Developmental sleep reallocation enables metabolic adaptation in desert flies
Sleep is essential for adaptation and survival across the lifespan, yet the ecological pressures shaping sleep ontogeny remain poorly understood. We investigated sleep across early developmental stages in Drosophila mojavensis, a stress-resilient desert-adapted species. While adult D.mojavensis exhibit prolonged and consolidated sleep, along with enhanced starvation tolerance and survival compared to Drosophila melanogaster, the developmental trajectory underlying these adaptation strategies for surviving in harsh environments is unknown. Moreover, during developmental (larval) periods, animals do not encounter the same environmental stressors experienced by adults (e.g., food scarcity, extreme temperatures). We find that in contrast to adults, D.mojavensis larvae exhibit reduced and fragmented sleep relative to D.melanogaster. D.mojavensis larval sleep is also deeper, reflecting a shift toward increased sleep efficiency rather than simple sleep loss. D.mojavensis larvae consume more food than D.melanogaster and survive longer under starvation, suggesting a strategic tradeoff by suppressing sleep to prioritize nutrient intake and energy storage early in life while resources are more abundant. Metabolic analyses reveal elevated triglyceride accumulation in D.mojavensis across their lifespan, indicating enhanced energy storage capacity. These findings provide an example of how, within a fixed genetic background, an animal can reallocate sleep in opposing manners to maximize survival and energetics depending upon ecological pressures unique to each phase of life.

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Spatial and semantic memory reorganize a hippocampal long-axis gradient
The hippocampus supports episodic memory by binding spatial and semantic information, yet how this information is simultaneously organized along its long axis remains debated. Gradient accounts propose a continuous shift in representational scale, from coarse coding in anterior to fine coding in posterior regions, whereas modular accounts posit discrete subregions specialized for distinct functions. Using high-resolution fMRI together with eye tracking as a readout of spatial and semantic memory during sequence learning, we directly tested these competing models. During predictable sequences, hippocampal activity continuously varied along the long axis. In contrast, modular organization emerged when sequences mismatched memory. Subregions in the anterior and posterior hippocampus were sensitive to semantic and spatial mismatches, respectively. Notably, the intermediate hippocampus was specifically sensitive to concurrent mismatches in both dimensions, but not to mismatches in either dimension alone. These content-sensitive subregions were embedded within distinct cortical networks that reorganized according to memory demands. Together, our findings show the hippocampus flexibly combines gradient and modular dynamics to simultaneously represent the spatial and semantic content that defines episodic memory.

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Using Information Geometry to Characterize Higher-Order Interactions in EEG
In neuroscience, methods from information geometry (IG) have been successfully applied in the modelling of binary vectors from spike train data, using the orthogonal decomposition of the Kullback-Leibler divergence and mutual information to isolate different orders of interaction between neurons. While spike train data is well-approximated with a binary model, here we apply these IG methods to data from electroencephalography (EEG), a continuous signal requiring appropriate discretization strategies. We developed and compared three different binarization methods and used them to identify third-order interactions in an experiment involving imagined motor movements. The statistical significance of these interactions was assessed using phase-randomized surrogate data that eliminated higher-order dependencies while preserving the spectral characteristics of the original signals. We validated our approach by implementing known second- and third-order dependencies in a forward model and quantified information attenuation at different steps of the analysis. This revealed that the greatest loss in information occurred when going from the idealized binary case to enforcing these dependencies using oscillatory signals. When applied to the real EEG dataset, our analysis detected statistically significant third-order interactions during the task condition despite the relatively sparse data (45 trials per condition). This work demonstrates that IG methods can successfully extract genuine higher-order dependencies from continuous neural recordings when paired with appropriate binarization schemes.

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Knockdown of endothelial Serpine1 improves stroke recovery by attenuating peri-infarct blood flow and blood brain barrier disruption
Focal stroke leads to complex changes in the cerebral microcirculation in surviving brain tissues that strongly influence recovery. Plasminogen activator inhibitor-1 (PAI-1; encoded by Serpine1) is highly upregulated in endothelial cells after stroke. Since the primary function of PAI-1 is to inhibit fibrin clot breakdown, we hypothesized that blocking this pathway would be beneficial for recovery since it is expected to increase capillary blood flow after stroke. Using longitudinal in vivo imaging in mice subjected to ischemic stroke, we unexpectedly found that knockdown of Serpine1 in brain endothelial cells leads to a long-lasting reduction in peri-infarct capillary width, red blood cell velocity and flux. Conversely, stimulating this pathway in naive mice increased capillary width and blood flow. Lowered peri-infarct blood flow in Serpine1 knockdown mice attenuated deleterious blood brain barrier disruption and pro-inflammatory gene expression. Serpine1 knockdown improved the progressive recovery of sensory evoked cortical responses, as well as cognitive and sensorimotor function. These findings challenge the assumption that increased blood flow after stroke is better for recovery and reveal that carefully tuning flow, rather than maximizing it, may be optimal. Further our data highlight the therapeutic potential of targeting endothelial Serpine1/PAI-1 signalling in promoting stroke recovery.

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Representational Competition of Spatially and Temporally Overlapped Target and Distractor
Representational competition occurs when a task-relevant target stimulus and a distractor overlap in space and time. Given limited neural resources, it is expected that stronger representations of the distractor will result in weaker representations of the target, leading to poorer behavioral performance. We tested this hypothesis by recording fMRI while participants (n = 27) viewed a compound stimulus consisting of randomly moving dots (the target) superimposed on IAPS affective pictures (the distractor). Each trial lasted ~12 seconds, during which the moving dots and the IAPS pictures were flickered at 4.29 Hz and 6 Hz, respectively. The task was to detect and report brief episodes of coherent motion in the moving dots. Depending on the emotion category of the IAPS pictures, the trials were classified as pleasant, neutral and unpleasant. Focusing on three ROIs: middle temporal cortex (MT), ventral visual cortex (VVC), as well as the primary visual cortex (V1), we performed MVPA analysis to decode the distractor categories in each ROI, and correlated the decoding accuracy, taken to index the strength of distractor representation, with the accuracy in detecting the episodes of coherent motion. The following results were found: (1) the decoding accuracy was above chance level in all ROIs, and (2) in MT and VVC but not in V1, the higher the decoding accuracy, the worse the behavioral performance. These results suggested that distractor information was represented in V1 as well as in the two motion-processing areas, and in the motion-processing areas, stronger representations of the distractor led to poorer ability to process attended information, leading to worse behavioral performance. The hypothesis was thus supported and trade-offs in the fidelity of stimulus representations prompted by neural competition demonstrated.

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Gene therapy-mediated overexpression of wild-type MFN2 improves Charcot-Marie-Tooth disease type 2A
Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common axonal CMT and is associated with an early onset and severe motor-dominant phenotype. CMT2A is mainly caused by dominant mutations in the MFN2 gene, encoding Mitofusin-2, a GTPase located in the outer membrane of the mitochondria and endoplasmic reticulum (ER). Mutations in MFN2 are known to affect mitochondrial dynamics. We previously demonstrated that the mutated MFN2Arg94Gln further disrupts contacts between the ER and the mitochondria, leading to progressive axonal degeneration. There is no effective therapeutic approach to slow or reverse the progression of CMT2A, and treatments currently under development primarily focus on restoring mitochondrial function. Here, we provide proof-of-concept that neuronal overexpression of wild-type MFN2 (MFN2WT) provides therapeutic benefit in transgenic CMT2A mice carrying the mutated MFN2Arg94Gln. Intrathecal delivery of an AAV9 vector expressing MFN2WT effectively targets motor and sensory neurons, restoring ER-mitochondria contacts and mitochondrial morphology, thereby preserving both neuromuscular junction integrity and motor function. Strikingly, therapeutic efficacy is also achieved following vector injection after the onset of symptoms, rescuing the molecular hallmarks of CMT2A pathology and reversing locomotor. Notably, AAV administration was well tolerated, with no evidence neither of hepatotoxicity nor dorsal root ganglion inflammation. These results establish that boosting MFN2 levels using gene therapy is a promising therapeutic avenue for CMT2A

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Mismatch negativity develops in adolescence and independently of microglia
Higher brain functions and cognition undergo a critical period of development during adolescence, when psychiatric disorders such as schizophrenia typically onset. Understanding how developmental processes during adolescence interact with schizophrenia pathophysiology and risk remains a central goal in psychiatry. Here we show that a well-established biomarker of schizophrenia, mismatch negativity, matures during adolescence in mouse primary visual cortex, along with a strengthening of fronto-visual functional connectivity. Because microglia are implicated in schizophrenia risk and disease states, we further investigated what role microglia may play in the development of mismatch responses under physiological conditions. We found that microglial depletion with PLX5622 in adolescence arrests the development of resting oscillations in frontal areas, but does not affect the development of deviance detection, other signatures of visual context processing, or prefrontal-visual functional connectivity. Our findings suggest (a) a key component of mismatch negativity develops in adolescence, a period of vulnerability to schizophrenia, and (b) the development underlying this component does not require robust microglia activity, clarifying the developmental role of microglia in higher order visual processing.

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Microglial morphology reflects cognitive status in the aging rat brain
Age-related cognitive decline affects millions of individuals worldwide, but the cellular mechanisms underlying this decline remain incompletely understood. Microglia undergo significant changes with aging, including alterations in morphology, that may reflect or contribute to cognitive dysfunction. However, the relationship between specific microglial morphologies and cognitive performance in relevant brain regions remains poorly understood. To address this, we evaluated the relationship between morphology-based microglial phenotypes and cognitive performance across domains affected by aging. Microglial morphology was analyzed in four cognitive brain regions of male and female 3-, 9-, and 15-month-old rats and features were subjected to hierarchical clustering on principal components to identify microglial subtypes. Rats underwent cognitive testing using a radial arm water maze and a T-maze set-shifting task to assess spatial working and reference memory, striatal-based learning, and cognitive flexibility. We observed age-related cognitive impairments alongside region-specific changes in microglial morphotype abundance. Importantly, the relative abundance of distinct microglial clusters correlated with cognitive performance in functionally relevant brain regions including the prefrontal cortex, the orbitofrontal cortex, and the hippocampus. Taken together, these findings highlight the utility of morphological profiling in capturing microglial heterogeneity and suggest that morphological changes may reflect or contribute to cognitive decline during aging.

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Biomimetic Cues Enable Predictive Mechanisms in Simulatedand Physical Robot-Human Object Handovers
Object handovers - while representing one of the simplest forms of physical interaction between two agents - involve a complex interplay of predictive and reactive control mechanisms in both agents. As human-human pairs have unrivaled skills in physical collaboration tasks, we take the approach of understanding and applying biomimetic concepts to human-robot interaction. Here, we apply the concept of passer movement cues, that is, slower movement for heavy objects and faster movements for lighter objects, to robot-human handovers. We first show that when a simulated passing agent's movement is scaled with object mass, participants as receivers adapt their anticipatory grip forces according to mass in a virtual environment. We then apply the same concept to a physical robot-human handover and show that our approach generalizes to the real-world. The predictive scaling of grip forces is learned iteratively upon repeated presentations of trajectory-mass pairings, whether the masses are presented in a random or blocked order. Overall we demonstrate that the presentation of robotic kinematic cues can provide intuitive and naturalistic human predictive control in object handover. This extends the use of non-verbal cues in robot-human handover tasks and facilitates more legible and efficient physical robot-human interactions.

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Detection of probable neuronal gene expression changes in skin biopsies from patients with paclitaxel-induced peripheral neuropathy
Our inability to obtain nerve samples from the vast majority of neuropathic pain patients impedes our ability to understand the disease, creates challenges in understanding mechanisms in specific patient populations, and limits our ability to make treatment decisions based on quantifiable molecular data. Fields like oncology have overcome these problems to take advantage of the insight that sequencing offers for understanding mechanisms of disease and have leveraged these molecular insights to dramatically change the treatment landscape in the past decade. Here we tested the hypothesis that skin biopsies could be used to gain insight into neuronal transcriptomic changes in patients with paclitaxel-induced peripheral neuropathy (PIPN). Our analysis reveals that hundreds of differentially expressed genes (DEGs) found through bulk RNA sequencing in these skin biopsies are likely contributed by dorsal root ganglion (DRG) neuronal axons and/or terminals. Up-regulated genes were representative of broad class of nociceptors whereas down-regulated genes were associated with putative injured DRG neurons expressing the PDIA2 gene. DEGs that could be confidently associated with specific subsets of skin cells were mostly expressed by keratinocytes supporting a growing literature tying keratinocyte-neuron communication abnormalities to pain in PIPN. Our findings warrant further assessment of skin biopsies in additional neuropathic pain populations to gain insight into DRG neuron changes that have previously been thought to be inaccessible in routine clinical or scientific assessment in most patients.

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Chronic Dietary Exposure to Methylparaben and Ethyl paraben Induces Developmental, Biochemical, and Behavioural Toxicity in Drosophila melanogaster
Abstract Parabens, particularly methylparaben (MP) and ethylparaben (EP), are extensively used preservatives in cosmetics, foods, and pharmaceuticals. Although considered safe at low concentrations, recent evidence questions their biological inertness under chronic exposure. This study evaluated the developmental, biochemical, and behavioural effects of continuous dietary MP and EP exposure in Drosophila melanogaster, an established in vivo model for toxicological screening. Flies were chronically exposed to MP (0.5 to 2%) or EP (0.5 to 1.5%) throughout development and adulthood. Developmental timing, lifespan, oxidative-stress markers (MDA, FRAP, total protein), and locomotor performance (negative geotaxis in adults, crawling in larvae) were quantified. Paraben exposure significantly delayed development (a 15% increase in eclosion time), reduced median lifespan (up to a 50% decrease at 2% MP), and increased oxidative damage (MDA and FRAP) in a dose-dependent manner. Protein content declined more rapidly with age, suggesting oxidative degradation or proteolysis. Both adult climbing and larval crawling performances were impaired, indicating a link between biochemical stress and neuromuscular dysfunction. MP produced stronger oxidative and behavioural effects than EP. Feeding controls confirmed that observed deficits were not due to nutritional differences. Chronic MP and EP exposure induces systemic toxicity in D. melanogaster, integrating endocrine disruption and redox imbalance as plausible mechanisms of action. Given conserved stress and hormonal pathways, these findings reinforce the need to re-evaluate low dose paraben safety limits and highlight Drosophila as a rapid, ethically viable platform for screening environmental preservatives and safer substitutes.

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Uncertainty Shapes Neural Dynamics in Motor Cortex During Reaching
Voluntary reaching movements are often made with incomplete information about the movement goal, which may require the brain to flexibly adjust motor plans and ongoing movements. To examine how uncertainty about a reach target influences neural preparation and execution, we recorded activity from dorsal premotor (PMd) and primary motor (M1) cortices of a rhesus macaque trained to reach to one of two potential targets. In the task, a timing cue flashed three times in succession. Potential targets were displayed at the time of the first flash and the monkey needed to initiate the movement almost simultaneously with the third flash. Colorings of potential targets indicated the probability that the target would be at one location or the other, thereby inducing varying levels of uncertainty about the final target location. On half the trials, the final target was displayed so late that the monkey had to "guess" the target location, based on cues provided by the potential targets. While the monkey performed this task, we recorded 165 neurons from PMd and 37 from M1. Population neural trajectories in the preparatory subspace of PMd (but not M1) were progressively less expansive with higher levels of uncertainty. Despite differences in preparatory states associated with uncertainty, the movements produced were the same. The narrower separation between states suggested a neural-based explanation for more rapid movement re-preparation with higher uncertainty. Furthermore, we found a dimension in neural state-space representing the level of uncertainty during movement preparation and execution.

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Oxidation of ΔFOSB at Cys172 Controls Hippocampal Gene Targets and Learning
Imbalance of reduction/oxidation (redox) in the brain is associated with numerous diseases including Alzheimers disease (AD), substance abuse disorders, and stroke. Moreover, cognitive decline can be caused by neuronal dysfunction that precedes cell death, and this dysfunction is in part produced by altered gene expression. However, the mechanisms by which redox state controls gene expression in neurons are not well understood. DeltaFOSB is a neuronally enriched transcription factor critical for orchestrating gene expression underlying memory, mood, and motivated behaviors. It is dysregulated in many conditions including AD. We showed recently that deltaFOSB forms a redox-sensitive disulfide bond between cysteine 172 (C172) of deltaFOSB and C279 of its preferred binding partner JUND. This bond works as a redox switch to control DNA-binding, based on studies of recombinant proteins in vitro. Here, we show that this redox control of deltaFOSB function in vitro is conserved in vivo. We show that deltaFOSB C172 forms a redox-sensitive disulfide bond with JUND that regulates the stability of this AP1-transcription factor complex and its binding to DNA in cells. We also validate the formation of deltaFOSB-containing complexes held together via disulfide bonds in mouse brain in vivo. We show that exogenous oxidative stress reduces deltaFOSB binding to gene targets in mouse brain and that Fosb C172S knock-in mice, which lack a functional deltaFOSB redox switch, are insensitive to this oxidation-dependent reduction in target gene binding, demonstrating that deltaFOSB is regulated by a redox switch that modulates binding to target genes in the hippocampus. Finally, we demonstrate that FosB C172S knock-in mice are less sensitive to cognitive dysfunction induced by oxidative stress. This evidence supports deltaFOSB as an important mediator of oxidative stress-driven changes in gene expression and cognition and implicates deltaFOSB as a possible therapeutic target for diseases associated with oxidative stress in the brain, including AD.

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Early reduction and impaired targeting of myelin-associated glycoprotein to myelin membranes in Huntington disease
Background. Huntington disease (HD) is a hereditary life-threatening disease marked by progressive neuronal loss and atrophy of grey matter structures, particularly the caudate putamen. Brain imaging studies have revealed that the degradation of the white matter occurs many years prior to symptomatic onset and neuronal loss, suggesting that the decay of brain white matter is an active contributor to the disease progression. However, the mechanisms by which the HD mutation triggers white matter loss is not well understood. Methods. Western blot, immunohistochemistry, and electron microscopy were conducted to assess white matter pathology and explore the relevant mechanisms in CAG140 knock-in mice, which express the HD protein in the same way as patients suffering from HD and thus biologically replicate HD in human. Results. Western blot analysis of proteins localized at different layers of the myelin coat revealed that the myelin-associated glycoprotein (MAG), which is localized at the innermost layer of the myelin coat and essential for maintaining the periaxonal space and the integrity of the myelin sheath, manifested as an early and progressive decline in HD mouse caudate putamen. The loss of MAG was detected at myelinated axons and in fiber bundles in HD mouse brains at an age when the abundance of myelinated axons was normal. Fluorescence immunohistochemical studies found that MAG labeling was concentrated in the soma of a subset of oligodendrocytes, which expressed breast carcinoma amplified sequence 1, a marker for new oligodendrocytes. While their abundance was normal, new oligodendrocytes in HD mouse caudate appeared to be impeded in acquiring the expression of MAG and in targeting MAG away from perinuclear punctate structures to processes, signs of impaired maturation. Compared with those in wildtype mouse brains, oligodendrocytes in HD mouse brains had a reduced abundance of small vesicles whereas an increased abundance of large punctate structures in the perinuclear region, implying defective generation of small vesicles transporting MAG from large punctate structures in the soma to processes. The MAG-containing perinuclear punctate structures were negative for proteins specifying trans-Golgi networks, early endosomes, or exosomes but had a minor portion labeled with lysosome-associated membrane protein 1, indicating that the structures where MAG accumulates in the soma are derived from the late endosomal lysosomal compartment. Conclusions. Our study suggests that the decay of the brain white matter in Huntington disease involves a deficit in trafficking of myelin-associated glycoprotein, preventing its proper delivery from the soma of oligodendrocytes to myelin-forming processes.

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Persistence of vestibular function in the absence of glutamatergic transmission from hair cells
Quantal synaptic transmission in vestibular end-organs is glutamatergic. Although genetic deletion of Slc17a8 (termed Vglut3) leads to deafness in mice, the dependence of vestibular function on VGLUT3-mediated quantal transmission is unknown. Here, we investigated the vestibular phenotype of Vglut3-/- mice at the cellular, systems, and behavioral levels. The type-II vestibular hair cells (VHCs) in Vglut3+/+ mice were strongly immunoreactive for VGLUT3, while type-I VHCs showed poor immunoreactivity. In Vglut3-/- mice quantal synaptic transmission in utricular calyces was reduced in rate and amplitude by > 95%. In vivo recordings of spontaneous activity in the vestibular nerve revealed similar action potential rates and regularity in Vglut3+/+ and Vglut3 /- mice, suggesting a divergent underlying mechanism compared to the silent Vglut3-/- auditory nerve. In behavioral studies, Vglut3-/- mice did not exhibit considerable sensorimotor or balance deficits. Collectively, these data support the view that non-quantal transmission is the predominant mode of neurotransmission between type I VHCs and vestibular calyceal afferent neurons. We propose that non-quantal transmission alone underlies the apparently normal vestibular nerve physiology and behavioral function in Vglut3-/- mice.

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Decoding with multivariate pattern analysis is superior for optically pumped magnetometer-based magnetoencephalography compared to superconducting quantum interference device-based systems
Background: Multivariate pattern analysis (MVPA) has become an increasingly important method for decoding distributed brain activity from neural electrophysiological recordings by leveraging both temporal and spatial features. These multivariate approaches have proven important for both cognitive neuroscience and brain-computer interfaces. MVPA might benefit from magnetoencephalography (MEG) systems based on optically pumped magnetometers (OPMs), as these sensors can be placed closer to the scalp, providing higher spatial resolution compared to conventional MEG systems that rely on superconducting quantum interference devices (SQUIDs). As OPM-based MEG systems become available at more institutions, it is essential to experimentally compare their performance with traditional SQUID-based systems using MVPA. Methods: We adapted a visual object-word paradigm from a previous study, originally implemented on a TRIUX MEGIN SQUID system, to the FieldLine HEDscan OPM system. Participants were recruited and we recorded their ingoing brain activity while did the same task in both systems. Visual stimuli of different objects were presented alternately in two modalities: pictures and the corresponding written words. For each modality, MVPA was used to classify the objects from OPM and SQUID magnetometers data respectively. To further investigate the advantages of OPM, we evaluated the effect classification accuracy of two spatial factors by controlling the number of sensors included and the spatial frequency content of the sensor data. Results: We found higher time-resolved decoding accuracy for the OPM compared to the SQUID data. Moreover, OPMs show higher classification performance compared to SQUIDs when controlling for the same number of sensors; consistently, the OPM system required fewer sensors to reach the performance limit of the SQUID system. Our analysis considering the spatial frequency content of the signal revealed that decoding accuracy plateaued for the SQUID system at lower spatial frequencies while the performance of the OPM system continued to improve when higher-order spatial components were included. Conclusion: Our OPM-MEG system outperformed the SQUID-MEG system on MVPA on decoding of visual processing. This advantage of OPM is driven by its higher spatial resolution, resulting from the sensors being positioned closer to the head and thus able to capture higher spatial frequency components of the brain signal. OPM may facilitate cognitive neuroscience research as well as brain-computer interfaces by providing higher sensitivity when employing paradigms using multi-variate data analysis.

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Iron Deficiency Impairs Mitochondrial Energetics and Early Axonal Growth and Branching in Developing Hippocampal Neurons
Each stage of neuronal development (i.e., proliferation, differentiation, migration, neurite outgrowth and synapse formation) requires functional and highly coordinated metabolic activity to ultimately ensure proper sculpting of complex neural networks. Energy deficits underlie many neurodevelopmental, neuropsychiatric and neurodegenerative diseases implicating mitochondria as a potential therapeutic target. Iron is necessary for neuronal energy output through its direct role in mitochondrial oxidative phosphorylation. Iron deficiency (ID) reduces mitochondrial respiratory and energy capacity in developing hippocampal neurons, causing permanently simplified dendritic arbors and impaired learning and memory. However, the effect of ID on early axonogenesis has not been explored. We used an embryonic mixed-sex primary mouse hippocampal neuron culture model of developmental ID to evaluate mitochondrial respiration and dynamics and effects on axonal morphology. At 7 days in vitro (DIV), ID impaired mitochondrial oxidative phosphorylation capacity and stunted growth of both the primary axon and branches, without affecting branch number. Mitochondrial motility was not altered by ID, suggesting that mitochondrial energy production --- not trafficking --- underlie the axon morphological deficits. These findings provide the first link between iron-dependent neuronal energy production and early axon structural development and emphasize the importance of maintaining sufficient iron during gestation to prevent the negative consequences of ID on brain health across the lifespan.

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Functional and Structural Plasticity in Cocaine-Seeking Ensembles of the Nucleus Accumbens Core
Relapse vulnerability in substance use disorder (SUD) is primarily driven by cue-induced activation of neurons within the nucleus accumbens core (NAcore), among other contributing factors. Neuronal ensembles within the NAcore, defined here as selectively co-activated neurons during specific behavioral experiences, are essential during cocaine sensitization and recall. While transient synaptic plasticity (t-SP) has been widely observed in general neuronal populations within the NAcore during reinstatement, its ensemble-specific dynamics remain unclear. Here, we used c-Fos-TRAP2-based tagging to identify cocaine-seeking ensembles in mice following cocaine intravenous self-administration, extinction, and cue-induced reinstatement. Structural spine plasticity was assessed via confocal microscopy, and functional changes were measured using whole-cell electrophysiology across multiple reinstatement time points. Ensemble neurons exhibited enhanced dendritic spine head diameter (dh) and AMPA/NMDA (A/N) ratios following cue exposure, consistent with t-SP. Notably, spine classification revealed a reduction in mature spines during reinstatement, suggesting morphological remodeling rather than new spine formation in both ensemble and non-ensemble cells. Non-ensemble neurons exhibited classical functional transient synaptic plasticity, characterized by increased A/N ratios but no significant changes in dh. To begin assessing if presynaptic vesicle release impacts t-SP, paired-pulse ratio analysis indicated no differences in population or time point. Importantly, ensemble neurons displayed elevated A/N ratio following cocaine exposure, suggesting prior silent synapse maturation. These findings demonstrate that t-SP is not uniformly distributed across NAcore neurons but differs significantly between ensemble and non-ensemble neurons. By linking ensemble identity to both structural and functional plasticity, this study refines our understanding of cue-induced relapse mechanisms.

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Region-specific human brain organoids reveal synaptic and cell state drivers of glioblastoma invasion
Glioblastoma (GBM) is a highly heterogenous and malignant brain tumor, in part because it disrupts normal brain circuits to fuel its own growth and invasion. Thus, there is a need to identify the molecular features of invasive GBM cells and their regulators in the neural microenvironment. To address this in a fully human model, we engrafted patient-derived GBM cells (total n=15 independent samples) from three sources - fresh neurosurgical resections, cell lines, and whole GBM organoids - into human induced pluripotent stem cell-derived organoids patterned to forebrain, midbrain, and spinal cord identities. GBM cells from all sources infiltrated brain organoids within 2 days post-engraftment, reaching maximal invasion by day 14. Across organoids of distinct spatial and maturational milieu, GBM cells showed a consistent reduction in astrocyte-like states and an enrichment in neuron/glia progenitor-like (NPC-like) states. These NPC-like GBM cells expressed neuronal and synaptic machinery, and tumors enriched in this transcriptomic state prior to engraftment achieved greater organoid coverage, suggesting enhanced infiltration and synaptic integration of this GBM cell type. Although GBM cell states converged across organoid types after engraftment, infiltration was greater in the forebrain than spinal cord. This is likely reflective of synaptic input from deep-layer TBR1 excitatory neurons in the forebrain, as demonstrated by a combination of rabies-based monosynaptic tracing and single-cell transcriptomics. In contrast, inhibitory neurons were the predominant synaptic partners of GBM in the spinal cord. Together, this fully human model of the neural-GBM connectome reveals how neuron-like GBM states and regionally distinct synaptic inputs cooperatively shape tumor invasion.

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Electrical synapses mediate visual approach behavior
Detecting salient visual objects and orienting toward them are commonplace tasks for animals, yet the underlying neural circuit mechanisms remain poorly understood. The fruit fly is an ideal model for a comprehensive analysis of feature detection mechanisms given its complete synaptic wiring diagrams, robust behavioral assays, and cell-type-specific gene expression datasets. We previously showed that columnar visual neurons T3 are required for saccadic orientation toward landscape features during flight. Here, we examine how signals downstream of T3 are processed in the central brain. We identify the LC17 type of visual projection neurons as key postsynaptic targets: they receive strong excitatory input from T3, project to premotor brain regions, and are thus positioned to support visual approach. Using in vivo optical physiology and virtual reality behavior, we demonstrate that LC17 neurons are indeed necessary for object tracking during flight. Furthermore, we find that electrical synapses in LC17 are also required for tracking behavior. Accordingly, we show that the innexin Shaking B (shakB) is highly expressed in LC17 dendrites, and genetic perturbations confirm an essential role for gap junctional coupling in this circuit. Our findings reveal mechanisms underlying visual approach, and highlight the interplay between electrical and chemical neurotransmission for rapid object detection and action selection.

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