In-vivo evidence for increased tau deposition in temporal lobe epilepsy
Temporal lobe epilepsy (TLE), the most common pharmaco-resistant epilepsy in adults, has been linked to structural brain changes extending beyond the mesiotemporal areas. While not traditionally viewed as a neurodegenerative disorder, recent ex-vivo studies have shown elevated levels of misfolded tau protein in TLE. This study investigated tau deposition in TLE patients using the in-vivo PET tracer [18F]MK-6240. 18 TLE patients and 20 healthy controls underwent PET imaging, with data analyzed to assess tau uptake and its relationship with brain connectivity, clinical variables, and cognitive function. Compared to controls, TLE patients exhibited markedly increased [18F]MK-6240 uptake in bilateral superior and medial temporal regions and the parietal cortex, with tau accumulation following regional functional and structural connectivity, disease duration, and cognitive impairment. These findings suggest that tau accumulation may contribute to the progression of TLE and cognitive decline, supporting a potential role of tau in epilepsy-related neurodegeneration.

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The relationship between task-related aperiodic EEG activity, neural inefficiency and verbal working memory in younger and older adults
Working memory (WM) decline in ageing may be related to increases in neural noise, potentially reflected in the EEG aperiodic exponent. We reanalysed previously published data to investigate age-related differences in the aperiodic exponent during verbal WM and its relationship with neural inefficiency. EEG was recorded from 24 younger (18-35 years) and 30 older adults (50-86 years) during a modified Sternberg task with 1-letter, 3-letter, and 5-letter load conditions. Younger adults consistently demonstrated steeper aperiodic slopes than older adults, though this difference was less pronounced in frontal regions during retention. Unexpectedly, both age groups showed decreased (i.e. flattened) aperiodic exponents during retention relative to fixation, with minimal load-dependent effects. Notably, the relationship between task-related exponent changes and WM performance was complex and dependent on the exponent at fixation, particularly in older adults. Finally, flatter exponents during fixation and late retention were associated with greater neural inefficiency during stimulus processing, reflected by increased P3b amplitudes without corresponding WM performance improvements. These findings suggest that flatter exponents are associated with less efficient neural processing and that older adults flexibly modulate their aperiodic exponent during retention to support WM performance.

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Dopaminergic processes predict temporal distortions in event memory
Our memories do not simply keep time - they warp it, bending the past to fit the structure of our experiences. For example, people tend to remember items as occurring farther apart in time if they spanned a change in context, or 'event boundary,' compared to the same context. While these distortions can sacrifice precise timing, they may serve to help separate temporally adjacent memories. However, the neural bases of this phenomenon are poorly understood. Here, we combined functional magnetic resonance imaging (fMRI; n = 32) with eye-tracking (n = 28) to test whether the dopaminergic system, known to influence encoding and time perception, predicts time dilation between adjacent events in memory. Participants encoded item sequences while listening to tones that mostly repeated over time, forming a stable auditory context, but occasionally switched, creating an event boundary. We found that boundaries predicted greater retrospective estimates of time between item pairs. Critically, tone switches significantly activated the ventral tegmental area (VTA), a key midbrain dopaminergic region, and these responses in turn predicted greater time dilation between item pairs spanning those switches. Boundaries furthermore predicted a momentary increase in blinks. VTA activation also predicted blinking in general, consistent with the idea that blink behavior is a potential marker of dopaminergic activity. On a larger timescale, higher blink rates predicted greater time dilation in memory, but only for boundary-spanning pairs. Together, these findings suggest that dopaminergic processes are sensitive to event structure and may drive temporal distortions that help disjoin memories of distinct events.

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Control of Blood Pressure Variability Across Behavioral States by Brainstem Adrenergic Neurons
Short-term blood pressure (BP) variability is increasingly recognized as an independent predictor of cardiovascular and cerebrovascular risk, yet the central mechanisms that govern this variability, particularly across behavioral states, remain poorly defined. In this study, we investigated the role of C1 adrenergic neurons in the rostral ventrolateral medulla (RVLMC1) in the short-term BP regulation during sleep-wake transitions and physical activity in freely behaving rats. Using genetically targeted fiber photometry, we show that RVLMC1 neurons exhibit state-dependent activity, with rapid activation during arousal from non-REM sleep, sustained activity in REM sleep, and further recruitment during physical activity. We further demonstrate that baroreflex input is essential for the dynamic response of RVLMC1 neurons to pharmacological manipulations of BP and transitions to REM sleep. Strikingly, selective ablation of RVLMC1 neurons did not affect mean BP but caused pronounced instability during arousal and movement, underscoring their role in buffering BP fluctuations. These findings demonstrate that RVLMC1 neurons integrate arousal-related central drive with baroreceptor feedback to stabilize BP during changes in behavioral state. These findings suggest that the disruption of RVLMC1 neurons could underlie increased BP variability observed in pathological conditions, such as multiple system atrophy, even when mean BP is preserved.

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PATZ1 Reinstates a Growth-Permissive Chromatin Landscape in Adult Corticospinal Neurons After Injury
As the CNS matures, chromatin at growth associated genes gradually becomes less accessible, but the timing of this shift, the mechanisms behind it, and whether it can be reversed in adults have remained unclear. To address this, we mapped chromatin accessibility in corticospinal neurons across postnatal development and found two distinct waves of restriction, an early, partial closure between P0 to P4, followed by a stronger, more widespread restriction from P7 into adulthood. We also asked whether the distance of injury influences chromatin remodeling and found that distal (thoracic) injuries triggered only modest changes, while proximal (intracortical) injuries led to much broader accessibility shifts, pointing to injury proximity as a key factor in epigenetic responsiveness. We then tested whether this restricted chromatin could be reopened by introducing PATZ1, a transcription factor normally expressed during early postnatal growth. AAV based delivery of PATZ1 after injury caused marked chromatin remodeling, including an 11.6 fold increase in H3K27ac at growth-relevant sites and large-scale reorganization of 3D genome structure, with compartment shifts toward active states and altered TAD boundaries. These changes were accompanied by reactivation of gene networks linked to developmental growth. Our results help define when and how chromatin becomes restrictive in CNS neurons and show that it can be reopened using targeted interventions like PATZ1 to support regeneration.

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Lipid nanoparticle-mediated CRISPR/Cas9 delivery enables efficient trabecular meshwork gene editing in mice
Lipid nanoparticles (LNPs) have emerged as a transformative platform for mRNA delivery, enabling vaccines and gene editing with transient expression and high cargo capacity. However, their potential for ocular gene editing remains underexplored. In this study, we assessed the transduction efficiency, inflammatory response, and gene editing capability of LNP-encapsulated mRNA in murine eyes. Intravitreal delivery of LNPs achieved targeted mRNA expression in the trabecular meshwork (TM) with superior specificity and efficiency compared to adenoviral or adeno-associated viral vectors, while inducing minimal microglial activation in the retina. Using LNPs co-encapsulating SpCas9 mRNA and sgRNA, we demonstrated efficient CRISPR-mediated knockout (KO) of Matrix Gla Protein (Mgp), a key inhibitor of TM calcification. Mgp-KO eyes exhibited sustained intraocular pressure (IOP) elevation and anterior chamber deepening with normal anterior chamber angle, recapitulating key features of primary open-angle glaucoma (POAG). Chronic IOP elevation led to reactive Muller gliosis and ganglion cell complex thinning, reflecting retinal stress and progressive neurodegeneration. Our findings establish LNP-CRISPR as a safe and efficient system for TM-targeted gene editing, with broad applicability in glaucoma pathogenesis modelling and therapeutic discovery.

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Mice discriminate odour source distance via sub-sniff temporal features of odour plumes
Rodents rely on olfaction to navigate complex environments, particularly where visual cues are limited. Yet how they estimate the distance to an odour source remains unclear. The spatiotemporal dynamics of natural odour plumes, shaped by airflow turbulence, offer valuable cues for locating odour sources. Here, we show that mice can discriminate odour sources placed at different distances by extracting information from the sub-sniff temporal structure of naturalistic odour plumes. Using a wind tunnel and an olfactory virtual reality system, we generated dynamic plumes and demonstrated, through high-throughput automated behaviour, that mice distinguish near from far sources based on odour fluctuations operating faster than their respiratory cycle. Two-photon calcium imaging of olfactory bulb projection neurons revealed that distance-dependent responses are present in a small subset of mitral and tufted cells, and that population activity encodes source distance. Critically, neural responses correlated more strongly with high-frequency plume features than with mean odour concentration. Our results identify a neural basis for distance estimation from odour dynamics and highlight the importance of rapid temporal processing in mammalian olfaction.

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Preventing light-induced toxicity in a new mouse model of rhodopsin sector retinitis pigmentosa
Retinitis Pigmentosa (RP) is an inherited retinal dystrophy characterized by the progressive loss of rod photoreceptors. Sector RP is a form of RP, where degeneration originates in the inferior retina, mainly influenced by light exposure. Over 200 RHO variants are pathogenic and associated with autosomal dominant RP. RHOM39R is one of the most common RHO variants linked to sector RP in the UK. A knock-in (KI) mouse model expressing RhoM39R was generated and characterized to investigate the mechanisms of degeneration associated with this variant and explore novel therapeutic strategies for rhodopsin sector RP. Under ambient light, RhoM39R/+ KI mice exhibited impaired retinal function by ERG, with some defects in OS ultrastructure, but retained normal outer nuclear layer (ONL) thickness. Repeated exposure to bright light led to photoreceptor loss. In contrast, RhoM39R/M39R KI mice in ambient light displayed severe retinal dysfunction, ONL thinning, and grossly abnormal OS ultra structure. In homozygous mice, a single bright light exposure significantly reduced ONL thickness within 48 h. The rescue of these models was achieved through reduced light exposure and pharmacological intervention. Rearing in dim red light (red cage condition) restored ERG responses in RhoM39R/+ KI mice and improved ONL thickness in RhoM39R/M39R KI mice. Transcriptomic analysis in RhoM39R/M39R KI mice revealed upregulation of Sphingosine 1-P Receptor (S1PR) transcripts. Treatment with the S1PR agonist Fingolimod (FTY720) before bright light exposure significantly reduced degeneration, demonstrating a protective effect in both heterozygous and homozygous models and suggesting potential a therapeutic approach for sector RP patients.

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Arithmetic learning is associated with developmental increases in similarity between brain activity and artificial neural networks
The ability to learn simple arithmetic is often thought to rely on the associative nature of human memory, where repeated exposure to arithmetic problems strengthens the relations between operands and outcomes. This view is reminiscent of learning in large language artificial neural networks (ANNs), where training involves statistical associations between symbolic inputs and outputs. Based on this parallel, we hypothesized that brain activity during arithmetic problem-solving should be increasingly similar to ANN-derived representations with learning and development. We used fMRI to investigate the relation between brain activity during single-digit addition problem-solving and ANN features in 104 participants across four age groups (8-, 11-, 14-year-olds, and adults). Vertex-wise encoding models were used to predict brain activity using latent features extracted from pre-trained ANNs. Results revealed that the ANN-based model better predicted arithmetic-related activity in older than younger participants in a specific region of the left precentral sulcus. Prediction accuracy was higher for smaller than larger problems, consistent with the idea that associations between problems may decrease in strength with problem size. Furthermore, ANN prediction patterns aligned with a model in which each addition problem was increasingly represented separately with age. On the one hand, these findings may support the idea that, with learning and development, some neural representations of arithmetic problems become discretely organized in memory and increasingly resemble ANN-like processing. On the other hand, the lack of relation between the ANN-based model and activity in other brain regions suggests some degree of dissimilarity between arithmetic processing in humans and ANNs, suggesting the existence of additional mechanisms for simple arithmetic learning in humans.

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Enhancing Biomedical Optical Volumetric Imaging via Self-Supervised Orthogonal Learning
Optical volumetric imaging grapples with inherent noise problems arising from photon budget constraints, light scattering, and space-bandwidth product bottlenecks, all of which degrade structural fidelity and become even more pronounced than in planar imaging. While deep learning presents potential for denoising, supervised methods are hindered by the impracticality of paired datasets, and existing self-supervised approaches fail to fully exploit the intrinsic volumetric structural redundancy inherent to optical imaging. Here, we present a self-supervised Volumetric biomedicAL Imaging Denoiser (VALID) that leverages intrinsic three-dimensional spatial coherence for highly efficient volumetric denoising through a self-supervised orthogonal learning framework. VALID demonstrates robust denoising performance across diverse imaging modalities, including two- and three-photon microscopy, light-field microscopy, and optical coherence tomography, substantially enhancing structural fidelity in deep-tissue, multimodal, and dynamic imaging scenarios. By combining computational efficiency with zero-shot adaptability, VALID establishes a transformative approach to volumetric image enhancement with structure-aware precision.

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The temporal and perceptual characteristics of emotion-induced blindness
Attentional capture by emotionally salient stimuli is adaptive, permitting identification of possible threats; however, an excessive bias towards emotional stimuli can interrupt goal-directed behavior. This is especially relevant in psychiatric disease, where severe emotional distress can interfere with daily function. As such, understanding the mechanisms by which emotional stimuli compete for attentional resources is a critical area of investigation. Previous studies using rapid serial visual presentation (RSVP) paradigms observe that emotional distractors disrupt the detection of subsequent stimuli, referred to as emotion-induced blindness (EIB). Our study expands upon this work, characterizing how temporal and perceptual factors shape the emergence and intensity of EIB. Contrary to previous assumptions regarding temporal dynamics of EIB, we found that effects of emotional distractors persisted across prolonged image presentation durations. Further, we investigated the extent to which the depth of distractor processing influences EIB using a distractor recall task. While recall was predictive of EIB magnitude, a significant effect of emotional distractors on target detection was nonetheless present even without conscious recall of the distractor. These findings demonstrate the robustness of the EIB effect in RSVP in the context of temporal and perceptual manipulations.

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Global motor system suppression as the primary mechanism of human action stopping: challenging the pause-then-cancel model
The ability to stop a planned or ongoing action is fundamental to inhibitory control. A recent theory proposes that stopping involves two distinct phases: an initial global suppression of motor activity ("pause") followed by a selective cancellation of the targeted action. However, the necessity of a second "cancel" stage remains debated. We tested whether global suppression alone is sufficient to stop movement by analysing electromyography from task-relevant agonist and antagonist muscles, alongside transcranial magnetic stimulation measures of global motor suppression from task-irrelevant muscles, during a stop-signal task in adult human participants of both sexes. In Experiment 1, reanalysis of ballistic finger movements revealed that agonist muscle offset consistently preceded behavioural stopping, aligning with the time course of global suppression. In Experiment 2, we extended these findings to whole-arm reaching movements, demonstrating that global motor suppression persisted beyond the termination of muscle activity when stopping prevented movement initiation, but disengaged in time for antagonist activation used to interrupt movements once they had begun. These findings challenge the pause-then-cancel model, instead supporting a single-stage global suppression framework. They also suggest that the global suppression mechanism is not a rigid, top-down stopping mechanism but rather part of a broader motor control system that flexibly adjusts movement commands based on task demands.

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Hypoxia and Cognitive Ability in Humans: A Systematic Review and Meta-Analysis
This systematic and meta-analytical review examined how a reduction in oxygen availability to tissue (hypoxia) affects cognitive function. Hypoxia had a moderate-to-large detrimental effect on general cognitive ability and across domains, including memory, attention, executive function, processing speed, and psychomotor speed. Increased hypoxic severity was associated with greater declines in general cognitive ability and executive function, while longer duration of exposure was associated with greater declines in executive function and psychomotor speed. Participant age was a moderator for executive function and psychomotor speed, with older adults experiencing greater impairments. For executive function and psychomotor speed, the magnitude of these effects was less pronounced during intermittent and hypobaric exposures, potentially due to adaptive physiological mechanisms. While our models accounted for exposure characteristics and age of participants, substantial unexplained variance remained. These findings highlight hypoxias impact on cognition and emphasize the need to investigate underlying neurophysiological mechanisms that may influence individual vulnerability.

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Volitional and forced running ability in mice lacking intact primary motor cortex
The coordination of various brain regions achieves both volitional and forced motor control, but the role of the primary motor cortex in proficient running motor control remains unclear. This study trained mice to run at high performance (>10,000 rotations per day or >2,700 rotations per hour) using a running wheel, and then assessed the effects of the removal of bilateral cortical areas including the primary motor cortex on volitional and forced running locomotion. The control sham-operated group revealed a quick recovery of volitional running, reaching half of the maximum daily rotation in 3.9 +/- 2.6 days (n = 10). In contrast, the cortical injury group took significantly a longer period (7.0 +/- 3.3 days, n = 15) to reach half of the maximum volitional daily rotation, but recovered to preoperative levels in about two weeks. Furthermore, even 3 days after surgery to remove cortical regions, the running time on a treadmill moving at 35.3 cm/sec, which is difficult for naive mice to run on, was not significantly different from that in the sham-operated group. These results suggest that the intact primary motor cortex is not necessarily required to execute trained fast-running locomotion, but rather contributes to the spontaneity of running in mice.

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Pervasive homeobox gene function in the male-specific nervous system of Caenorhabditis elegans
We explore here how neuronal cell type diversity is genetically delineated in the context of the large, but poorly studied male-specific nervous system of the nematode Caenorhabditis elegans. Mostly during postembryonic development, the C. elegans male adds 93 male-specific neurons, falling into 25 cardinal classes, to the predominantly embryonically generated, sex-shared nervous system, comprised of 294 neurons (116 cardinal classes). Using engineered reporter alleles, we investigate here the expression pattern of 40 phylogenetically conserved homeodomain proteins within the male-specific nervous system of C. elegans, demonstrating that in aggregate, the expression of these homeodomain proteins covers each individual male-specific neuron. We show that the male-specific nervous system can be subdivided along the anterior/posterior axis in HOX cluster expression domains. The extent of our expression analysis predicts that each individual neuron class is likely defined by unique combinations of homeodomain proteins. Using a collection of newly available molecular markers, we undertake a mutant analysis of five of these genes (unc-30, unc-42, lim-6, lin-11, ttx-1) and identified defects in cell fate specification and/or male copulatory defects in each of these mutant strains. Our analysis expands our understanding of the importance of homeobox genes in nervous system development and function.

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sKL/mKL Transcript Ratio and Protein Localization Define a Species- and Region-Specific Klotho Signature in the CNS and AD Progression
-Klotho is a multifunctional protein widely recognized for its anti-aging and neuroprotective properties. This study investigates the expression and localization of the secreted Klotho (s-KL) isoform in the human brain and its potential role in Alzheimer's disease. Using RT-qPCR, we observed that the s-KL transcript predominates over the membrane-bound KL (m-KL) in multiple brain regions, a pattern consistent in macaques and lemurs. Immunohistochemistry and immunoprecipitation assays confirmed the presence of the s-KL protein in human and mouse brain parenchyma, revealing species-specific cellular localization. In human cerebrospinal fluid (CSF), s-KL constitutes ~28% of total KL, with levels significantly reduced in mild dementia-AD patients. These findings underscore s-KL's potential neuroprotective role and highlight its differential regulation and expression during AD progression.

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Macrophage migration inhibitory factor is a potential therapeutic target for cisplatin induced peripheral neuropathy in breast cancer
Background: Cisplatin (CP) is an effective chemotherapy drug for several cancers. However, the use of CP is associated with peripheral neuropathy, a painful nerve disorder. Unfortunately, no therapies are available for CP-induced peripheral neuropathy (CisIPN). This study explored the role of a cytokine, the macrophage migration inhibitory factor (MIF), as a potential therapeutic target for CisIPN. Methods: The role of neuroinflammation and MIF in CisIPN was evaluated in mice models of CisIPN, with and without breast cancer, after treatment with the anti-inflammatory drug Dexamethasone (Dex). Circulating MIF levels in animals were examined using ELISA. Pharmacological inhibition of MIF was achieved using the small molecule inhibitors, CPSI-1306 and ISO-1. Mechanical and thermal sensitivities of animals were assessed using von frey filament and cold acetone assays. Macrophage infiltration in peripheral nerve tissues was examined using CD68 and Iba-1 staining. Results: Our results showed that Dex suppressed mechanical hyperalgesia in CisIPN animals, which was accompanied by downregulation of MIF. We also found that circulating MIF levels were increased in CisIPN animals. Furthermore, direct inhibition of MIF using CPSI-1306 and ISO-1 led to suppression of mechanical hyperalgesia, without compromising the anti-tumor efficacy of CP, in CisIPN animals. We did not find any significant change in macrophage infiltration in the peripheral nerve tissues of CisIPN animals. Immunostaining results indicated that sensory neurons in the DRGs and Schwann Cells in the sciatic nerves are potential sources for increased MIF in CisIPN. Interpretation: Overall, our results strongly suggest that MIF is a promising therapeutic target for CisIPN.

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Dibutyryl cyclic AMP downregulates tenascin-C in neurons and astrocytes and reduces AAV-mediated gene expression in DRG neurons
Functional recovery after spinal cord injury (SCI) is hindered by the limited ability of axons to regenerate in the adult mammalian central nervous system (CNS). Overcoming this barrier is critical for achieving effective recovery. Axonal regeneration depends on the activation of intracellular processes like transcription factor induction, protein and lipid trafficking, and cytoskeletal remodelling. Targeting these pathways offers a promising approach for promoting neuronal repair. This study examined the combined therapeutic effects of dibutyryl-cAMP (db-cAMP), which primes neurons for growth, and integrin 9 overexpression, which supports axonal extension. Using in vitro models with dorsal root ganglion (DRG) neurons and astrocytes, as well as an in vivo SCI model, we evaluated the potential of this approach. In vitro, the combination of db-cAMP and integrin 9 significantly enhanced neuronal growth. However, in vivo results were less consistent, with db-cAMP affecting AAV-mediated transcription and the expression of tenascin C (TnC) in neurons and astrocytes. These findings highlight the potential of modulating intracellular signalling and integrin activation but underscore the challenges posed by the complexity of the in vivo environment. Further studies are necessary to unravel these mechanisms and refine therapeutic strategies for effective SCI recovery.

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See-through science: Danionella cerebrum as a model for neuroregeneration
Rebuilding functional neuronal circuits after injury in the adult central nervous system (CNS) is unachievable for many vertebrates. In pro-regenerative models, it is unclear how regeneration and re-wiring is achieved in the CNS over long distances. The size and opacity of the adult vertebrate brain makes it difficult to study axon topography and dynamic cellular interactions during long-distance axon regeneration. Here, we harnessed the properties of the small and transparent adult Danionella cerebrum for longitudinal in vivo imaging of retinal ganglion cell axon regeneration, correlating cellular events with functional recovery. Our results suggest that some axons regenerate along tracts of degenerating myelin debris. However, the topography of re-innervation is different after regeneration, suggesting that new axon tracts are created to restore functional vision. The D. cerebrum model provides a unique opportunity to visualize and experimentally manipulate the spatial and temporal events during CNS regeneration in intact adult vertebrates.

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Inhibition of phosphodiesterase 4B as a novel therapeutic strategy for the treatment of refractory epilepsy
Despite the availability of nearly 40 approved anti-seizure medications (ASMs), at least one-third of individuals with epilepsy remain refractory to treatment, and many experience life-limiting cognitive or psychiatric side effects. Using a machine learning-guided platform, we identified PDE4 as an underexplored anti-seizure target, which became further validated based on its enriched expression in seizure-relevant brain regions and its potential to modulate excitatory/inhibitory neuronal tone via cAMP signaling. The pan-PDE4 inhibitor crisaborole partially protected against hyperthermia-induced seizures and reduced spontaneous seizures in Scn1a+/- mice, while rolipram and roflumilast showed no efficacy at tolerable doses. SN-2000, a first-in-kind allosteric modulator of PDE4B, was rationally designed for isoform selectivity and brain penetration, and demonstrated versatile reduction of seizure activity across multiple zebrafish and rodent genetic and acquired epilepsy models, with efficacy comparable to standard-of-care ASMs. SN-2000 also demonstrated favorable behavioral outcomes, reducing post-ictal aggression and anxiety-like behaviors, and improving cognitive performance in both wild-type and epileptic mice. These effects were linked to paradoxical regulation of excitatory and neuronal activity in the cortex and thalamus of epileptic mice, respectively, as well as elevated cAMP signaling and downstream pCREB activation. Together, these findings support PDE4B inhibition as a disease-relevant mechanism in epilepsy, and position SN-2000 as a promising therapeutic candidate offering seizure control without the neuropsychiatric burden of existing ASMs and potential pro-cognitive properties.

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