bioRxiv Subject Collection: Neuroscience's Journal

Topical administration of novel FKBP12 ligand MP-004 improves retinal function and structure in retinitis pigmentosa models.
Purpose: This study evaluates the therapeutic potential of MP-004, a novel FKBP12 ligand, in the treatment of inherited retinal dystrophies (IRDs). MP-004 targets FKBP12/RyR interaction, which is disrupted in several neurological disorders with underlying oxidative stress. Methods: The toxicity and efficacy of MP-004 were examined in vitro in 661W cells. Efficacy was evaluated in phototoxic and H2O2-induced damage using impedance assays, calcium imgaing and in situ PLA. In vivo, MP-004 efficacy was evaluated in the rd10 mouse model of retinitis pigmentosa (RP) by topical ocular instillation. Retinal function was assessed by electroretinography (ERG), visual acuity was measured using a water maze test, and retinal structure was analyzed morphometrically. Results: MP-004 exhibited low toxicity (LD50: 1.22 mM) and effectively protected 661W cells from phototoxicity (EC50: 30.6 nM). Under oxidative stress conditions, MP-004 preserved FKBP12.6/RyR2 interaction, partially restored endoplasmic reticulum calcium stores and prevented cell death. In vivo, MP-004 significantly preserved retinal function in rd10 mice, with ERG wave amplitude increases of up to 50% in scotopic and 71% in photopic conditions, corresponding to rod and cone functions, respectively. Additionally, MP-004 improved visual acuity for low spatial frequency patterns, and preserved retinal structure with a 23% increase in outer nuclear layer thickness, and preservation in the number of rods and cones and their segment length. Conclusions: MP-004 shows promise as a therapeutic agent for RP, preserving retinal structure and function, likely through modulation of FKBP12.6/RyR2 interaction. Further studies are needed to explore its pharmacokinetics and efficacy in other IRD models.

Comparative analysis of six adeno-associated viral vector serotypes in mouse inferior colliculus and cerebellum
Adeno-associated viral vector (AAV) serotypes vary in how effectively they express genes across different cell types and brain regions. Here we report a systematic comparison of the AAV serotypes 1, 2, 5, 8, 9, and the directed evolution derived AAVrg, in the inferior colliculus and cerebellum. The AAVs were identical apart from their different serotypes, each having a synapsin promotor and expressing GFP (AAV-hSyn-GFP). Identical titers and volumes were injected into the inferior colliculus and cerebellum of adult male and female mice and brains were sectioned and imaged 2 weeks later. Transduction efficacy, anterograde labeling of axonal projections, and retrograde labeling of somata, were characterized and compared across serotypes. Cell-type tropism was assessed by analyzing the morphology of the GFP-labeled neurons in the cerebellar cortex. In both the cerebellum and inferior colliculus, AAV1 expressed GFP in more cells, labeled a larger volume, and produced significantly brighter labeling than all other serotypes, indicating superior transgene expression. AAV1 labeled more Purkinje cells, unipolar brush cells, and molecular layer interneurons than the other serotypes, while AAV2 labeled a greater number of granule cells. These results provide guidelines for the use of AAVs as gene delivery tools in these regions.

Foamy microglia link oxylipins to disease progression in multiple sclerosis
Multiple sclerosis (MS) is a neuroinflammatory disease characterized by expanding demyelinating lesions, leading to severe and irreversible disability. The mechanisms driving lesion expansion, however, remain poorly understood. Here, using a multi-omics approach, we identified foamy microglia as primary contributors to the molecular profile of lesions and disease progression in secondary progressive MS. Lesions with foamy microglia are marked by the accumulation of cholesterol esters, bismonoacylglycerolphosphates (BMP), and oxylipins, along with high B-cell infiltration, increased levels of immunoglobulin G1, and elevated expression of Fcgamma- and complement receptors. Lesions with foamy GPNMB+-microglia display markers of enhanced phagocytosis, lipid metabolism, lysosomal dysfunction, and antigen presentation, but lack classical pro-inflammatory markers. Our data suggest that sustained phagocytosis of myelin overwhelms microglial endo-lysosomal capacity, leading to lipid droplet and oxylipin formation. This microglial phenotype may induce further recruitment of adaptive immune cells, axonal damage, drive lesion expansion and prevent remyelination. Monoacylglycerol lipase, involved in producing oxylipin precursors, was identified as a potential therapeutic target to disrupt this cycle and prevent chronic lesion expansion.

Mu and Delta Opioid Receptors Modulate Inhibition within the Prefrontal Cortex through Dissociable Cellular and Molecular Mechanisms
Aberrant signaling within cortical inhibitory microcircuits has been identified as a common signature of neuropsychiatric disorders. Interneuron (IN) activity is precisely regulated by neuromodulatory systems that evoke widespread changes in synaptic transmission and principal cell output. Cortical interneurons express high levels of Mu and Delta opioid receptors (MOR and DOR), positioning opioid signaling as a critical regulator of inhibitory transmission. However, we lack a complete understanding of how MOR and DOR regulate prefrontal cortex (PFC) microcircuitry. Here, we combine whole-cell patch-clamp electrophysiology, optogenetics, and viral tools to provide an extensive characterization MOR and DOR regulation of inhibitory transmission. We show that DOR activation is more effective at suppressing spontaneous inhibitory transmission in the prelimbic PFC, while MOR causes a greater acute suppression of electrically-evoked GABA release. Cell type-specific optogenetics revealed that MOR and DOR differentially regulate inhibitory transmission from parvalbumin, somatostatin, cholecystokinin, and vasoactive intestinal peptide-expressing INs. Finally, we demonstrate that DOR regulates inhibitory transmission through pre- and postsynaptic modifications to IN physiology, whereas MOR function is predominantly observed in somato-dendritic or presynaptic compartments depending on cell type.

Modelling human social vision with cinematic stimuli
Sociability is central for humans. Visual information ranging from low-level physical features (e.g. luminance) to semantic information (e.g. face recognition) and high-level social inference (e.g. emotional valence of social interactions) is constantly sampled for navigating the social world. Here we utilize large-scale eye tracking during natural vision for mapping how different levels of visual information guide the perception of social scenes. In three experiments, participants (N = 166) watched full-length films and short movie clips with varying social content (total duration: 193 minutes) during eye tracking. To model the association between the perceptual features and spatiotemporal eye movement parameters (gaze position, gaze synchronization, pupil size and blinking), we extracted 39 stimulus features from the movies including low-level audiovisual features (e.g. luminance, motion), presence and location of mid-level semantic categories (e.g. faces, objects) and high-level social information (e.g. body movements, pleasantness). Pupil size was modulated by luminance, scene cuts and emotional arousal while gaze position was most accurately predicted by a combination of the presence of human faces, local motion and entropy. Faces and eyes were prioritized over other semantic categories and blinking rate decreased during periods of attentional engagement. Altogether the results show that human social vision is primarily guided by low-level physical features and mid-level semantic categories, while high-level social features such as emotional arousal primarily modulate pupillary responses.

Does Unfairness Evoke Anger or Disgust? A Quantitative Neurofunctional Dissection Based on 25 Years of Neuroimaging
Over the last decades, the traditional 'Homo economicus' model has been increasingly challenged by convergent evidence underscoring the impact of emotions on decision-making. A classic example is the perception of unfairness operationalized in the Ultimatum Game where humans readily sacrifice personal gains to punish those who violate fairness norms. While the emotional mechanism underlying costly punishments has been widely acknowledged, the distinct contributions of moral emotions (anger or disgust) remain debated, partly due to methodological limitations of the conventional experiments. Here, we capitalize on a quantitative neurofunctional dissection approach by combining recent developments in neuroimaging meta-analyses, behavioral-level, network-level, and neurochemical-level decoding and data from 3,266 participants from functional neuroimaging studies to determine the common and distinct neural representations between unfairness and the two moral emotions. Experience of unfairness engaged a widespread bilateral network encompassing insular, cingulate, and frontal regions, with dorsal striatal regions mediating the decision to reject unfair offers. Disgust engaged a defensive-avoidance circuit encompassing amygdalar, occipital, and frontal regions, while anger engaged non-overlapping systems including mid-cingulate, thalamic, and frontal regions. Unfairness and anger or disgust respectively commonly engaged the anterior and mid-insula, while the latter additionally showed common recruitment of ventrolateral prefrontal and orbitofrontal cortices. Multimodal network, behavioral, and serotonergic decoding provided a more granular and convincing dissection of these results. Findings indicate a shared neuroaffective basis underlying the impact of emotions on unfairness-induced punishment behavior and suggest a common brain circuit has been evolutionarily shaped to protect individuals from personal harm and enforce societal norms.

Neuronal TDP-43 aggregation drives changes in microglial morphology prior to immunophenotype in amyotrophic lateral sclerosis
Microglia are the innate immune cells of the brain with the capacity to react to damage or disease. Microglial reactions can be characterised in post-mortem tissues by assessing their pattern of protein expression, or immunophenotypes, and cell morphologies. We recently demonstrated that microglia have a phagocytic immunophenotype in early-stage ALS but transition to a dysfunctional immunophenotype by end stage, and that these states are driven by TAR DNA-binding protein 43 (TDP-43) aggregation in the human brain. However, it remains unclear how microglial morphologies are changed in ALS. Here we examine the relationship between microglial immunophenotypes and morphologies, and TDP-43 pathology in motor cortex tissue from people with ALS and from a TDP-43-driven ALS mouse model. Post-mortem human brain tissue from 10 control and 10 ALS cases was analysed alongside brain tissue from the bigenic NEFH-tTA/tetO-hTDP-43{triangleup}NLS (rNLS) mouse model of ALS at distinct disease stages. Sections were immunohistochemically labelled for microglial markers (HLA-DR, CD68, and Iba1) and phosphorylated TDP-43 (pTDP-43). Single-cell microglial HLA-DR, CD68, and Iba1 average intensities, and morphological features (cell body area, process number, total outgrowth, and branch number) were measured using custom image analysis pipelines. In human ALS motor cortex, we identified a significant change in microglial morphologies from ramified to hypertrophic, which was associated with increased Iba1 and CD68 levels. In the rNLS mouse motor cortex, the microglial morphological changed from ramified to hypertrophic and increased Iba1 levels occurred in parallel with pTDP-43 aggregation, prior to increases in CD68 levels. Overall, the evidence presented in this study demonstrates that microglia change their morphologies prior to immunophenotype changes. These morphological changes may prime microglia near neurons with pTDP-43 aggregation for phagocytosis, in turn triggering immunophenotype changes; first, to a phagocytic state then to a dysfunctional one.

Cytoplasmic accumulation of a splice variant of hnRNP A2/B1 contributes to FUS-associated toxicity in a mouse model of ALS
Genetic and experimental findings point to a crucial role of RNA dysfunction in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). Evidence suggests that mutations in RBPs such as FUS, a gene associated with ALS, affect the regulation of alternative splicing. We have previously shown that the overexpression of wild-type FUS in mice, a condition that induces ALS-like phenotypes, impacts the splicing of hnRNP A2/B1, a protein with key roles in RNA metabolism, suggesting that a pathological connection between FUS and hnRNP A2/B1 might promote FUS-associated toxicity. Here we report that the expression and distribution of different hnRNP A2/B1 splice variants are modified in the affected tissues of mice overexpressing wild-type FUS. Notably, degenerating motor neurons are characterized by the cytoplasmic accumulation of splice variants of hnRNP A2/B1 lacking exon 9 (hnRNP A2b/B1b). In vitro studies show that exon 9 skipping affects the nucleocytoplasmic distribution of hnRNP A2/B1, promoting its localization into stress granules (SGs), and demonstrate that cytoplasmic localization is the primary driver of hnRNP A2b recruitment into SGs and cell toxicity. Finally, boosting exon 9 skipping using splicing switching oligonucleotides exacerbates disease phenotypes in wild-type FUS mice. Altogether, these findings reveal that alterations of the nucleocytoplasmic distribution of hnRNP A2/B1, driven by FUS-induced splicing changes, likely contribute to motor neuron degeneration in ALS.

The non-hallucinogenic serotonin 1B receptor is necessary for the antidepressant-like effects of psilocybin in mice
Recent studies highlight the promising use of psychedelic therapies for psychiatric disorders, including depression. The persisting clinical effects of psychedelics such as psilocybin are commonly attributed to activation of the serotonin 2A receptor (5-HT2AR) based on its role in the acute hallucinatory effects. However, the active metabolite of psilocybin binds to many serotonin receptor subtypes, including the serotonin 1B receptor (5-HT1BR). Given the known role of 5-HT1BR in mediating depressive phenotypes and promoting neural plasticity, we hypothesized that it mediates the effects of psilocybin on neural activity and behavior. We first examined the acute neural response to psilocybin in mice lacking 5-HT1BR. We found that 5-HT1BR expression influenced brain-wide activity following psilocybin administration, measured by differences in the patterns of the immediate early gene c-Fos, across regions involved in emotional processing and cognitive function, including the amygdala and prefrontal cortex. Functionally, we demonstrated that 5-HT1BR is necessary for the acute and persisting behavioral effects of psilocybin. Although there was no effect of 5-HT1BR expression on the acute head twitch response, mice lacking 5-HT1BRs had attenuated hypolocomotor responses to psilocybin. We also measured the persisting antidepressant-like effects of psilocybin using transgenic and pharmacological 5-HT1BR loss-of-function models and found that 5-HT1B was required for the decreased anhedonia and reduced anxiety-like behavior. Finally, using a network analysis, we identified neural circuits through which 5-H1BR may modulate the response to psilocybin. Overall, our research implicates the 5-HT1BR, a non-hallucinogenic serotonin receptor, as a critical mediator of the behavioral and neural effects of psilocybin in mice.

A Measure of Event-Related Potentials (ERP) Indices of Motivation During Cycling
Although motivation is a central aspect of the practice of a physical activity, it is a challenging endeavour to predict an individual's level of motivation during the activity. The objective of this study was to assess the feasibility of measuring motivation through brain recording methods during physical activity, with a specific focus on cycling. The experiment employed the Effort Expenditure for Reward Task (EEfRT), a decision-making task based on effort and reward, conducted under two conditions: one involving cycling on an ergometer at moderate intensity and the other without cycling. The P300, an event-related potential linked to motivation, was recorded using electroencephalography. A total of 20 participants were recruited to complete the EEfRT, which involved making effort-based decisions of increasing difficulty in order to receive varying levels of monetary reward. The results demonstrated that the P300 amplitude was influenced by the act of cycling, exhibiting a reduction during the cycling session. This reduction may be explained by a reallocation of cognitive resources due to the exertion of physical effort, which is consistent with the transient hypofrontality theory. In terms of behaviour, participants demonstrated a tendency to make more challenging choices when the potential rewards were higher or the probability of gaining them was lower. This pattern was observed in both the cycling and non-cycling conditions. A positive correlation was identified between P300 amplitude and the proportion of difficult choices, particularly under conditions of low reward probability. This suggests that P300 may serve as a neural marker of motivation. The study demonstrates the feasibility of using electroencephalography to monitor motivation during exercise in real-time, with potential applications in rehabilitation settings. However, further research is required to refine the design and explore the effects of different exercise types on motivation.

Single trial characterization of frontal Theta and parietal Alpha oscillatory episodes during Spatial Navigation in humans
Theoretical proposals and empirical findings both highlight the relevance of Theta brain oscillations in human Spatial Navigation. However, whilst the general assumption is that the relevant Theta band activity is purely oscillatory, most empirical studies fail to disentangle oscillatory episodes from wide band activity. In addition, experimental approaches often rely on averaged activity across trials and subjects, disregarding moment-to-moment fluctuations in Theta activity, contingent on key aspects of the task. Here, we used novel oscillation detection approaches to investigate the dynamics of Theta and Alpha episodes in human subjects performing a Spatial Navigation task, resolved at single trial level. The results suggest that bouts of Theta oscillatory activity are related to task difficulty and access to previously encoded information, across different time-scales. Alpha episodes, instead, seem to anticipate successful navigational decisions and could be related to shifts in internal attention.

A body detection inversion effect revealed by a large-scale inattentional blindness experiment
As a highly social species, humans preferentially attend to the faces and bodies of other people to efficiently recognize their identities, emotions, actions, and intentions. Previous research revealed specialized cognitive mechanisms for processing human faces and bodies. For example, upright person silhouettes are more readily found than inverted silhouettes in visual search and detection tasks. It is unclear, however, whether these findings reflect a top-down attentional bias to social stimuli or bottom-up sensitivity to visual cues signaling the presence of other people. Here, we tested whether the upright human form is preferentially detected in the absence of attention. To rule out influences of top-down attention and expectation, we conducted a large-scale single-trial inattentional blindness experiment on a diverse sample of naive participants (N=13.539). While participants were engaged in judging the length of a cross at fixation, we briefly presented an unexpected silhouette of a person or a plant next to the cross. Subsequently, we asked whether participants noticed anything other than the cross. Results showed that silhouettes of people were more often noticed than silhouettes of plants. Crucially, upright person silhouettes were also more often detected than inverted person silhouettes, despite these stimuli being identical in terms of their low-level visual features. Finally, capitalizing on the exceptionally large and diverse sample, further analyses revealed strong detection differences across age and gender. These results indicate that the visual system is tuned to the form of the upright human body, allowing for the quick detection of other people even in the absence of attention.

Developmental changes in the control of primary motoneuron excitability by the M-current in larval zebrafish
Spinal circuits for locomotion undergo maturation during early development. How intrinsic properties of individual spinal neuron populations change throughout motor maturation is not fully understood. Here we identify for the first time the presence of the persistent outward potassium current known as the M-current in primary motoneurons of larval zebrafish. We show that the M-current controls excitability of primary motoneurons and its role in excitability control changes during development such that the magnitude of the M-current in primary motoneurons transiently increases at 3 days post-fertilization. These findings reveal a novel mechanism by which control over excitability of primary motoneurons in larval zebrafish is ensured, underscoring developmental changes in ion current contributions to intrinsic properties. Broadly, these data support the M-current as a conserved means to control motoneuron excitability across vertebrates.

Multi-timescale neural adaptation underlying long-term musculoskeletal reorganization.
The central nervous system (CNS) can effectively control body movements despite environmental changes. While much is known about adaptation to external environmental changes, less is known about responses to internal bodily changes. This study investigates how the CNS adapts to long-term alterations in the musculoskeletal system using a tendon transfer model in non-human primates. We surgically relocated finger flexor and extensor muscles to examine how the CNS adapts its strategy for finger movement control by measuring muscle activities during grasping tasks. Two months post-surgery, the monkeys demonstrated significant recovery of grasping function despite the initial disruption. Our findings suggest a two-phase CNS adaptation process: an initial phase enabling function with the transferred muscles, followed by a later phase abolishing this enabled function and restoring a more efficient and 'good enough' control strategy resembling the original. These results highlight a multi-phase CNS adaptation process with distinct time constants in response to sudden bodily changes, offering potential insights into understanding and treating movement disorders.

On the analysis of functional PET (fPET)-FDG: baseline mischaracterization can introduce artifactual metabolic (de)activations
Functional Positron Emission Tomography (fPET) with (bolus plus) constant infusion of [18F]-fluorodeoxyglucose FDG), known as fPET-FDG, is a recently introduced technique in human neuroimaging, enabling the detection of dynamic glucose metabolism changes within a single scan. However, the statistical analysis of fPET-FDG data remains challenging because its signal and noise characteristics differ from both classic bolus-administration FDG PET and from functional Magnetic Resonance Imaging (fMRI), which together compose the primary sources of inspiration for analytical methods used by fPET-FDG researchers. In this study, we present an investigate of how inaccuracies in modeling baseline FDG uptake can introduce artifactual patterns to detrended TAC residuals, potentially introducing spurious (de)activations to general linear model (GLM) analyses. By combining simulations and empirical data from both constant infusion and bolus-plus-constant infusion protocols, we evaluate the effects of various baseline modeling methods, including polynomial detrending, regression against the global mean time-activity curve, and two analytical methods based on tissue compartment model kinetics. Our findings indicate that improper baseline removal can introduce statistically significant artifactual effects, although these effects characterized in this study (~2-8%) are generally smaller than those reported by previous literature employing robust sensory stimulation (~10-30%). We discuss potential strategies to mitigate this issue, including informed baseline modeling, optimized tracer administration protocols, and careful experimental design. These insights aim to enhance the reliability of fPET-FDG in capturing true metabolic dynamics in neuroimaging research.

Male-specific sNPF peptidergic circuits control energy balance for mating duration through neuron-glia interactions.
This study reveals a sexually dimorphic sNPF-sNPF-R circuit in the Drosophila brain that regulates energy balance behavior, specifically the shorter-mating-duration (SMD) response to sexual experience. sNPF is predominantly expressed in neurons, while sNPF-R is expressed in both neurons and glial cells, particularly astrocyte-like glia (ALG) in a subset of cells outside the mushroom body (MB) termed "Rishi cells" (RS cells). Sexual experience induces global alterations in calcium signaling and synaptic plasticity within this circuit, with sNPF-R expressing neurons and glia in RS cells playing a critical role in encoding sexual experience-related information into energy balance behavior related to mating duration. Neuronal glucose metabolism, specifically the Tret1l transporter, is essential for maintaining the high calcium levels and proper function of sNPF neurons near RS cells. This novel and intricate neuron-glia sNPF-sNPF-R network acts as critical circuits within the Drosophila brain for processing interval timing behaviors, highlighting the dynamic interplay between metabolism, neural circuits, and behavior in regulating energy balance.

Wideband ratiometric measurement of tonic and phasic dopamine release in the striatum
Reward learning, cognition, and motivation are supported by changes in neurotransmitter levels across multiple timescales. Current measurement technologies for various neuromodulators (such as dopamine and serotonin) do not bridge timescales of fluctuations, limiting the ability to define the behavioral significance, regulation, and relationship between fast (phasic) and slow (tonic) dynamics. To help resolve longstanding debates about the behavioral significance of dopamine across timescales, we developed a novel quantification strategy, augmenting extensively used carbon-fiber Fast Scan Cyclic Voltammetry (FSCV). We iteratively engineered the FSCV scan sequence to rapidly modify electrode sensitivity within a sampling window and applied ratiometric analysis for wideband dopamine measurement. This allowed us to selectively eliminate artifacts unrelated to electrochemical detection (i.e., baseline drift), overcoming previous limitations that precluded wideband dopamine detection from milliseconds to hours. We extensively characterize this approach in vitro, validate performance in vivo with simultaneous microdialysis, and deploy this technique to measure wideband dopamine changes across striatal regions under pharmacological, optogenetic, and behavioral manipulations. We demonstrate that our approach can extend to additional analytes, including serotonin and pH, providing a robust platform to assess the contributions of multi-timescale neuromodulator fluctuations to cognition, learning, and motivation.

Morphine-induced hyperalgesia impacts small extracellular vesicle miRNA composition and function
Morphine and other synthetic opioids are widely prescribed to treat pain. Prolonged morphine exposure can paradoxically enhance pain sensitivity in humans and nociceptive behavior in rodents. To better understand the molecular mechanisms underlying opioid-induced hyperalgesia, we investigated changes in miRNA composition of small extracellular vesicles (sEVs) from the serum of mice after a morphine treatment paradigm that induces hyperalgesia. We observed significant differential expression of 18 miRNAs in sEVs from morphine-treated mice of both sexes compared to controls. Several of these miRNAs were bioinformatically predicted to regulate cyclic AMP response element binding protein (CREB), a well-characterized transcription factor implicated in pain and drug addiction. We confirmed the binding and repression of Creb mRNA by miR-155 and miR-10a. We tested if serum-derived sEVs from morphine-treated mice could elicit nociceptive behavior in naive recipient mice. Intrathecal injection of 1 microgram sEVs did not significantly impact basal mechanical and thermal threshold in naive recipient mice. However, prophylactic 1 microgram sEV administration in recipient mice resulted in faster resolution of complete Freund adjuvant-induced mechanical and thermal inflammatory hypersensitivity. Other behaviors assayed following administration of these sEVs were not impacted including sEV conditioned place preference and locomotor sensitization. These results indicate that morphine regulation of serum sEV composition can contribute to analgesia and suggest a potential for sEVs to be a non-opioid therapeutic intervention strategy to treat pain.

Systemic CGRP and PACAP-38's Effects on Motion-Induced Nausea and Balance Behaviors in C57BL/6J Mice: A Comparison
Pituitary adenylate-cyclase-activating polypeptide (PACAP), particularly its dominant isoform PACAP-38, is implicated in migraine and represents a promising therapeutic target. We investigated if intraperitoneally delivered (IP) PACAP-38 impacts motion-induced nausea, postural sway, and imbalance in C57BL/6J wildtype mice using the motion-induced thermoregulation, center of pressure (CoP), rotarod, and balance beam assays. We also assessed CGRPs effects on these behaviors in parallel. Our findings indicate that IP PACAP-38 significantly disrupts motion-induced thermoregulation in mice, with notable blunting of tail vasodilation responses in both sexes. Additionally, PACAP-38 administration increased postural sway in female mice only and caused balance beam imbalances. Contrary to IP CGRP, IP PACAP-38 did not affect rotarod performance when mice were trained on a dowel with 1.5 cm radius. Our findings provide preclinical evidence supporting a potential role of PACAP-38 in vestibular migraine pathophysiology. Future research will explore if PACAP antagonism can protect against PACAP-38s effects on nausea and balance behaviors, relevant to treatment of vestibular migraine (VM), especially for patients unresponsive to triptans or CGRP-targeting therapies.

Exact Continuous Spiking Rate Inference
Many cognitive functions involve multiple brain areas simultaneously processing, distributing, and sharing information. The wide-field imaging technique can record such brain-wide activity since it offers a unique combination of simultaneous recordings from a wide field of view at a high rate. This unique combination is achieved by using a single-photon camera, which is set to capture, from a large area, neural activity-driven light emission generated by calcium indicators. Adequately analyzing this captured data requires inferring the underlying neural activity from the recorded fluorescence, a challenging mathematical problem. The challenge arises from the calcium indicator dynamics, which distort the neural dynamics as it transforms the neural activity into light emission and from the presence of noise. The wide-field setting adds a distinctive challenge. Its wide field of view recordings at a high rate constrains the spatial resolution to be limited. As a result, each fluorescence trace captured by each camera's pixel originates from many neuron activities and not a single neuron as typical of other recording techniques. No previous, rigorously studied analytic solution exists for inferring neural activity from recorded fluorescence in the wide-field setting. Here, we phrase the inference problem arising from wide-field recordings as an optimization problem and solve it exactly. To ensure the robustness of our solution and provide a solid foundation for its application, we rigorously verify it using real data. We further suggest a novel approach for the optimization problem parameter-tuning. Beyond recovering the neural dynamics, our inference will allow future studies to retrieve accurate, correlation-based analyses of brain-wide activity.

Neural and behavioral reinstatement jointly reflect retrieval of narrative events
When recalling past events, patterns of gaze position and neural activity resemble those observed during the original experience. We hypothesized that these two phenomena, known as gaze reinstatement and neural reactivation, are linked through a common process that underlies the reinstatement of past experiences during memory retrieval. Here, we tested this proposal based on the viewing and recall of a narrative movie, which we assessed through fMRI, deep learning-based gaze prediction, and language modeling of spoken recall. In line with key predictions, gaze behavior adhered to the same principles as neural activity; it was event-specific, robust across individuals, and generalized across viewing and recall. Additionally, gaze-dependent brain activity overlapped substantially across tasks. Collectively, these results suggest that retrieval engages mechanisms that direct our eyes during natural vision, reflecting common constraints within the functional organization of the nervous system. Moreover, they highlight the importance of considering behavioral and neural reinstatement together in our understanding of remembering.

Superimposed inhibitory surrounds underlying Saliency-based Stimulus Selection in avian Midbrain isthmi pars magnocellularis
In the avian midbrain network, bottom-up spatial attention is directed by saliency-based stimulus selection. However, it remains unclear whether the isthmi pars magnocellularis (Imc), the first site in the midbrain network to represent stimulus selection, can represent stimulus salience and what is the mechanism by which the midbrain network computes salience. Here, we used two separate translational motion stimuli as the main stimulation protocols and conducted in vivo electrophysiological experiments in the pigeon's Imc. By combining bio-plausible model validation, we found two types of inhibitory surrounds of the Imc neuron receptive field, homogenous inhibitory surrounds (HIS) and non-homogenous inhibitory surrounds (non-HIS), and elucidated the mechanism by which both arise. While HIS is local and depends on stimulus feature similarity, which can be used to compute stimulus saliency, non-HIS is global and doesn't depend on stimulus feature similarity, which can be used to compute stimulus selection. Moreover, the superimposition of HIS and non-HIS modulates the neural response of Imc. The two inhibitory surrounds of Imc identified in this study more clearly elucidate the full process of achieving bottom-up stimulus selection based on saliency in the midbrain network and show that Imc is a nucleus that can represent both stimulus saliency and stimulus selection.

Glutamine Transport via Neurotransmitter Transporter 4 (NTT4, SLC6A17) Maintains Presynaptic Glutamate Supply at Excitatory Synapses in the Central Nervous System
The glutamate-glutamine cycle is thought to be the principle metabolic pathway that recycles glutamate at excitatory synapses. In this cycle, synaptically released glutamate is sequestered by astrocytes and converted to glutamine before being returned to the presynaptic terminal for conversion back into glutamate to replenish the neurotransmitter pool. While many aspects of this cycle have been extensively studied, a key component remains unknown: the nature of the transporter responsible for the presynaptic uptake of glutamine. We hypothesise that neurotransmitter transporter 4 (NTT4/SLC6A17) plays this role. Accordingly, we generated NTT4 knockout mice to assess its contribution to presynaptic glutamine transport and synaptic glutamate supply. Using biochemical tracing of [1-13C] glucose and [1,2-13C] acetate in awake mice, we observe a reduction of neuronal glutamate supply when NTT4 is absent. In addition, direct electrical recording of hippocampal mossy fibre boutons reveals a presynaptic glutamine transport current that is entirely inhibited by genetic or pharmacological elimination of NTT4. The role of NTT4 in neurotransmission was demonstrated by electrophysiological recordings in acute hippocampal slices, which reveal that NTT4 is required to maintain vesicular glutamate content and to sustain adequate levels of glutamate supply during periods of high-frequency neuronal activity. Finally, behavioural studies in mice demonstrate a deficit in trace fear conditioning; a hippocampus-dependent memory paradigm, and abnormalities in nest building, anxiety behaviour, and social preference. These results demonstrate that NTT4 is a presynaptic glutamine transporter which is a central component of the glutamate-glutamine cycle. NTT4 and hence the glutamate-glutamine cycle maintain neuronal glutamate supply for excitatory neurotransmission during high-frequency synaptic activity, and are key regulators of memory retention and normal behaviour.

Synaptic accumulation of GluN2B-containing NMDA receptors mediates the effects of BDNF-TrkB signalling on synaptic plasticity and in epileptogenesis
Brain-derived neurotrophic factor (BDNF) is a key mediator of synaptic plasticity and memory formation in the hippocampus. However, the BDNF-induced alterations in the glutamate receptors coupled to the plasticity of glutamatergic synapses in the hippocampus have not been elucidated. In this work we investigated the putative role of GluN2B-containing NMDA receptors in the plasticity of glutamatergic synapses induced by BDNF. Stimulation of hippocampal synaptoneurosomes with BDNF led to a significant time-dependent increase in the synaptic surface expression of GluN2B-containing NMDA receptors as determined by immunocytochemistry with colocalization with pre- (vesicular glutamate transporter) and post-synaptic markers (PSD95). Similarly, BDNF induced the synaptic accumulation of GluN2B-containing NMDA receptors at the synapse in cultured hippocampal neurons, by a mechanism sensitive to the PKC inhibitor G[O]6983. The effects of PKC may be mediated by phosphorylation of Pyk2, as suggested by western blot experiments analyzing the phosphorylation of the kinase on Tyrosine 402. GluN2B-containing NMDA receptors mediated the effects of BDNF in the facilitation of the early phase of long-term potentiation (LTP) of hippocampal CA1 synapses induced by -burst stimulation, since the effect of the neurotrophin was abrogated in the presence of the GluN2B inhibitor Co 101244. The inhibitor was without effect on LTP in the absence of BDNF. In addition, we observed a surface accumulation of GluN2B-containing NMDA receptors in hippocampal synaptoneurosomes isolated from rats subjected to the pilocarpine model of temporal lobe epilepsy, after reaching Status epilepticus, an effect that was inhibited by administration of the TrkB receptor inhibitor ANA-12. Together, these results show that the synaptic accumulation of GluN2B-containing NMDA receptors mediate the effects of BDNF in the plasticity of glutamatergic synapses in the hippocampus.

The representational geometry for naturalistic textures in macaque V1 and V2
Our understanding of visual cortical processing has relied primarily on studying the selectivity of individual neurons in different areas. A complementary approach is to study how the representational geometry of neuronal populations differs across areas. Though the geometry is derived from individual neuronal selectivity, it can reveal encoding strategies difficult to infer from single neuron responses. In addition, recent theoretical work has begun to relate distinct functional objectives to different representational geometries. To understand how the representational geometry changes across stages of processing, we measured neuronal population responses in primary visual cortex (V1) and area V2 of macaque monkeys to an ensemble of synthetic, naturalistic textures. Responses were lower dimensional in V2 than V1, and there was a better alignment of V2 population responses to different textures. The representational geometry in V2 afforded better discriminability between out-of-sample textures. We performed complementary analyses of standard convolutional network models, which did not replicate the representational geometry of cortex. We conclude that there is a shift in the representational geometry between V1 and V2, with the V2 representation exhibiting features of a low-dimensional, systematic encoding of different textures and of different instantiations of each texture. Our results suggest that comparisons of representational geometry can reveal important transformations that occur across successive stages of visual processing.

Structural compromise in spiking cortex and connected networks
INTRODUCTION: Epilepsy is increasingly conceptualized as a network disorder, and advancing methods for its diagnosis and treatment requires characterizing both the epileptic generator and related networks. We combined multimodal magnetic resonance imaging (MRI) and high-density electroencephalography (HD-EEG) to interrogate alterations in cortical microstructure, morphology, and local function within and beyond spiking tissue in focal epilepsy. METHODS: We studied 25 patients with focal epilepsy (12F, mean {+/-} SD age = 31.28 {+/-} 9.30 years) and 55 age- and sex-matched healthy controls, subdivided into a group of 30 for imaging feature normalization (15F, 31.40 {+/-} 8.74 years) and a group of 25 for replication (12F, 31.04 {+/-} 5.65 years). The 3T MRI acquisition included T1-weighted, diffusion, quantitative T1 relaxometry, and resting-state functional imaging. Open-access MRI processing tools derived cortex-wide maps of morphology and microstructure (cortical thickness, mean diffusivity, and quantitative T1 relaxometry) and intrinsic local function and connectivity (timescales, connectivity distance, and node strength) for all participants. Multivariate approaches generated structural and functional alteration scores for each cortical location. Using HD-EEG, the predominant spike type was localized and we quantified MRI alterations within spike sources, as well as in proximal and connected networks. RESULTS: Regions harboring spike sources showed increased structural MRI alterations (mean: 27.98%) compared to the rest of the brain (mean: 17.67%) in patients. Structural compromise extended to all regions with close functional coupling to spike sources (paired t-tests; FDR-corrected p < 0.05), but not to anatomical neighbors of spike sources. This finding was replicated using average control functional, structural, and anatomical matrices instead of patient-specific matrices. CONCLUSION. Spiking regions contain more marked alterations in microstructure and morphology than the remaining cortex, which may help localize the epileptogenic zone non-invasively. There are nevertheless broader networks effects, which may relate to a cascading of structural changes to functionally connected cortices. These results underscore the utility of combining high-definition MRI and EEG approaches for characterizing epileptogenic tissue and assessing distributed network effects.

Prioritization of decisions by importance and difficulty in human planning
In our everyday lives, we continually need to commit to courses of future action even when direct feedback is not available. The expected reward of an action depends not only on a single decision but on a sequence of interdependent choices that will happen in the future. Admittedly, most decisions we make concern sequences of actions as opposed to single-step choices. To make these decisions, we rely on our ability to plan and forecast the potential outcomes of sequential decisions. However, how humans plan under novel real-world scenarios remains poorly understood. We developed a novel task to investigate how humans evaluate options and prioritize their decisions during planning in realistic situations. In each trial, a written planning scenario (for example, plan your birthday party) was followed by 9 pictures divided into three categories (e.g., 3 birthday cakes, 3 party locations, and 3 decorations). Participants were asked to choose one option from each category to create the best possible plan - the one with the highest subjective value - while both their response and gaze were tracked. With each option possibly having a different subjective value according to the other selected options, the required planning process resembles the navigation of an internal decision tree, whose complexity grows exponentially with the number of choices and future outcomes considered. Our results show that participants gather information at all levels of the decision trees, as suggested by their gaze-switching behavior. In addition, based on their assessments of importance and difficulty, we find that participants generally choose first what they report to be the most important and easiest category and then the least important and most difficult one. Overall, our task provides a novel means to study planning behavior in realistic, multi-alternative situations, as participants can freely navigate through all levels of the decision tree by subjectively evaluating potential scenarios through internal sampling and imagination.

Quality assessment and control of unprocessed anatomical, functional, and diffusion MRI of the human brain using MRIQC
Quality control of MRI data prior to preprocessing is fundamental, as substandard data are known to increase variability spuriously. Currently, no automated or manual method reliably identifies subpar images, given pre-specified exclusion criteria. In this work, we propose a protocol describing how to carry out the visual assessment of T1-weighted, T2-weighted, functional, and diffusion MRI scans of the human brain with the visual reports generated by MRIQC. The protocol describes how to execute the software on all the images of the input dataset using typical research settings (i.e., a high-performance computing cluster). We then describe how to screen the visual reports generated with MRIQC to identify artifacts and potential quality issues and annotate the latter with the "rating widget" - a utility that enables rapid annotation and minimizes bookkeeping errors. Integrating proper quality control checks on the unprocessed data is fundamental to producing reliable statistical results and crucial to identifying faults in the scanning settings, preempting the acquisition of large datasets with persistent artifacts that should have been addressed as they emerged.

Differential enrichment of retinal ganglion cells underlies proposed core neurodegenerative transcription programs
In a published Correction, a revised analysis updated two "core transcription programs" proposed to underlie axon injury-induced retinal ganglion cell (RGC) neurodegeneration. Though extensive, the Correction purported to leave the two principal conclusions of its parent study unaltered. The first of those findings was that a core program mediated by the Activating Transcription Factor-4 (ATF4) and its likely heterodimeric partner does not include numerous canonical ATF4 target genes stimulated by RGC axon injury. The second was that the Activating Transcription Factor-3 (ATF3) and C/EBP Homologous Protein (CHOP) function with unprecedented coordination in a parallel program regulating innate immunity pathways. Here those unexpected findings are revealed to instead reflect insufficient knockout coupled with differences in RGC enrichment across conditions. This analysis expands on the published Correction's redefinition of the purported transcription programs to raise foundational questions about the proposed functions and relationships of these transcription factors in neurodegeneration.

Lifting the degeneracy of optical fiber neural interfaces for optogenetics and electrophysiology by using axialtrodes
Optogenetics and electrophysiology are powerful methods in neuroscience for precise spatiotemporal control and recording of neural activity. Conventional flat optical fibers, commonly used in deep brain regions, can only interface with limited tissue volume at their distal end. However, depth-resolved neuromodulation and recordings are crucial for decoding neuronal connections across various brain domains. In this work, we address this limitation by introducing an axialtrode developed using soft polymers integrated with multiple metal electrodes via a scalable thermal drawing process. We employ the developed fiber-based neural interface, controllably angled-cleaved, for multisite optogenetics and electrophysiology at different brain regions. Its suppressed inflammatory responses indicate improved biocompatibility compared to conventional fibers. This concept can be adapted to any fiber material and application where depth-resolved stimulation and electrical recordings are important, bringing the community a step closer to understanding complex neuronal dynamics.

ER Aggregation Causes Synaptic Protein Imbalance in Retinitis Pigmentosa Mutant Photoreceptor Neurons
Rod photoreceptor neurons in the retina detect scotopic light by packaging large quantities of the visual pigment protein rhodopsin (Rho) into stacked membrane discs within their outer segments (OS). Efficient Rho trafficking to the OS through the inner rod compartments is critical for long-term rod health since diseases like retinitis pigmentosa (RP) induce Rho mislocalization in these inner compartments, including in the rod presynaptic terminals (i.e., spherules). Given the importance of protein trafficking to the OS, less is known about the trafficking of rod synaptic proteins that maintain critical synapses between rods and inner retina neurons. Furthermore, the subcellular impact of Rho mislocalization on rod spherules has not been investigated. In this study we used super-resolution and electron microscopies, along with proteomic measurements of rod synaptic proteins, to perform an intensive subcellular analysis of Rho synaptic mislocalization in P23H-Rho-RFP RP mutant mice of both sexes. We discovered mutant P23H-Rho-RFP protein mislocalized in distinct ER aggregations within the spherule cytoplasm which we confirmed in wild type (WT) rods overexpressing P23H-Rho-RFP. Additionally, we found significant protein abundance differences in Dystrophin, BASSOON, ELFN1 and other synaptic proteins in P23H-Rho-RFP mice. By comparison, Rho mislocalized along the spherule plasma membrane in WT rods and in rd10 RP mutant rods, in which there was no synaptic protein disruption. Throughout the study, we also identified a network of ER membranes within WT rod presynaptic spherules. Together, our findings establish a previously uncharacterized ER-based secretory system that mediates normal trafficking and turnover at mouse rod synapses.

Deficiency of Hv1 Proton Channel Enhances Macrophage Antigen Presentation and Anti-Tumor Responses in Glioma
In the tumor microenvironment of glioblastoma, myeloid cells act as a double-edged sword: they are a major cellular component modulating the immune response while presenting a potential therapeutic target. Our study highlights the voltage-gated proton channel Hv1, predominantly expressed in myeloid cells, as a crucial regulator of their physiological functions. We discovered a strong correlation between increased Hv1 expression and poor prognosis in glioblastoma patients. Depleting Hv1 significantly extended survival in a mouse model of glioma. Employing multiple novel transgenic mouse lines, we demonstrated that Hv1 is upregulated in response to tumor presence, with glioma-associated macrophages as the principal contributors. Specifically, we identified that Hv1 in infiltrating macrophages as the major driver of survival phenotype differences. Through a combination of in vivo two-photon imaging, spectral flow cytometry, and spatial transcriptomic sequencing, we found that Hv1 depletion leads to reduced macrophage infiltration and enhanced antigen presentation, ultimately fostering a stronger adaptive immune response. These findings establish the Hv1 channel as a crucial new immune regulator within the brain tumor milieu, offering a promising target for reprogramming macrophage function to combat glioblastoma.

Competitive interactions shape brain dynamics and computation across species
Adaptive cognition relies on cooperation across anatomically distributed brain circuits. However, specialised neural systems are also in constant competition for limited processing resources. How does the brain's network architecture enable it to balance these cooperative and competitive tendencies? Here we use computational whole-brain modelling to examine the dynamical and computational relevance of cooperative and competitive interactions in the mammalian connectome. Across human, macaque, and mouse we show that the architecture of the models that most faithfully reproduce brain activity, consistently combines modular cooperative interactions with diffuse, long-range competitive interactions. The model with competitive interactions consistently outperforms the cooperative-only model, with excellent fit to both spatial and dynamical properties of the living brain, which were not explicitly optimised but rather emerge spontaneously. Competitive interactions in the effective connectivity produce greater levels of synergistic information and local-global hierarchy, and lead to superior computational capacity when used for neuromorphic computing. Altogether, this work provides a mechanistic link between network architecture, dynamical properties, and computation in the mammalian brain.

Fiber Microstructure Quantile (FMQ) Regression: A Novel Statistical Approach for Analyzing White Matter Bundles from Periphery to Core
The structural connections of the brain's white matter are critical for brain function. Diffusion MRI tractography enables the in-vivo reconstruction of white matter fiber bundles and the study of their relationship to covariates of interest, such as neurobehavioral or clinical factors. In this work, we introduce Fiber Microstructure Quantile (FMQ) Regression, a new statistical approach for studying the association between white matter fiber bundles and scalar factors (e.g., cognitive scores). Our approach analyzes tissue microstructure measures based on quantile-specific bundle regions. These regions are defined according to the quantiles of fractional anisotropy (FA) from the periphery to the core of a population fiber bundle, which pools all individuals' bundles. To investigate how fiber bundle tissue microstructure relates to covariates of interest, we employ the statistical technique of quantile regression. Unlike ordinary regression, which only models a conditional mean, quantile regression models the conditional quantiles of a response variable. This enables the proposed analysis, where a quantile regression is fitted for each quantile-specific bundle region. To demonstrate FMQ Regression, we perform an illustrative study in a large healthy young adult tractography dataset derived from the Human Connectome Project-Young Adult (HCP-YA), focusing on particular bundles expected to relate to particular aspects of cognition and motor function. Importantly, our analysis considers sex-specific effects in brain-behavior associations. In comparison with a traditional method, Automated Fiber Quantification (AFQ), which enables FA analysis in regions defined along the trajectory of a bundle, our results suggest that FMQ Regression is much more powerful for detecting brain-behavior associations. Importantly, FMQ Regression finds significant brain-behavior associations in multiple bundles, including findings unique to males or to females. In both males and females, language performance is significantly associated with FA in the left arcuate fasciculus, with stronger associations in the bundle's periphery. In males only, memory performance is significantly associated with FA in the left uncinate fasciculus, particularly in intermediate regions of the bundle. In females only, motor performance is significantly associated with FA in the left and right corticospinal tracts, with a slightly lower relationship at the bundle periphery and a slightly higher relationship toward the bundle core. No significant relationships are found between executive function and cingulum bundle FA. Our study demonstrates that FMQ Regression is a powerful statistical approach that can provide insight into associations from bundle periphery to bundle core. Our results also identify several brain-behavior relationships unique to males or to females, highlighting the importance of considering sex differences in future research.

Mitochondrial small RNA alterations associated with increased lysosome activity in an Alzheimer's Disease Mouse Model uncovered by PANDORA-seq
Emerging small noncoding RNAs (sncRNAs), including tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs), are critical in various biological processes, such as neurological diseases. Traditional sncRNA-sequencing (seq) protocols often miss these sncRNAs due to their modifications, such as internal and terminal modifications, that can interfere with sequencing. We recently developed panoramic RNA display by overcoming RNA modification aborted sequencing (PANDORA-seq), a method enabling comprehensive detection of modified sncRNAs by overcoming the RNA modifications. Using PANDORA-seq, we revealed a novel sncRNA profile enriched by tsRNAs/rsRNAs in the mouse prefrontal cortex and found a significant downregulation of mitochondrial tsRNAs and rsRNAs in an Alzheimer's disease (AD) mouse model compared to wild-type controls, while this pattern is not present in the genomic tsRNAs and rsRNAs. Moreover, our integrated analysis of gene expression and sncRNA profiles reveals that those downregulated mitochondrial sncRNAs negatively correlate with enhanced lysosomal activity, suggesting a crucial interplay between mitochondrial RNA dynamics and lysosomal function in AD. Given the versatile tsRNA/tsRNA molecular actions in cellular regulation, our data provide insights for future mechanistic study of AD with potential therapeutic strategies.

Academic Success and Mental Health: The Paradox of Frontoparietal-Default Mode Network Coupling among Children Facing Poverty
Childhood family income is a powerful predictor of academic achievement and mental health. Here, we ask whether children living in poverty who succeed academically are subsequently protected from, or at risk for, internalizing symptoms. Prior research indicates that children in poverty with better academic performance tend to have higher temporal coupling between the Lateral Frontoparietal Network (LFPN) and Default Mode Network (DMN) than lower-performing children in poverty. An open question is whether higher LFPN-DMN coupling has maladaptive long-term consequences for mental health for this population. In this pre-registered longitudinal study, we analyzed data from 10,829 children (1,931 in poverty) in the ABCD study across four time points (ages 9-13). Higher grades correlated with fewer internalizing symptoms; this association was more pronounced for children below poverty. Longitudinally, LFPN-DMN connectivity correlated positively with internalizing symptoms across both groups and timepoints. Thus, although higher academic performance was associated with better mental health outcomes for all children, the specific pattern of LFPN-DMN connectivity that supports academic resilience among children in poverty may be a risk factor for developing internalizing symptoms. These findings highlight the complex nature of academic resilience in the context of structural inequity.

Dorsal-caudal and ventral hippocampus target different cell populations in the medial frontal cortex in rodents
Direct projections from the ventral hippocampus (vHPC) to the medial frontal cortex (MFC) play crucial roles in memory and emotional regulation. Using anterograde transsynaptic tracing and in vitro electrophysiology in mice, we document a previously unexplored pathway that parallels the established vHPC-MFC connectivity. This pathway connects the dorsal-caudal hippocampus (dcHPC) to specific subregions of the ventral MFC, in particular the dorsal peduncular cortex. Notably, this pathway exerts a strong inhibitory influence on ventral MFC by targeting a substantial proportion of inhibitory neurons. Retrograde transsynaptic tracing in rats indicated that ventral MFC subregions project disynaptically back to vHPC. These results, altogether, suggest the existence of a remarkable functional circuit connecting distinct functional areas: the cognition-related dcHPC with the emotion-related ventral MFC and vHPC. These findings further provide valuable insights in the cognitive and emotional abnormalities associated with the HPC-MFC connectivity in neurological and psychiatric disorders.

Targeting the acetyltransferase NAT10 corrects pathologies in human frontotemporal neurons and extends lifespan in an in vivo Drosophila tauopathy model
Disruption of the neuronal nuclear membrane and perturbation of nucleocytoplasmic transport are features of neurodegenerative diseases, including Alzheimer's disease, that involve the microtubule-associated protein tau (MAPT). We previously identified that missense and splicing mutations in the MAPT gene, causal for frontotemporal dementia, result in nuclear envelope deformation and disrupted nucleocytoplasmic transport in human neurons. This is most likely due to microtubule mechanical stress, similar to that observed in Hutchinson-Gilford Progeria Syndrome (HGPS). A small molecule inhibitor of the acetyltransferase NAT10 has been shown to correct nuclear membrane defects in HGPS by modulating microtubule dynamics. We report here that NAT10 inhibition alters microtubule dynamics and corrects nuclear lamina defects and aberrant nucleocytoplasmic transport in human iPSC-derived FTD-MAPT neurons. Similarly, NAT10 inhibition and haploinsufficiency correct neuronal nuclear shape defects and extend lifespan in vivo in a Drosophila model of tauopathy. Our results show that NAT10 mediates neuronal pathologies in tauopathies and is a promising new therapeutic target in these diseases.

Connectomic Organization of the Suprachiasmatic Nucleus
The suprachiasmatic nucleus (SCN), the mammalian master clock, is a special structure dedicated to the time computation. However, a connectomic understanding of the nucleus as a whole is lacking. Using serial section electron microscopy, we reconstructed multiscale and multimodal SCN communication networks. Intra-SCN synaptic network consists of 9,566 morphologically similar neurons and 4.3 million synapses, organized into multiscale circuitries that interact with SCN-traversing axon fascicles. Strikingly, SCN neurons engage in unique soma-soma ephaptic interaction, forming 2,038 electrotonic integrative units with the largest overlapping the light-responsive area (LRA). SCN's paracrine modality contains 47,396 m3 dense core vesicles, with notable scarcity in the LRA, suggesting cross-modal coordination and functional integration. These distinct network features provide comprehensive insights into the system architecture of the mammalian circadian clock.

Key contribution of prefrontal inhibition to passive coping behaviour: chronic stress and fast-acting antidepressant
Persistent passive coping behaviour is a hallmark feature in major depression and is reversed by fast-acting antidepressants (such as ketamine). This behaviour is regulated by a specific cortico-midbrain circuit. However, whether the prefrontal cortex (PFC), especially inhibition in PFC, contributes to the modulation of passive coping, and whether this modulation is important for mediating the impacts of chronic stress and/or fast-acting antidepressants, are poorly understood. Here, we found that rostral prelimbic cortex (rPL) bidirectionally controls the occurrence of passive coping behaviour where excitatory and inhibitory neurons play opposite roles. Chronic stress leads to reduced excitation/inhibition (E/I) ratio, reflected as alterations in in vivo spiking rate, synaptic inputs and intrinsic excitability of both excitatory and inhibitory neurons. A fast-acting antidepressant, (2R, 6R)-hydroxynorketamine (HNK), reduced passive coping behaviour, restored rPL E/I ratio and partially reversed altered properties in rPL neurons, in chronically stressed mice. Importantly, chronic stress and HNK mostly affected fast-spiking/parvalbumin inhibitory neurons instead of other inhibitory neurons, indicating the important role of this subtype of inhibitory neurons in the above processes. These findings demonstrate the importance of rPL E/I balance in regulating passive coping, which can be modulated by chronic stress and rapidly restored by fast-acting antidepressant.

Data Science in Olfaction
Advances in neural sensing technology are making it possible to observe the olfactory process in great detail. In this paper, we conceptualize smell from a Data Science and AI perspective, that relates the properties of odorants to how they are sensed and analyzed in the olfactory system from the nose to the brain. Drawing distinctions to color vision, we argue that smell presents unique measurement challenges, including the complexity of stimuli, the high dimensionality of the sensory apparatus, as well as what constitutes ground truth. In the face of these challenges, we argue for the centrality of odorant-receptor interactions in developing a theory of olfaction. Such a theory is likely to find widespread industrial applications, and enhance our understanding of smell, and in the longer-term, how it relates to other senses and language. As an initial use case of the data, we present results using machine learning-based classification of neural responses to odors as they are recorded in the mouse olfactory bulb with calcium imaging. Our larger objective is to create the equivalent of an MNIST database for olfaction, which we call oMNIST, so that researchers are able to work from a standard dataset to further the state of the art, similar to how the availability of standard datasets catalyzed research in computer vision.