaining the SB state. For the DN case, we distinguish between two ways of explaining how a neural mechanism could casually interact with the main complex: an IIT-inspired "dispositionalist" explanation, and a more conventional "actualist" explanation. Drawing on the work of Imre Lakatos, we conclude with a discussion of how the distinction between the two explanations sheds light on why it is so difficult to resolve theoretical disputes about consciousness. Despite these difficulties, we provide a framework that can lead to concrete progress for consciousness science.
Successful repair after brain injury requires a chain of events, including the generation, migration, and successful integration of adult-born neurons into preexisting circuits. In mammals, the capacity for neuronal regeneration is extremely limited and further declines with age, constraining recovery. Regeneration-competent vertebrates offer a unique opportunity to uncover mechanistic principles of seamless brain repair. We here introduce the African turquoise killifish, a naturally short-lived vertebrate in which tissue repair occurs at young but not old age. We established an integrative approach combining i) an optimized retroviral vector application to birthdate GFP-labeled dividing neural stem cells and their progeny, ii) targeted electrophysiology to quantify synaptic and intrinsic maturation of such neurons, and iii) a conditioned avoidance assay to track recovery of learned behavior in adult killifish. We applied this workflow to the dorsomedial telencephalon, a region homologous to the mammalian amygdala. We reveal that injury-induced adult-born neurons survive, mature, and integrate synaptically into preexisting circuits, and that this coincides with the recovery of learned avoidance behavior by two months postinjury. Only when newborn neurons display mature morpho-electric properties, including complex dendritic arborization and abundant dendritic spines, recovery of behavior is accomplished. That full functional recovery takes around 50 d, substantially longer than previously inferred from histological analyses alone, is a striking finding given the killifish's short lifespan. These findings establish the killifish as a powerful vertebrate model and introduce a scalable platform for experimentally manipulating neuronal maturation and integration in vivo, particularly in the context of aging and age-related regenerative decline.
N6-methyladenosine (m6A) facilitates functional recovery following ischemic stroke (IS). This study investigated the role of Sptbn2 in post-stroke cognitive impairment (PSCI) and the mechanisms regarding m6A. HT-22 cell damage and ferroptosis were analyzed following OGD exposure. pMCAO surgery was performed to establish an IS mouse model. We assessed neurological deficits and cognitive impairment in mice using the mNSS, adhesive removal test, rotarod test, novel object recognition test, and Y-maze test. Adeno-associated viral vectors with overexpression of Sptbn2 combined with pMCAO surgery were used to analyze cognitive dysfunction and ferroptosis. Sptbn2 was reduced in neurons of PSCI mice. Sptbn2 overexpression alleviated ferroptosis-induced neuronal damage by promoting the membrane translocation of Slc7a11. Hnrnpa2b1 promoted Sptbn2 stability through an m6A-related mechanism. Knockdown of Sptbn2 reversed the mitigation of ferroptosis by Hnrnpa2b1 and exacerbated the neuronal injury. Under OGD, Bard1 knockdown reduced the Hnrnpa2b1 ubiquitination, slowed Hnrnpa2b1 degradation, and restored Sptbn2 expression. Knockdown of Bard1 alleviated neuronal ferroptosis, thereby reducing the development of cognitive impairment in mice, a phenotype reversed by Hnrnpa2b1 or Sptbn2 knockdown. In IS, Bard1-associated regulation of Hnrnpa2b1 ubiquitination is accompanied by reduced Sptbn2 expression and impaired Slc7a11 membrane translocation, and is involved in neuronal ferroptosis-related damage.
Chronic stress is a major risk factor for anxiety disorders and is often accompanied by disruptions in female reproductive cyclicity, but the stress-responsive neural populations that shape these comorbid behavioral and physiological outcomes remain poorly defined. The bed nucleus of the stria terminalis (BNST) is a major node for sustained anxiety and stress integration, yet the contribution of genetically defined BNST neurons to restraint stress is not fully resolved in females. Here, we identify proenkephalin-expressing neurons in the anterior dorsal BNST (adBNSTPENK) as a restraint-responsive population that constrains anxiety-like behaviors and modulates cytology-based estrous cycle organization. Acute chemogenetic inhibition of adBNSTPENK neurons produced anxiety-like behaviors in females, whereas activation attenuated acute restraint stress (ARS)-induced anxiety-like behaviors. Female mice subjected to chronic restraint stress (CRS) exhibited both anxiety-like avoidance and disrupted estrous-cycle organization, which can be mitigated by sustained activation of adBNSTPENK neurons. These findings suggest that adBNSTPENK neurons form a stress-recruited limbic circuit node that buffers stress-induced anxiety-like behaviors and is associated with improved vaginal cytology-based estrous-cycle organization under chronic stress.
Spinal muscular atrophy (SMA) results from biallelic loss of functional survival motor neuron 1 (SMN1), reducing production of full-length survival motor neuron (SMN) protein and leaving endogenous SMN supply largely dependent on inefficient survival motor neuron 2 (SMN2) splicing. This review conceptualizes SMA as a disorder in which available SMN supply fails to meet tissue- and stage-specific SMN requirement, defined as the minimum effective SMN level needed to maintain normal cellular or tissue function. Disease-modifying therapies (DMTs) have transformed SMA outcomes, particularly when initiated presymptomatically or very early after symptom onset. However, treatment responses remain heterogeneous, especially among infants with two SMN2 copies and patients treated after symptomatic progression. These observations suggest that therapeutic response is shaped not only by SMN restoration but also by timing, residual SMN reserve, and tissue vulnerability already present at treatment initiation. This review argues that SMN requirement varies across tissues, developmental stages, and biological states. It proposes a three-component framework: developmental mismatch, post-developmental dynamic mismatch, and tissue-state transitions. Developmental mismatch is the most directly supported component and highlights tissue- and stage-specific vulnerability before and shortly after birth, particularly in the motor unit; early SMN insufficiency may leave latent developmental vulnerability even after early DMT. Post-developmental dynamic mismatch is presented as an evidence-informed, hypothesis-generating extension in which constrained SMN supply may be sufficient at baseline but inadequate during maintenance, remodeling, repair, intercurrent illness, or catabolic stress. Tissue-state transitions distinguish preserved tissue, functionally impaired but structurally retained tissue, and structurally degenerated tissue with limited reversibility. Together, this framework may help interpret residual deficits after early treatment, incomplete recovery after delayed treatment, and the need for multimodal biomarkers and longitudinal monitoring strategies that distinguish potentially reversible functional impairment from structural degeneration with limited reversibility.
While the recent clinical approval of amyloid-targeting monoclonal antibodies represents a landmark in Alzheimer's disease (AD) management, these immunotherapies fundamentally function as agents of mitigation rather than restoration, failing to reconstitute decimated neural circuitry. Direct in situ astrocyte-to-neuron reprogramming offers a compelling regenerative alternative by leveraging the abundant endogenous glial reservoir. However, translating this cellular plasticity in vivo is severely bottlenecked by the hostile pathological microenvironment and the deeply entrenched epigenetic memory of reactive astrocytes. In this review, we delineate a tripartite neuroregenerative framework. First, we evaluate the prerequisite use of senotherapeutics to engineer a permissive parenchymal niche for nascent neuronal survival. Second, we explore epigenomic editing strategies-including CRISPR-dCas9 platforms and targeted pharmacological modulators-required to dismantle repressive heterochromatin and unlock sequestered neurogenic loci. Third, we dissect the molecular execution of reprogramming via pioneer transcription factors (TFs), emphasizing the obligatory metabolic rewiring from astrocytic glycolysis to neuronal oxidative phosphorylation (OXPHOS). Finally, to overcome formidable translational hurdles, we highlight the convergence of AI-optimized lipid nanoparticles (LNPs) for non-viral blood-brain barrier (BBB) transcytosis alongside Neurological Digital Twins (NDTs) to computationally predict the optimal presymptomatic intervention window. By harmonizing microenvironmental conditioning, epigenetic rejuvenation, and precision delivery, this systems-level blueprint provides a promising rationale for transitioning AD therapeutics from passive deceleration to active structural restoration.
Deeper understanding of ketamine's mechanism of action would contribute to the discovery of novel therapeutic targets with fast-onset actions. To gain insight on the mechanism underlying the antidepressant-like effects of ketamine, we focused on perineuronal nets (PNNs), an extracellular matrix structure that surrounds fast-spiking parvalbumin-positive interneurons and regulates synaptic plasticity, whose integrity is known to be compromised under stress-induced depressive conditions. We first performed the description of the plastic remodeling of PNNs in the Chronic restraint stress (CRS) mice treated or un-treated with ketamine, by quantifying the number of WFA, marker of PNNs, parvalbumin (PV) and c-Fos positive cells, as a surrogate of neuronal activity. And then, we investigated the the transcripts of a number of proteins involved in the formation or degradation of PNNs with or without ketamine in CRS mice. Next, we evaluated the expression of IBA1, a microglial marker, in the hippocampus and medial prefrontal cortex after CRS treated or un-treated with ketamine. We found that ketamine effectively alleviated the animals' depression like behavior as well as attenuates CRS-induced reduction of WFA-positive cells in the hippocampus and medial prefrontal cortex of mice. Although ketamine treatment had little or no effect on the number of PV, c-Fos positive cells and the transcripts of proteins involved in the formation or degradation of PNNs. Notably, ketamine treatment lead to remarkably reduced the number of IBA1-positive cells in the hippocampus and medial prefrontal cortex after CRS. Our findings suggest that PNNs is characterized by region-specific changes in chronic stress mouse brain and provide extensive evidence that ketamine exposure initiates microglia to remodel PNN, instead of the PNN accumulation and degradation enzymes.
The primary aim was to explore the relationship between neck weakness in people with motor neurone disease (MND) and their respiratory function. The secondary aim was to identify whether neck weakness can be a prognostic factor. This was a retrospective observational cohort study. Data was collected from patient records on MND characteristics, neck weakness, respiratory function, and noninvasive ventilation (NIV) use. Multivariate modeling explored the effect of neck weakness on respiratory variables. MND-related neck weakness was evident in 41% of 324 participants. Fifty-four percent used NIV and 17% became dependent on NIV during disease progression. The presence of neck weakness in MND was predictive of time to respiratory function decline, for respiratory outcomes (forced vital capacity (FVC) <65%, FVC <50% and NIV use) as well as having an effect on time to death. Median time from neck weakness onset to death was 8 months (IQR 10 months; range 0 to 60 months) with bulbar onset the quickest, median of 7 months (IQR 7 months, range 0 to 43 months). The presence of neck weakness is associated with a more rapid respiratory function decline in MND. In addition, neck weakness can be considered a prognostic factor in MND survival. People with motor neurone disease (MND) experience weakness in different parts of their body including muscles that are responsible for breathing. As the disease worsens, it is expected that their breathing worsens, resulting in death. To help prolong the person’s life, timely equipment that makes breathing easier is important. It is thought that there may be a relationship between weakness spreading to the neck muscles and the person’s ability to breathe and whether it could help predict how the disease will progress. To explore this further, we reviewed the medical records of 324 people with MND. We found that about 4 in 10 people had neck weakness from their MND and over half were using breathing support. We also found that those with neck weakness tended to lose their breathing function more quickly and needed breathing support sooner. People with neck weakness were also found to have a shorter survival time, with an average of 8 months once their neck weakness began, however this varied depending on the type of MND the person had.
The ketogenic diet is used to treat drug-resistant epilepsy, yet the molecular mechanisms coupling metabolic state to seizure suppression remain understudied. β-Hydroxybutyrate (β-HB), a principal ketone body, exerts antiseizure effects, yet its downstream ionic mechanisms remain unclear. We used 69 C57BL/6 mice, including males and females (4-week-old for ex vivo electrophysiology and calcium imaging and 8-week-old for in vivo seizure experiments). β-HB or saline was administered after the onset of status epilepticus, induced in mice by continuous hippocampal stimulation. Intrinsic excitability and excitatory synaptic currents on hippocampal granule cells were measured using the patch clamp technique. Calcium imaging was performed after viral delivery of a genetically encoded calcium indicator into the hippocampus. In vivo, β-HB rapidly reduced the duration of status epilepticus. At the cellular level, patch-clamp recordings showed that β-HB hyperpolarized dentate granule cells (DGCs) increased action potential threshold and reduced firing frequency. Moreover, β-HB suppressed excitatory synaptic transmission onto DGCs. At the network-level, β-HB perfusion significantly decreased DGC population activity by reducing neuronal excitability and excitatory synaptic currents. Mechanistically, pharmacological blockade of G protein-gated inwardly rectifying potassium (GIRK) channels prevents the β-HB-induced suppression of DGC intrinsic excitability, excitatory synaptic transmission, and population-level activity. In contrast, inhibition of adenosine triphosphate-sensitive potassium channels had no detectable impact on β-HB-mediated modulation of DGC intrinsic excitability or network responses. These findings identify GIRK channels as a key downstream effector of β-HB signaling, providing a mechanistic link between ketogenic states and neuronal excitability, revealing a new mechanistic target for ketogenic therapies.
To investigate whether selected Malaysian plant extracts modulate the antioxidant-autophagy axis to enhance neuronal and skeletal muscle protection. Four standardized extracts (Persicaria minor, Eurycoma longifolia (EL), Labisia pumila, and Ipomoea aquatica) were evaluated for antioxidant activity at 100, 200, and 300 μg/mL using ABTS, DPPH, and ORAC assays. The most active extract was further examined in SH-SY5Y neuronal-like cells and differentiated C2C12 myotubes. Cell viability was assessed using CCK-8, oxidative DNA damage was measured by 8-OHdG ELISA, and autophagy-related changes were evaluated by LC3/p62 immunofluorescence and western blot analysis of LC3-II and p62 with chloroquine (CQ) as a lysosomal inhibitor. Among the four extracts, EL exhibited the strongest antioxidant activity, achieving the highest values in ABTS (107.59 ± 7.98 μmol Trolox/g), DPPH (27.28 ± 1.29 μmol Trolox/g), and ORAC (81.12 ± 4.81 μmol Trolox/g) at 300 μg/mL, also showing the lowest IC₅₀ (167.22, 97.64, and 67.90 μg/mL for ABTS, DPPH, and ORAC, respectively), with regression analyses confirming significant dose-response relationships (R² > 0.96, p < 0.05). CCK-8 analysis showed that EL at 100-300 μg/mL did not cause overt cytotoxicity in either cell model after 24 h treatment (p > 0.2), whereas the positive cytotoxicity control markedly reduced viability (p < 0.001). 8-OHdG ELISA showed that EL reduced oxidative DNA damage, with significant reductions at 200 and 300 μg/mL in both SH-SY5Y and C2C12 cells (p < 0.05). H2O2 markedly increased 8-OHdG levels in both models (p < 0.001). Immunofluorescence analysis showed concentration-dependent modulation of LC3 and p62 autophagy-related markers. In SH-SY5Y cells, treatment with EL induced a dose-dependent increase in LC3 puncta (p < 0.001) and a significant reduction in p62 fluorescence (p < 0.01). Similar trends were observed in C2C12 myotubes, where LC3 puncta formation was enhanced (p < 0.05), and p62 levels decreased (p < 0.01). Western blot validation further showed that EL increased LC3-II abundance and that EL + CQ further increased LC3-II accumulation compared with CQ alone, particularly at 300 μg/mL (p < 0.05). p62 decreased under basal EL treatment but showed a non-canonical decrease in the CQ-only group and was therefore interpreted cautiously. EL showed the strongest antioxidant activity among the tested Malaysian plant extracts and modulated autophagy-related cellular markers without overt cytotoxicity. These findings identify EL as a promising candidate for further investigation in oxidative stress- and proteostasis-related cellular protection.
The brain's ability to detect unexpected events, deviance detection (DD), is critical for survival. While DD has been computationally explained by synaptic plasticity, the role of neuromodulators such as acetylcholine (ACh) remains less understood. Here, we examine how ACh modulates DD. Using a cholinergic-sensitive Hodgkin-Huxley network of 200 neurons arranged in 2D space and stimulated via five spatially distinct inputs (A-E), we implemented an oddball paradigm with three conditions: standard (80% A, 20% B), deviant (20% A, 80% B), and a multi-standard control (20% each of A-E). ACh levels were modeled by varying the conductance of a slow K⁺ current, reflecting cholinergic modulation of the M-current. In the absence of ACh, the network already exhibited DD, responding more strongly to deviant A compared to control A. Notably, introducing a small amount of ACh amplified DD, while further increases suppressed it. Maximal DD occurred when strong spike frequency adaptation to standard B reduced competition, and enhanced phase-locking synchronized the network's response to deviant A. These findings reveal how neuromodulation can shape context-sensitive neural computation, optimizing detection of salient events through a dynamic balance of suppression and synchronization. The online version contains supplementary material available at 10.1007/s11571-026-10522-3.
Epilepsy is a chronic neurological disorder characterized by recurrent seizures, neuroinflammation, and epigenetic instability, with around one-third of patients experiencing drug-resistant epilepsy. While ion channels and neurotransmitter imbalances have been thoroughly examined in relation to epilepsy, the significance of piRNAs and their interaction with PIWI proteins in gene regulation, transposon silencing, and inflammatory signaling inside the epileptic brain is gaining recognition. This summary encapsulates the existing understanding of piRNA synthesis, the epigenetic control through PIWI-piRNA interactions, and their novel roles in epileptogenesis. PIWI-piRNA complexes target highly expressed genomic areas, such as LINE-1 retrotransposons, and mute them by recruiting chromatin modifiers such DNMT3A and H3K9 methyltransferase complexes, therefore influencing genome stability and neuronal excitability. Additionally, piRNAs initiate pathways associated with neuroinflammation, including the activation of the Toll-like receptor-4/NF-kB signaling pathway and the NLRP3 inflammasome, and indirectly influence GABAergic homeostasis through interactions with the extensive noncoding RNA regulatory network. Targeted modulation of kainic acid, pilocarpine, and hereditary epilepsy models has been documented to provide decreases in seizure load; however, the extent of this effect varies among the models and modulation techniques employed. The review critically evaluates emerging therapeutic strategies, including AAV9 vectors, lipid nanoparticles, exosome-based delivery systems, and antisense oligonucleotides, along with their associated challenges such as blood-brain barrier penetration, off-target effects, immune activation, and long-term safety. In conclusion, the PIWI-piRNA axis represents a potential yet nascent domain for biomarker creation and disease modulation in epilepsy.
The dynamical behaviour of a population-based rate model with firing adaptation is studied. An excitatory and inhibitory population of neurons is recurrently coupled and a negative feedback term is added to the excitatory population as firing adaptation. In several studies of these models, the UP-DOWN transitions are in focus, which are also exhibited by the investigated model. In this paper we provide a full characterization of equilibrium points with the precise conditions for their existence and stability. Calculations can be performed analytically and explicit formulas can be provided due to the fact that the activation function is a threshold linear function. We use bifurcation analysis to detect significant changes in the phase space. Complete list of bifurcation diagrams is provided with respect to the number of steady states. Oscillatory dynamics of neurobiological relevance are examined through local bifurcation analysis. The study demonstrates that sharp wave-ripple oscillations may emerge in certain regions of the parameter space.
Parkinson's disease is characterized by dopaminergic neuron loss and accumulation of α-synuclein aggregates in the brain. G51D α-synuclein knock-in mice provide a genetically and clinically relevant model of disease, exhibiting early olfactory deficits, age-dependent motor impairment, and progressive phospho-α-synuclein accumulation. In multiple Parkinson's disease models, striatal cholinergic and parvalbumin interneurons, as well as astrocytes, lose primary cilia and the neurotrophic signaling needed to sustain dopaminergic neurons. We show here that G51D α-synuclein mice share these phenotypes. Phospho-Ser129 α-synuclein accumulation correlates with cilia loss in cholinergic interneurons but not in spiny projection neurons that accumulate higher phospho-α-synuclein levels. In the piriform cortex, parvalbumin neurons lose primary cilia and downregulate Neurturin, potentially contributing to olfactory dysfunction. Within the peripheral olfactory epithelium, horizontal basal cells lose cilia, whereas multiciliated olfactory sensory neuron cilia remain intact. These findings reveal convergent cellular vulnerabilities across Parkinson's disease models and highlight a pathogenic role for impaired ciliary signaling.
Central nervous system (CNS) disorders, including spinal cord injury, stroke, multiple sclerosis, and motor neuron diseases, are major causes of long-term disability largely due to the persistent failure of axonal regeneration. Over recent decades, diverse strategies have been developed to overcome these barriers, including modulation of extracellular matrix composition, engineering of biomaterial scaffolds, and reactivation of intrinsic growth-associated signaling pathways. However, interventions targeting isolated molecular or environmental factors have produced limited regenerative outcomes. Here, we propose a conceptual framework in which neural repair is understood as the reconstruction of a permissive regenerative niche that aligns intrinsic neuronal growth programs with engineered extracellular microenvironments. We synthesize current knowledge on the cellular and molecular determinants of axonal regeneration and discuss how extracellular matrix architecture and biomaterial scaffolds provide instructive physical and biochemical cues that stabilize growth cones and guide axonal extension. In parallel, intrinsic strategies targeting pathways such as mTOR, STAT3, Krüppel-like factors, and the Lin28/let-7 axis can reestablish neuronal growth competence. Advanced in vitro platforms further enable controlled integration of intrinsic and extrinsic variables, providing experimental models of regenerative niches and testbeds for combinatorial interventions. By framing axonal regeneration as an emergent property of coordinated neuron-environment interactions, this review bridges neurobiology and bioengineering to propose a disease-relevant conceptual framework for neural repair and highlights the need for integrative strategies capable of aligning neuronal state with engineered extracellular landscapes.
Excessive microglial activation after subarachnoid hemorrhage (SAH) contributes to early brain injury (EBI) and poor clinical outcomes. This study explores the role of complement C3a receptor 1 (C3aR1) in microglial activation after SAH and evaluates Vorinostat as a potential therapeutic agent. Differentially expressed genes were identified from GEO datasets (GSE36791, GSE73378), followed by WGCNA and machine learning to pinpoint key SAH-related genes. Molecular docking and molecular dynamics simulation identified Vorinostat as a potential C3aR1-targeting compound. Functional studies were conducted using C3aR1 knockout mice and BV2 microglial cells. Neurological outcomes were assessed through Garcia score, rotarod, and pole tests. Histological staining and immunofluorescence evaluated neuronal injury and microglial activation. ELISA was used to measure plasma C3aR1 and inflammatory markers in SAH patients and correlate them with 6-month modified Rankin Scale (mRS) scores. C3aR1 was identified as a key SAH-related gene and was significantly upregulated after SAH. C3aR1 deficiency alleviated brain edema, neuronal apoptosis, neuroinflammation, and neurological dysfunction in SAH mice. Transcriptomic and functional analyses demonstrated that these protective effects were mediated, at least in part, through activation of the TGF-β/Smad signaling pathway. In vitro, C3aR1 knockdown suppressed microglial proliferation, migration, phagocytosis, and inflammatory responses, while reducing oxidative stress in co-cultured neurons; opposite effects were observed following C3aR1 overexpression. Vorinostat exhibited strong binding affinity to C3aR1, reduced C3aR1 protein expression, activated TGF-β/Smad signaling, and attenuated EBI after SAH. Clinically, plasma C3aR1 levels were significantly elevated in SAH patients, correlated with inflammatory cytokines and 6-month modified Rankin Scale scores, and independently predicted poor functional outcomes. C3aR1 promotes microglial overactivation and neuronal injury after SAH, partly via suppression of TGF-β signaling. Vorinostat attenuates EBI and is associated with reduced C3aR1 expression. Plasma C3aR1 may serve as a prognostic biomarker in SAH.
Alprazolam (Alp) is a clinically common benzodiazepine (BZD) with a potential risk of abuse, yet the mechanisms underlying its reinstatement remain unclear. In this study, a conditioned place preference (CPP) paradigm combined with forced swim stress (FSS) was employed to induce CPP reinstatement in male mice with prior Alp exposure. The results demonstrated that the activity of CaMKIIα neurons in the ventromedial hypothalamus (VMH) was significantly increased following FSS-induced reinstatement of Alp-CPP. The lateral hypothalamus (LH) receives innervation from the VMH, and GABAergic neurons in the LH were activated during this process. Chemogenetic inhibition of VMHCaMKIIα-LH circuit significantly reduced FSS-induced reinstatement of Alp-CPP. Furthermore, chemogenetic activation of LH GABAergic neurons reversed the suppressive effects of inhibiting VMH CaMKIIα neurons projecting to the LH on Alp-CPP reinstatement. Collectively, these findings elucidate a critical role for the VMHCaMKIIα-LHGABA circuit in mediating stress-induced reinstatement of Alp-CPP in male mice, thereby advancing our understanding of the neural mechanisms underlying Alp reinstatement and providing novel insights for the prevention and treatment of BZD addiction.
Our understanding of visual cortical processing has relied primarily on studying the selectivity of individual neurons in different areas. A complementary approach is to study how the representational geometry of neuronal populations differs across areas, which can reveal encoding strategies difficult to infer from single neuron responses. We measured neuronal population responses in primary visual cortex (V1) and area V2 of macaque monkeys to naturalistic textures. Responses were lower dimensional in V2 than V1, and there was a better alignment among V2 population responses to different textures. The representational geometry in V2 afforded better discriminability between out-of-sample textures. We performed complementary analyses of standard convolutional network models, which did not replicate the representational geometry of cortex. We conclude that from V1 to V2 the visual representation changes to emphasize a low-dimensional, systematic encoding of different textures and of different instantiations of each texture.
Excessive aggression induced by social isolation (SI) has been closely linked to dysfunction in prefrontal circuits, particularly the anterior cingulate cortex (ACC). Topiramate, an antiepileptic drug known to enhance GABAergic and inhibit glutamatergic transmission, has demonstrated antiaggressive effects. In our previous work, we showed that topiramate's antiaggressive effects were associated with reduced neuronal death, improved neuronal morphology, and attenuated neuroinflammation in the ACC following SI. However, its impact on ACC neuronal activity remains poorly understood. In this study, we investigated the effects of topiramate on the spontaneous activity of ACC neurons in a mouse model of SI-induced aggression. Additionally, we explored whether direct restoration of ACC activity via high-frequency stimulation could similarly reduce excessive aggression. Systemic administration of topiramate (30 mg/kg, intraperitoneally) significantly increased attack latency, reduced attack frequency, and enhanced sociability. In vivo extracellular recording of spontaneous activity revealed a 50% reduction in ACC firing in isolated mice, which was partially restored (∼30%) by topiramate treatment. Moreover, high-frequency stimulation applied to the ACC markedly decreased aggressive behavior and robustly promoted social interaction. Together, these results provide convergent behavioral and electrophysiological evidence that SI-induced aggression is associated with ACC hypoactivity. The finding that both topiramate treatment and high-frequency stimulation of the ACC effectively reversed these deficits highlights the ACC as a key target for therapeutic interventions to treat aggression-related neuropsychiatric conditions. (PsycInfo Database Record (c) 2026 APA, all rights reserved).