KCNK18 c.1107del frameshift in peripheral neuropathy links TRESK dysfunction to neuropathic pain
Neuropathic pain is commonly accompanied by hyperexcitability of nociceptive neurons, which is driven by regulation of several ion channels, including two-pore domain potassium channels (K2P) that stabilize the resting membrane potential. The TWIK-Related Spinal cord potassium channel (TRESK, K2p18.1) is predominantly expressed in sensory ganglia, where it provides major background K+ conductance. We describe a heterozygous c.1107del frameshift mutation in KCNK18, encoding TRESK, found in a patient with painful small fiber neuropathy and dysautonomia. This C-terminal c.1107del mutant is predicted to generate an elongated C-terminal domain, with an altered protein sequence. Whole-cell patch calmp recordings showed that the c.1107del variant reduced K+ current density, while heterozygous-like expression resulted in intermediate currents, consistent with a haploinsufficiency mechanism. Confocal imaging revealed decreased plasma membrane expression, indicating a trafficking-dependent loss of function while oligomerization with TRESK (homomeric channels) or TREK1 remained intact. In silico analysis revealed an altered phosphorylation pattern and reduced C-terminal hydrophobicity in the mutant TRESK. Overall, these findings support c.1107del as a pathogenic KCNK18 variant causing TRESK haploinsufficiency, offering mechanistic insight into the pathophysiology of neuropathic pain.

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Taking it slow: A positive feedback chloride current in cone photoreceptors supports slow motion detection
Photoreceptors gate and shape visual information. Since perception ultimately guides action, the way photoreceptors transform light into neural signals constrains an animal's behavioural repertoire. Yet, the physiological role of the highly conserved calcium-dependent chloride current in cone photoreceptors has remained elusive. Whereas calcium-activated currents typically provide negative feedback, we identify a counter-intuitive positive feedback mechanism that enhances detection of slow motion. Using genetics, electrophysiology, and behavioural assays in zebrafish, we show that loss of this current exaggerates the biphasic character of cone impulse responses and diminishes their voltage response amplitude to low temporal frequencies (<1 Hz). These changes in photoreceptor properties translate to behaviour, reducing the gain of the optokinetic response to slow-moving stimuli. Mechanistically, the calcium-dependent chloride current acts as a positive feedback loop that sustains the photovoltage response and counteracts strong adaptation within the cone phototransduction cascade.

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Disruption of Striatal Intrinsic Ignition in Huntington's Disease: an In-Silico Perturbational Approach to Emulate Disease Progression and Recovery
Huntington's disease (HD) is a neurodegenerative disorder caused by a single gene that severely affects motor, cognitive, and behavioral functions and is ultimately fatal. While disruptions in the structural integrity of the striatum are well documented, less is known about how the underlying functional impairments relate to the disease. We developed a large-scale modeling framework based on intrinsic ignition to uncover functional anomalies during HD progression. We first measured how much a spontaneous event in one brain region influences the rest of the brain, then systematically perturbed the activity of the striatum to predict the empirical changes in functional connectivity (FC) by re-optimizing the model parameters and conducting in-silico experiments. Results showed that disruption of the activity dynamics in the caudate, and to some extent the putamen, are the key factors that explain a substantial amount of the variance in FC alterations during HD progression. We then assessed the ability to recover whole-brain functional activity by driving the caudate and putamen activity towards a healthy-like regime and found that, by tuning the local bifurcation parameter of caudate and putamen, it is possible to recover whole-brain healthy functional activity, albeit moderately. Surprisingly, although the functional disruptions in the caudate better explained the alterations in FC, the recovery of the dynamics was more effective in the putamen. Overall, our results suggest that the disruptions of the dynamics in the striatum can explain the gross functional connectivity changes in HD. Our study demonstrates that computational modeling is an important tool to reveal the underlying patterns behind the observed data and provides an opportunity to test interventional mechanisms in silico.

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Gene Therapy for Efficient Suppression of T-Type Channels in Treating Diabetic Neuropathy
Painful diabetic neuropathy (PDN), a chronic and often incurable syndrome, is one of the most common and unpleasant complications of diabetes. Effective clinical interventions for PDN are very limited and already developed approaches are characterized by lack of molecular or cellular target specificity and a short duration of therapeutic effects. Numerous investigations causally link upregulation of the Cav3.2 T-type Ca2+ channels in peripheral nociceptive neurons to painful symptoms of PDN. Here we suggest an approach to alleviate these symptoms based on implementation of virus-mediated cell-specific delivery of vectors expressing small hairpin RNAs (shRNAs). Processed by Dicer into specific small interfering RNA (siRNA), they would suppress the expression of T-type Ca2+ channels. In order to experimentally validate this approach, we have initially confirmed the ability of designed Dicer-substrate small interfering RNAs (DsiRNAs) to suppress expression of T-type channels in neurons of primary hippocampal and dorsal root ganglia (DRG) cultures. Target sequences of the effectively interfering DsiRNA were then used to design shRNAs and the coding sequences of shRNAs were cloned into the vector pAAV under U6 promotor. This plasmid was also proved to be effective in interference with expression of the T-type channels in the rat cultured DRG neurons. The expression cassette of this plasmid will be packed into AAV6 particles with tropism to unmyelinated fibers to suppress T-type channel expression in nociceptive DRG neurons and to alleviate painful symptoms of PDN.

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Attentional focus and emotion modulate voice recognition deficits in cerebellar stroke patients
The cerebellum, long regarded as a motor structure, is increasingly recognized for its role in higher-order cognitive and socio-emotional functions. Its contribution to vocal emotion decoding, however, remains insufficiently understood. While prior work has linked the cerebellum to attentional control and predictive coding, direct evidence for its role in modulating prosody recognition under explicit versus implicit attentional demands is lacking. This study investigated how cerebellar stroke, controlled for time since stroke in months, and with an equal number of left- and right-lateralized lesions, alters vocal emotion processing depending on attentional focus. We aimed to disentangle sensory encoding and integration from decisional contributions of the cerebellum by combining behavioral analyses, drift diffusion modeling (DDM), and functional MRI in cerebellar stroke. Fifteen patients with chronic, isolated cerebellar stroke and fifteen matched controls performed two tasks on vocal stimuli expressing anger, happiness, or neutrality. In the explicit task, participants categorized the expressed emotion; in the implicit task, they categorized speaker gender while ignoring emotional tone. Behavioral performance was analyzed using mixed-effects logistic regression and DDM (angle model). Functional MRI analyses included conventional contrasts as well as model-based regressors derived from behavioral and computational parameters. Patients showed lower accuracy than controls, with deficits particularly pronounced in the explicit task. Performance also varied by emotion: gender recognition for angry voices (implicit processing) was relatively preserved, whereas happy and neutral voices were more vulnerable. Contrary to predictions, DDM parameters did not differ between groups. Instead, task effects dominated: implicit processing yielded higher drift rates, larger boundary separation, faster non-decision times, and stronger attentional focus compared to explicit recognition, suggesting that explicit evaluation imposes additional cognitive costs. At the neural level, patients recruited extended networks during explicit processing, including orbitofrontal cortex, amygdala, anterior insula, and cerebellar lobule IX, alongside cerebello-cortical tracts. Implicit processing was associated with more restricted activations, particularly in frontal opercular and cerebellar regions (lobule IX). Model-based analyses further revealed that successful categorization in patients relied on the left inferior frontal gyrus, inferior parietal lobule, and pre-supplementary motor area, although these effects were not significant when controlling for time since stroke. Our findings demonstrate that the cerebellum does not primarily shape decision dynamics but optimizes sensory representations of prosodic cues for downstream evaluation. When predictive tuning is compromised, patients maintain intact decision processes yet rely on compensatory cortical recruitment, particularly during explicit tasks. This pattern supports predictive coding accounts of cerebellar function in socio-emotional communication and highlights the need to consider subtle socio-affective deficits in cerebellar patients.

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Effective connectivity reveals a shift to left-hemisphere dominance for spatial attention with diminishing arousal
In healthy righthanders, spatial attention typically becomes biased to the right side when alertness wanes. The underlying neural mechanisms of healthy spatial attention and these drowsiness-related spatial biases remain contested. Competing theories propose that attention is governed either by the interaction of two bilateral networks (dual-network model) or by a dominant right hemisphere (right hemisphere dominance model). To adjudicate between these models, we investigated how effective connectivity within the auditory cortical hierarchy is modulated by drowsiness. We recorded high-density Electroencephalography (EEG) in 32 healthy participants performing a lateralised auditory localisation task in both awake and drowsy states. Time-resolved multivariate pattern analysis revealed that arousal states become decodable approximately 150 ms post-stimulus. We used Parametric Empirical Bayes and Dynamic Causal Modelling to map arousal-dependent changes in effective connectivity between left-sided and right-sided auditory stimuli. Consistent with the right hemisphere dominance model of spatial attention, right-sided stimuli elicited stronger bidirectional information flow between bilateral inferior frontal gyri during wakefulness. However, we observed a significant reduction in right-hemispheric frontoparietal connectivity alongside a strengthening of a left-hemispheric pathway from the inferior parietal cortex to the inferior frontal gyrus during drowsiness. This finding supports the dual-network theory and conflicts with the right hemisphere theory's prediction of a bilateral decrease in activity during drowsiness. Overall, our findings provide a mechanistic account of how diminishing arousal shifts cortical processing from a bilaterally integrated network to a left-lateralised state. Our results therefore support the dual-network model of spatial attention while retaining elements of the right hemisphere model.

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ALS/FTD-associated TDP-43 mutations promote fragility of genes governing excitatory neurotransmission via topoisomerase IIβ impairment
Abnormal TAR DNA/RNA-binding protein 43 (TDP-43) is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), characterized by cytoplasmic mislocalization, aggregation, and pathogenic mutations. Altered excitatory neuronal transmission is an early functional defect in these diseases; however, the underlying mechanisms remain unclear. Neuronal activity can induce DNA double-strand breaks (DSBs), suggesting a potential link between altered excitability and genomic instability. Here, we demonstrate for the first time that TDP-43 is involved in neuronal activity-induced DSBs. Moreover, we show that ALS/FTD-associated TDP-43 mutations (A90V and A315T) disrupt this mechanism, leading to the accumulation of DSBs and altered neuronal activity compared to wild-type TDP-43 protein. Using the BLISS technique, we mapped genome-wide DSBs in primary mouse neurons expressing wild-type or mutant (A90V, A315T) TDP-43 and found enrichment of DSBs within genes regulating excitatory transmission. Mechanistically, the TDP-43 A90V mutation impairs topoisomerase II{beta} function, resulting in enzyme trapping and/or DNA supercoiling that predisposes DNA to breaks. Notably, this impairment is partially rescued by tyrosyl-DNA phosphodiesterase 2 (Tdp2) overexpression. These findings uncover a novel mechanism linking aberrant neuronal activity and DNA damage, bridging two key pathological hallmarks of ALS/FTD associated with TDP-43 dysfunction. It also paves the way for developing novel therapeutic approaches that rely on targeted DSB repair and/or modulating topoisomerase II{beta}-DNA complexes.

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Normative modeling of brain morphology reveals neuroanatomical heterogeneity and biological subtypes in major depressive disorder
BACKGROUND: Major Depressive Disorder (MDD) is characterized by high neurobiological heterogeneity, which hinders precise diagnosis and treatment. Traditional group-level neuroimaging analyses fail to capture individual differences, while normative modeling offer a promising approach to quantify individual deviations from healthy brain structure patterns, facilitating the identification of biological subtypes and offering a data-driven framework to dissect this heterogeneity. METHODS: Using 1,190 healthy controls (age 22-37), we constructed normative developmental trajectories of gray matter volume (GMV) across 246 Brainnetomedefined regions using Bayesian linear regression. Deviation maps were derived for 398 MDD patients. k-means clustering was employed to identify GMV-based biotypes. Then, the clinical characteristics and anatomical differences among these subtypes were explored, along with the post-treatment clinical features and treatment responses of participants who completed the 8-week antidepressant treatment within each subtype. RESULTS: Patients with MDD exhibited widespread yet individually variable GMV deviations. Clustering analysis revealed two subtypes: Subtype 1 displayed predominantly negative deviations in sensorimotor and occipital cortices, whereas Subtype 2 showed widespread positive deviations in temporal and posterior cingulate regions. Subtype 1 had higher extraversion and symptom-linked deviation patterns; in Subtype 2, deviation burden correlated with generalized anxiety. Longitudinally, Subtype 1's GMV deviation changes predicted symptom improvement, while Subtype 2's deviations correlated with baseline severity. CONCLUSIONS: Normative modeling of GMV reveals marked neuroanatomical heterogeneity in MDD and identifies subtypes with distinct clinical and treatment-related characteristics, laying a foundation for precision psychiatry and individualized interventions.

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A compact glutamic acid decarboxylase 67 promoter enables inhibitory neuron-targeted AAV gene therapy for treatment-resistant epilepsy
Epilepsy often becomes treatment-resistant, partly due to impaired inhibitory neurotransmission and reduced gamma-aminobutyric acid (GABA) function. Enhancing inhibitory neuron activity via gene therapy may restore excitation-inhibition (E/I) balance. We developed a compact 410-bp glutamic acid decarboxylase 67 promoter (cmGAD67) that enables strong, selective transgene expression in inhibitory neurons while preserving AAV packaging capacity. When delivered systemically, AAV vectors carrying cmGAD67 preferentially targeted parvalbumin interneurons and supported effective circuit manipulation. To evaluate therapeutic potential, we expressed glutamic acid decarboxylase 65 (GAD65) under cmGAD67 (AAV-GAD65) in pentylenetetrazole (PTZ) epilepsy models. Systemic AAV-GAD65 suppressed abnormal delta oscillations, reduced seizure-like events, normalized anxiety-like behavior, and improved survival in a severe PTZ paradigm. Biochemical analyses confirmed increased cortical and hippocampal GABA levels, linking behavioral and electrophysiological improvements to enhanced inhibitory neurotransmitter synthesis. Prior clinical evidence indicates that AAV-GAD65 delivery to the subthalamic nucleus is safe and effective in Parkinson's disease. Building on this foundation, our findings establish the cmGAD67 promoter as a powerful platform for inhibitory neuron-targeted AAV gene therapy and highlight AAV-cmGAD67-GAD65 as a promising approach for treatment-resistant epilepsy and other disorders involving disrupted E/I balance.

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Traumatic Conditioning Induces a Combination of Anesthesia Resistant Memory and Protein Synthesis Dependent Long-Term Memory in Adult Drosophila
Stressful experiences elicit long-lasting memory trace that often persists for life-time. Though storage of experience dependent memory is key to survival, post-traumatic memories are detrimental to the physical and emotional wellbeing. The generation of any form of long-term memory culminates from synaptic plasticity and potentiation through persistent change in protein synthesis. Drosophila has been a robust model for the study of memory mechanisms; olfactory memory paradigms have been enormously successful in elucidating neuroanatomical, molecular, physiological and signalling pathways underlying the process. Long-term memory (LTM) has been induced by protein synthesis dependent mechanisms followed by a post-learning consolidation process whereas a medium-term anaesthesia resistant memory (ARM) is mediated by the Radish protein in flies. Here we present a novel and simple memory paradigm in adult flies for inducing sustained stress-induced memory paradigm, where a single attractive odorant is associated with an aversive stimulus- copper sulfate, which provides bitter taste as well as sustained malaise due to toxicity. We find that the elicited memory is a combination of ARM and LTM which is dependent on the number of training cycles. The eight-cycle training paradigm leads to robust, CREB and protein synthesis dependent memory persisting for about 7 days. The mushroom body (MB) Kenyon cells neurons as well as the dopaminergic input neurons (PPL1 subset) are involved in the formation of memory mediated by enhanced calcium as well as synaptic elaboration in the {gamma} subset of the MB neurons.

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Morphometric Latent Factors in Autism and Their Association with Receptor Profiles and Behavior
The profound heterogeneity of Autism Spectrum Disorder (ASD) is a major barrier to developing targeted therapies. While dimensional subtyping using functional connectivity (FC) has advanced the field, the intrinsic instability of FC limits its power to identify stable trait-like biomarkers. This study provides a direct comparison of latent factors derived from both FC and a stable morphometric measure, Morphometric Inverse Divergence (MIND), within the same ASD cohort. We hypothesized that stable structural factors would provide a more behaviorally relevant and biologically grounded account of ASD heterogeneity. Our findings reveal an important dissociation between functional and morphometric features. Latent factors derived from morphometric similarity (MIND) significantly correlated with core ASD behavioral traits (SCQ, SRS), while functional factors showed no association. This dissociation was also found at the neural level. Specifically, we observed weaker structure-function correspondence in the ASD group compared to the healthy control group (HC). Moreover, the stable structural factors were linked to trait-like neurodevelopmental mechanisms: the association with the CB1 receptor (important for synaptic pruning) observed in the HC was notably missing in the ASD group. Conversely, the functional factors were associated with a state-like arousal system (the norepinephrine transporter, NET). Collectively, our results demonstrate that stable morphometric-based factors, rather than time-varying functional ones, are predictive of behavioral traits in ASD. This work validates MIND as a robust approach and suggests that the link between structural organization and its neurodevelopmental (CB1) underpinnings is a more powerful and stable target for developing biomarkers in autism.

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Diminished spatial dynamics and maladaptive spatial complexity link resting brain network disruption to cognition in schizophrenia
Resting-state fMRI studies increasingly emphasize the dynamic nature of brain networks. While most approaches examine temporal fluctuations in connectivity, we focus on the spatial dynamics and complexity at voxel level - how networks expand and contract, and change their structural complexity over time. Using dynamic independent component analysis (ICA), we investigate the hierarchical structure of the resulting time-varying spatial networks, from their broad periphery to their most active core. We combine this with fractal dimension (FrD) as a measure of a network's spatial complexity and analyze temporal changes (dynamic flexibility) in a network and synchronized fluctuations between network pairs (fractal dimension coupling, FrDC). We refer to this approach as 'dynamic spatial network complexity and connectivity (dSNCC)'. Using a combined cohort of 508 subjects (315 healthy controls, 193 schizophrenia patients), we found that schizophrenia is associated with higher mean FrD in several networks, suggesting more irregular patterns/boundaries and a disorganized network structure. Critically, patients showed significantly reduced dynamic flexibility, indicating their networks are 'stuck' in a less adaptable state. This robust finding is evidenced by a synergistic loss of temporal standard deviations in both network volume and FrD across multiple networks and activity thresholds. This maladaptive complexity was associated with cognitive impairment, with several dSNCC measures showing significant associations with subject scores for processing speed, visual learning, and verbal learning. Higher complexity in these networks and more significantly, their reduced dynamic flexibility as seen in patients, were particularly associated with impaired performance. Furthermore, we found aberrant connectivity (FrDC) in schizophrenia, with certain network pairs exhibiting overly synchronized complexity changes. Our results demonstrate that dSNCC is a powerful tool for characterizing network dynamics and may potentially provide a measurable mechanism for maladaptation in schizophrenia, where the brain's inability to fluidly change its complexity may contribute to cognitive deficits and symptoms like disorganized thought. These findings highlight the importance of studying the intrinsic spatial dynamic properties to reveal the fundamental principles of brain network organization in health and disease. Our work represents a significant leap in complex systems neuroscience and provides a novel, quantifiable biomarker framework highly relevant for understanding and targeting other complex disorders characterized by network dysfunction, such as Alzheimer's disease, autism, or other mental health conditions.

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Gait transition mechanism from quadrupedal to bipedal locomotion in the Japanese macaque based on inverted pendulum
The ability of non-human primates to transition from quadrupedal to bipedal locomotion offers critical insights into both the evolution of human bipedalism and the principles of complex motor control. While quadrupedal and bipedal gaits in non-human primates have been studied, the dynamic mechanisms underlying the transition between these gaits remain poorly understood. Japanese macaques trained to walk bipedally have been reported to utilize inverted pendulum dynamics to achieve efficient bipedal locomotion. Given the intrinsic instability of inverted pendulum systems, which can induce large changes in movement with minimal control input, we hypothesized that this mechanism also contributes to the gait transition. To test this, we developed a neuromusculoskeletal model of the Japanese macaque that integrates a detailed musculoskeletal structure with a physiologically inspired motor control system. Through forward dynamics simulations, we generated a variety of movement patterns by systematically parameterizing motor commands, including failed transitions that are difficult to capture experimentally. We then applied dynamical systems analysis using on an inverted pendulum model to examine the underlying principles of the transition process. Our results demonstrate that successful gait transitions depend on generating an inverted pendulum motion through appropriate control of the forward step length of one hindlimb. These findings provide mechanistic insights into how Japanese macaques coordinate their complex musculoskeletal systems to perform skilled, full-body movements in the gait transition, offering a deeper understanding of both advanced motor control and the evolution of human bipedalism.

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Semantic reasoning takes place largely outside the language network
The brain's language network is often implicated in the representation and manipulation of abstract semantic knowledge. However, this view is inconsistent with a large body of evidence suggesting that language processing is neurally distinct from the rest of cognition. Here, we use precision brain imaging to uncover a set of brain regions, separate from the language network, that are engaged in semantic processing of both linguistic and pictorial stimuli. In three fMRI experiments, participants (total n=41 tested across 49 sessions) viewed sentences and pictures depicting simple events. In separate blocks, they performed either a semantic task or a difficulty-matched perceptual task. Across all three experiments, several areas in left lateral prefrontal cortex, left temporo-parietal cortex, and right cerebellum responded to semantic tasks for both sentences and pictures. These semantic processing areas are spatially and functionally distinct from the nearby language-selective areas, as well as from the multiple demand and default mode networks, exhibiting a unique response profile. Our results provide evidence for a new kind of selectivity in the human brain and pave the way for future explorations of the neural mechanisms that underlie semantic reasoning.

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Equiluminant Border Ownership Cells as a Missing Link in Color Form Perception
We propose the existence of a sub-population of border ownership neurons that signal figure side along equiluminant borders, those defined purely by color contrast. We postulate that these neurons, similar to primate equiluminant V1 [26] and V4 [5] cells, are strongly activated by equiluminant contrast on their preferred side, with diminished response for strictly luminance contrast. To test this hypothesis, we propose a hierarchical and mechanistic model that explains how equiluminant border ownership signals can be achieved in the ventral stream. Our simulation results suggest that model equiluminant neurons are highly color-selective while exhibiting similar orientation and border ownership selectivity as their luminance counterparts. Additionally, our model equiluminant cells indeed exhibited the above postulated pattern of responses. We suggest that these neurons are the missing links in the equiluminance channels in the ventral stream that transform equiluminant oriented edge signals in V1 to equiluminant object-centered shape representations in V4. Our findings point to the importance of re-examining the border ownership neuron population to further detail their role in equiluminant channels in the ventral stream.

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The protein interactome of the Neuron Specific Gene family (NSG1-3)
The Neuron-Specific Gene (NSG) family members (NSG1-3) play critical and diverse roles in neuronal protein trafficking, but their precise molecular functions remain poorly understood. Here, we employed proximity-labeling proteomics to map the interactomes of each NSG protein. Unlabeled mass spectrometry identified over 1,000 significantly enriched interactors compared with a cytoplasmic control, revealing substantial overlap between NSG1 and NSG2, and a more divergent profile for NSG3. Gene ontology and KEGG pathway analysis confirmed established associations with glutamatergic synapses and endosomal trafficking, while also uncovering unexpected links to presynaptic machinery, inhibitory synapses, and endoplasmic reticulum-associated protein translation, particularly for NSG3. Reciprocal biotinylation patterns and co-immunoprecipitation revealed novel heteromeric complex formation between NSG1 and NSG2, with limited interactions involving NSG3. All three NSGs biotinylated core AMPA receptor subunits and auxiliary proteins, while NSG1 and NSG2 also associated with NMDA receptors, GABA receptor subunits, as well as multiple presynaptic proteins. Moreover, NSG1 and NSG2 specifically biotinylated components of multiunit tethering complexes including neuron-specific retromer, and biotinylated a preponderance of ADAM10 substrates, reinforcing their role in proteolytic processing. Finally, despite the relatively divergent interactomes of NSG1 and NSG2 compared to NSG3, all family members robustly biotinylated amyloid precursor protein (APP), suggesting possible synergistic or competitive interactions that could shape APP proteolytic processing and/or trafficking. Together, these data provide a comprehensive systems-level view of NSG protein interactions, establishing a molecular framework for future investigations into NSG-mediated neural plasticity and disease mechanisms.

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NMDA receptor ablation in medial prefrontal cortex disrupts value updating and reward history integration
Schizophrenia, a serious mental illness, is associated with evidence of NMDA receptor (NMDAR) dysfunction and characterized by cognitive impairments that reflect impaired value updating and feedback-driven control; however the cellular and circuit-level mechanisms underlying these disruptions remain unclear. Here we test how NMDA receptor (NMDAR) signaling in the medial prefrontal cortex (mPFC) contributes to adaptive decision-making by combining targeted genetic ablation in mice and systemic pharmacology. Using a CRISPR-Cas9 approach to eliminate the obligate GluN1 subunit, we induced spatially confined NMDAR hypofunction in mPFC and compared its effects to systemic pharmacological blockade with the NMDAR antagonist MK-801 during performance of a touchscreen-based restless bandit task. Prefrontal NMDAR ablation impaired value discrimination, weakened the use of negative feedback, and reduced mutual information between recent outcomes and current choices, indicating disrupted reward-history integration. Reinforcement-learning models incorporating a choice-kernel term best captured behavior and revealed that NMDAR ablation selectively dampened learning and choice-history parameters governing flexible updating. Systemic MK-801 produced broad impairments in control animals, reducing accuracy, mutual information, and outcome sensitivity, yet exerted only modest additional effects after NMDAR ablation, suggesting that prefrontal NMDAR loss occluded much of the pharmacological disruption. Simulations using fitted RLCK parameters reproduced these patterns, showing convergent flattening of choice dynamics under MK-801 and persistent deficits in GluN1 ablated animals. Together, these findings demonstrate that prefrontal NMDAR signaling is necessary for effective value updating and feedback-driven learning, and that its loss recapitulates core features of systemic NMDAR hypofunction. This work establishes a mechanistic bridge between localized cortical glutamatergic dysfunction and the reinforcement-learning disturbances characteristic of schizophrenia.

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Windows to the goal: Pupillary working memory signatures prospectively adapt to task demands
The pupillary light response was once considered a brainstem reflex, but newer findings indicate that pupil dilation can also reflect content held 'in mind' with working memory (WM). This suggests that WM may recruit even the earliest sensorimotor apparatus for maintenance. Here, we tested two boundaries of this pupillary WM response: whether it generalizes beyond low-level stimuli and whether it adapts to changing behavioral goals. Namely, we tested whether the pupils reflect remembered brightness for realworld scene images, and whether the effect varies when different features dimensions are emphasized for the memory test (i.e., visual detail vs. semantic category). We found a feature-specific pupillary WM effect for remembering natural scenes, but only when the task encouraged a visual maintenance strategy. Rather than a retrospective echo of sensory-evoked stimulus features, the pupillary WM response prospectively adapts to how the memory content will be used.

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Age-specific Aβ-Tau interactions underlie spatial memory deficits in an APP/PS1 amyloidosis model
Background: Amyloid-beta (Ab) and tau pathology are key molecular hallmarks of Alzheimer's disease (AD), yet how their interaction contributes to cognitive decline remains unclear. We investigated the relationship between Ab burden, tau pathology, presynaptic density, and spatial learning and memory in the APPswe/PSEN1dE9 (APP/PS1) transgenic (TG) mouse model of amyloidosis. Methods: Spatial learning and memory were assessed with the Barnes maze test in male TG and wild-type (WT) littermate mice, aged 6, 12, and 18 months. Gross visual function was assessed indirectly in 18-month-old animals using the light/dark exploration test. Brains were collected for autoradiography of tau pathology and presynaptic density with [18F]Flortaucipir and [3H]UCB-J, respectively, while Ab plaque load was measured by immunohistochemistry. Correlation and linear mixed-effects regression analyses were used to assess relationships between behavioral and pathological measures. Results: APP/PS1 mice showed normal cognitive performance at 6 months, a selective long-term memory deficit at 12 months, and severe impairments in learning and retention at 18 months, independent of visual confounds. Age-dependent increases in [18F]Flortaucipir binding and Ab plaque load were observed in all brain regions of TG compared to WT mice, whereas [3H]UCB-J binding was increased in a region-dependent manner in 18-month-old TG vs. WT animals. Barnes maze performance during the final day of testing correlated negatively with both Ab and tau pathology across all areas examined. Linear regression revealed a significant association between tau and age and between tau and Ab in the cortex, indicating that memory decline in ageing TG mice was driven by the combined effects of these pathologies. Conclusions: Deficits in memory retention precede impairments in task learning performance in APP/PS1 mice. Spontaneous tau accumulation contributes to the progressive cognitive decline, capturing key aspects of the Ab-tau interaction observed in human AD.

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Restoring Amyloid Clearance via Astrocytes: Z17 Is a Selective Inhibitor of CHI3L1 in Alzheimers Disease
Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, accumulation of hallmark protein aggregates and substantial neuroinflammation. Chitinase-3-like protein 1 (CHI3L1) which is predominantly produced by activated astrocytes in the central nervous system (CNS). Overexpression of CHI3L1 has been implicated with AD progression and worsening of symptoms. Herein, we report the identification of Z17 as a novel and selective CHI3L1 inhibitor which directly bind to CHI3L1 an equilibrium dissociation constant (KD) of 6.0 M. In human iPSC-derived astrocytes, Z17 acted as a dual-action regulator by reinstating astrocytic function and suppressing inflammation. Additionally, Z17 rescued CHI3L1-induced impairment by dose-dependently restoring A{beta} uptake and normalizing lysosomal proteolytic activity and pH. Furthermore, Z17 effectively blocked CHI3L1-driven activation of the NF-{kappa}B pathway in human astrocytes, providing a mechanistic explanation for the functional rescue. The in vitro pharmacokinetic (PK) profiling of Z17 demonstrated favorable drug-like properties for CNS development. These findings support the advancement of Z17 as a selective CHI3L1 inhibitor capable of simultaneously mitigating neuroinflammation and restoring astrocytic clearance mechanisms, making it a highly promising therapeutic candidate for Alzheimers disease.

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