bioRxiv Subject Collection: Neuroscience's Journal

Apoptosis is increased in cortical neurons of female Marfan Syndrome mice
Marfan Syndrome (MFS) is an autosomal dominant genetic disorder that affects connective tissue throughout the body due to mutations in the FBN1 gene. Individuals with MFS display symptoms in different organs, particularly in the vasculature, but the mechanisms of this multi-system dysfunction are still under investigation. There is still a gap in our understanding of the impact of monogenic connective tissue aberrations on the brain. This study aims to determine the impact of MFS on neurodegeneration, in cortical brain tissue of male and female MFS mice. Brain tissue of 6-month-old female and male mice with the FBN1C1041G/+ mutation and wildtype litter mates was collected and stained for active caspase-3 (ac3), brain derived neurotrophic factor (BDNF), and neuronal nuclei (NeuN) or with TUNEL and DAPI. Data revealed increased levels of ac3 in neurons within the sensory and motor cortical areas of female MFS mice compared to sex- and age-matched controls. We confirm increased levels of apoptosis in MFS mice using TUNEL staining within the same brain areas. We also report increased levels of neuronal BDNF levels in cortical brain tissue of male and female MFS mice. These results indicate a heightened susceptibility for neurodegeneration in the mouse model of MFS.

Disentangling the effects of Anxious, Autistic and Psychotic Traits on Perceptual Inference
The brain combines sensory information and prior information, taking into account uncertainty, to perceive the world. This inference process approaches optimality in humans but with inter-individual differences associated with psychological traits. Previous results on these differences are in fact highly heterogeneous and even contradictory. We highlight experimental, modeling, and analysis choices that may contribute to this heterogeneity. We propose a set of tasks utilizing explicit and implicit priors, combined with computational modeling, to isolate the decision and learning stages of perceptual inference. Using a multidimensional approach, we characterized differences in perceptual inference associated with anxious, autistic and psychotic traits in two large samples from the general population. Our findings reveal that anxious, autistic, and psychotic traits form three distinct, yet correlated, dimensions. More anxious traits were associated with enhanced performance and greater reliance on sensory information at the decision stage. Autistic traits were not associated with any difference in perceptual inference; results for psychotic traits were inconsistent across the two samples. Results are partly different when using unidimensional analyses. Together, these results stress the importance of a multidimensional approach that takes anxious traits into account to characterize inter-individual differences in perceptual inference.

Direct segmentation of cortical cytoarchitectonic domains using ultra-high-resolution whole-brain diffusion MRI
We assess the potential of detecting cortical laminar patterns and areal borders by directly clustering voxel values of microstructural parameters derived from high-resolution mean apparent propagator (MAP) magnetic resonance imaging (MRI), as an alternative to conventional template-warping-based cortical parcellation methods. We acquired MAP-MRI data with 200m resolution in a fixed macaque monkey brain. To improve the sensitivity to cortical layers, we processed the data with a local anisotropic Gaussian filter determined voxel-wise by the plane tangent to the cortical surface. We directly clustered all cortical voxels using only the MAP-derived microstructural imaging biomarkers, with no information regarding their relative spatial location or dominant diffusion orientations. MAP-based 3D cytoarchitectonic segmentation revealed laminar patterns similar to those observed in the corresponding histological images. Moreover, transition regions between these laminar patterns agreed more accurately with histology than the borders between cortical areas estimated using conventional atlas/template-warping cortical parcellation. By cross-tabulating all cortical labels in the atlas- and MAP-based segmentations, we automatically matched the corresponding MAP-derived clusters (i.e., cytoarchitectonic domains) across the left and right hemispheres. Our results demonstrate that high-resolution MAP-MRI biomarkers can effectively delineate three-dimensional cortical cytoarchitectonic domains in single individuals. Their intrinsic tissue microstructural contrasts enable the construction of whole-brain mesoscopic cortical atlases.

Background optic flow modulates responses of multiple descending interneurons to object motion in locusts
Animals flying within natural environments are constantly challenged with complex visual information. Therefore, it is necessary to understand the impact of the visual background on the motion detection system. Locusts possess a well-identified looming detection pathway, compromised of the lobula giant movement detector (LGMD) and the descending contralateral movement detector (DCMD). The LGMD/DCMD pathway responds preferably to objects on a collision course, and the response of this pathway is affected by the background complexity. However, multiple other neurons are also responsive to looming stimuli. In this study, we presented looming stimuli against different visual backgrounds to a rigidly-tethered locust, and simultaneously recorded the neural activity with a multichannel electrode. We found that the number of discriminated units that responded to looms was not affected by the visual background. However, the peak times of these units were delayed, and the rise phase was shortened in the presence of a flow field background. Dynamic factor analysis (DFA) revealed that fewer types of common trends were present among the units responding to looming stimuli against the flow field background, and the response begin time was delayed among the common trends as well. These results suggest that background complexity affects the response of multiple motion-sensitive neurons, yet the animal is still capable of responding to potentially hazardous visual stimuli.

Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein aggregation
Parkinson disease-causing mutations in the LRRK2 gene hyperactivate LRRK2 kinase activity, leading to increased phosphorylation of a subset of RAB GTPases, which are master regulators of intracellular trafficking. In neurons, processive retrograde transport of autophagosomes is essential for autophagosome maturation and effective degradation of autophagosomal cargo in the axon. We found that knockout of the LRRK2-counteracting RAB phosphatase PPM1H resulted in a gene dose-dependent disruption of the axonal transport of autophagosomes, leading to impaired degradation of axonal alpha-synuclein (aSyn), a key protein in Parkinson disease pathophysiology. Defective autophagosome transport and impaired aSyn degradation also correlated with increased aSyn aggregation in primary PPM1H knockout neurons exposed to preformed fibrils of aSyn, an effect that was dependent on LRRK2 kinase activity. Thus, our results link LRRK2-mediated RAB hyperphosphorylation to aSyn pathology in Parkinson disease and further establish a role for impaired autophagy in Parkinson disease pathophysiology.

m6A-mediated epi-transcriptomic dysregulation underlies synaptic dysfunction in fragile X syndrome
Fragile X syndrome (FXS), the leading genetic cause of intellectual disability, arises from FMR1 gene silencing and loss of the FMRP protein. FMRP is known to bind to and regulate the stability of m6A-containing transcripts. However, how loss of FMRP impacts on transcriptome-wide m6A modifications in FXS patients remains unknown. To answer this question, we generated cortical neurons differentiated from induced pluripotent stem cells (iPSC) derived from healthy subjects and FXS patients. In electrophysiology recordings, we validated that synaptic and neuronal network defects in iPSC-derived FXS neurons corresponded to the clinical EEG data of the patients from which the corresponding iPSC line was derived. In analysis of transcriptome-wide methylation, we show that FMRP deficiency led to increased translation of m6A writers, resulting in hypermethylation that primarily affecting synapse-associated transcripts and increased mRNA decay. Conversely, in the presence of an m6A writer inhibitor, synaptic defects in FXS neurons were rescued. Taken together, our findings uncover that an FMRP-dependent epi-transcriptomic mechanism contributes to FXS pathogenesis by disrupting m6A modifications in FXS, suggesting a promising avenue for m6A-targeted therapies.

Perivascular and parenchymal fluid characteristics are related to age and cognitive performance across the lifespan
Perivascular spaces (PVS) play a critical role in fluid transfer and waste clearance in the brain, but few studies have explored how alterations to perivascular fluid flow may impact brain maturation and behavior. This study aims to characterize age-related alterations to perivascular and parenchymal fluid flow characteristics across the lifespan in typically developing children (8-21 years) and aging adults (35-90 years) and assess their contribution to cognition. In this study, we employ multi-compartment diffusion models, neurite orientation dispersion and density imaging (NODDI) and tissue tensor imaging (TTI), to quantify free water diffusion characteristics within automatically defined perivascular spaces using enhanced PVS contrasts, the surrounding parenchyma, and at variable distances from the PVS. Our findings show free water diffusion characteristics within the PVS and surrounding parenchyma are associated with age and cognitive scores.

Microbially produced bile acids are associated with high levels of IgG autoantibodies and worse mental wellbeingin fibromyalgia subjects
Fibromyalgia (FM) is a disease primarily associated with chronic widespread pain, but other common symptoms are anxiety and depression. We previously proposed that autoimmunity contributes to FM based on findings of increased immunoglobulin G binding to satellite glial cells (anti-SGC IgG) in FM subjects compared to healthy controls (HC). Emerging research suggests that an altered gut microbiota composition is connected to psychological symptoms in FM rather than pain. Gut microbiota can produce or alter bile acids (BAs) and short-chain fatty acids (SCFAs), which have immune and inflammatory functions. Here, we investigate alterations in BA and SCFA concentrations in FM subjects compared to healthy controls (HC) and potential associations with FM symptoms and anti-SGC IgG levels. Bile acids and SCFAs were quantified using liquid chromatography coupled with high-resolution mass spectrometry and anti-SGC IgG levels were assessed with immunocytochemistry. The correlations between FM symptoms, anti-SGC IgG levels, and serum concentrations of 24 BAs and 11 SCFAs in 35 FM subjects and 32 matched HC were examined. Fibromyalgia subjects had significantly higher levels of microbially produced BAs than HC. Strikingly, 11 out of 24 BAs were significantly elevated in FM subjects with high, compared to those with low, anti-SGC IgG levels. Concentrations of specific BAs were associated with increased disease severity and worse mental well-being. These results revealed increased levels of secondary BAs in FM subjects compared to HC. The strong association between BAs, anti-SGC IgG levels, and mental well-being may help elucidate the importance of BAs in the psychological symptoms of FM.

Spatial frequency channels mediate a visual metric for human spatial perception
An intriguing and ubiquitous phenomenon in vision is the perception of spatial property information (e.g. separation, size, shape etc.) that departs from the raw physical inputs yet conforms to the visual context. While it has been postulated that visual system employs an internal adaptable metric by which the signals conveying the spatial property information are scaled, it remains unknown whether and how such putative visual metric is represented in the brain. Here, we hypothesized the putative visual metric is mediated by the joint responses of differently-tuned spatial frequency (SF) channels, and investigated this idea by combining the use of psychophysics, fMRI-based population receptive field (pRF) mapping and computation modeling. We found that reweighting of spatial frequency (SF) channels, either by adaption or presentation of the corresponding SF background, led to systematic distortions of the perceived spatial property information. Moreover, the pRFs in V1 were more concentrated towards the fovea under the high SF stimulation regardless of their positions in the visual field. Importantly, both the perceptual distortions and the global-scale pRF displacement were functionally coupled with the changes in the population SF response induced by SF channel reweighting. Our findings revealed, for the first time, the neural apparatus signaling the putative visual metric that constrains spatial vision by establishing the comprehensive three-way connection between SF channel reweighting, pRF position displacement and perceptual distortions of spatial property information.

A bounded accumulation model of temporal generalization outperforms existing models and captures modality differences and learning effects
Multiple systems in the brain track the passage of time and can adapt their activity to temporal requirements (Paton & Buonomano, 2018). While the neural implementation of timing varies widely between neural substrates and behavioral tasks, at the algorithmic level many of these behaviors can be described as bounded accumulation (Balci & Simen, 2024). So far, from the range of temporal psychophysical tasks, the bounded accumulation model has only been applied to temporal bisection, in which participants are requested to categorize an interval as "long" or "short" (Balci & Simen, 2014; Ofir & Landau, 2022). In this work, we extend the model to fit performance in the temporal generalization task, in which participants are required to categorize an interval as being the same or different compared to a standard, or reference, duration (Wearden, 1992). Previous models of performance in this task focused on either the group level or performance of highly trained animals (Birngruber et al., 2014; Church & Gibbon, 1982; Wearden, 1992). Whether the same models can fit performance from a few hundreds of trials of single participants, necessary for comparing performance across experimental manipulations, has not been tested. A drift-diffusion model with two decision boundaries fits the data of single participants better than the previous models. We ran two experiments, one comparing performance between vision and audition and another examining the effect of learning. We found that decision boundaries can be modified independently: While the upper boundary was higher in vision compared to audition, the lower boundary decreased with learning in the task.

Mindfulness training impacts brain network dynamics linked to stress response in young adolescents.
Mindfulness-based interventions (MBI) may lead to lower levels of psychological distress, including depression, anxiety, and stress in adolescents. Past research has advanced the discovery of neural architecture recruited by MBI. However, the brain mechanisms through which mindfulness exerts more resilient responses to social stressors in teens remain unclear. Here, we examined how MBI modulates changes in brain network dynamics following social stress with different affective valence (i.e., neutral, negative, and positive). For this aim, we carried out a longitudinal randomized controlled trial in which non-clinical adolescents underwent MBI for 8 weeks. They completed a psychosocial stress task before and following MBI. Functional magnetic resonance imaging (fMRI) and self-reported measurements of psychological distress were collected in both measurement points (i.e., pre and post MBI). We computed co-activation patterns on fMRI data to characterize dynamic functional connectivity within whole-brain networks. The results depicted how MBI modulates transient co-activation changes in dorsal medial regions of the brain default network (DN) following the experience of stress. However, these brain changes were not specific to the affective valence of stressful stimuli. The relationship between the DN dynamics and the measurements of psychological distress was mediated by MBI. Globally, our findings support a model in which MBI causally mediate brain-behavior interactions related to psychosocial stress in adolescents.

Detecting single motor-unit activity in magnetomyography
Studying the discharge patterns of motor units (MUs) is key to understanding the mechanisms underlying human motor behavior. Intramuscular electromyography (iEMG) allows direct study of MU activity, but is invasive. Surface electromyography (sEMG) offers a non-invasive alternative, but with lower spatial resolution. Recent advances in optically pumped magnetometers (OPMs) have sparked interest in the magnetic counterpart of EMG, magnetomyography (MMG), as an additional non-contact modality to study the neuromuscular system. However, it remains unclear whether MMG signals recorded with superconducting quantum interference devices (SQUIDs) or OPMs can be used to directly detect individual MUs. We addressed this question in a proof-of-principle study in which we recorded MMG signals from the abductor digiti minimi (ADM) muscle using SQUIDs and OPMs. Critically, we simultaneously recorded iEMG from the same muscle to validate the non-invasive measurements. First, we found that invasively recorded MUs can be detected in simultaneously recorded SQUID and OPM MMG signals. Second, we found that invasively validated MUs can be extracted directly from SQUID and OPM MMG. This provides converging evidence that individual MU activity is accessible using non-contact MMG. Our findings highlight the potential of MMG as a non-contact modality to measure and study muscle activity in health and disease.Studying the discharge patterns of motor units (MUs) is key to understanding the mechanisms underlying human motor behavior. Intramuscular electromyography (iEMG) allows direct study of MU activity, but is invasive. Surface electromyography (sEMG) offers a non-invasive alternative, but with lower spatial resolution. Recent advances in optically pumped magnetometers (OPMs) have sparked interest in the magnetic counterpart of EMG, magnetomyography (MMG), as an additional non-contact modality to study the neuromuscular system. However, it remains unclear whether MMG signals recorded with superconducting quantum interference devices (SQUIDs) or OPMs can be used to directly detect individual MUs. We addressed this question in a proof-of-principle study in which we recorded MMG signals from the abductor digiti minimi (ADM) muscle using SQUIDs and OPMs. Critically, we simultaneously recorded iEMG from the same muscle to validate the non-invasive measurements. First, we found that invasively recorded MUs can be detected in simultaneously recorded SQUID and OPM MMG signals. Second, we found that invasively validated MUs can be extracted directly from SQUID and OPM MMG. This provides converging evidence that individual MU activity is accessible using non-contact MMG. Our findings highlight the potential of MMG as a non-contact modality to measure and study muscle activity in health and disease.

Unveiling the Functional Connectivity of Astrocytic Networks with AstroNet, a Graph Reconstruction Algorithm Coupled to Image Processing
Astrocytes form extended intercellular networks, displaying complex calcium activity. However, the specific organization of these astrocytic networks and the precise extent of their functional connectivity in different brain areas remain unexplored. To unveil the functional architecture of astrocytic networks, we developed, using a data-driven methodology, a novel algorithm called AstroNet that uses two-photon calcium imaging to map temporal correlations in activation events among neighboring astrocytes. Our approach involves reconstructing functional astrocytic networks by organizing individual astrocyte activation events chronologically. This chronological order creates activity paths that enable the extraction of local astrocyte functional correlations. Ultimately, by tallying the occurrences of direct co-activations between pairs of cells along these pathways, we construct a graph that mirrors the underlying astrocyte functional network. By applying this method to two distinct brain regions (CA1 hippocampus and motor cortex), we identified notable differences in local network organizations in sub-regions of around 20-40 astrocytes. Specifically, the cortex exhibited a lower connectivity, while astrocytes in the hippocampus displayed stronger connections. Moreover, we found that in both regions, astrocytic networks consist of smaller, tightly connected sub-networks embedded within a larger, more loosely connected one. Altogether, our innovative method enables the identification of activation paths among astrocytes, facilitates the characterization of local network functional connectivity, and quantifies distinct connectivity patterns among astrocytes from different brain regions. This approach sheds light on the heterogeneous functional organization of astrocytic networks within the brain, pointing to region-specific astrocyte connectivity.

A Cortical Microcircuit for Region-Specific Credit Assignment in Reinforcement Learning
The distributed architecture of the cortex poses a fundamental challenge for reinforcement learning: how to assign credit specifically to regions that contribute to successful behavior? Cortical neurons can be driven by both global reinforcers, like rewards, and local sensory features, making it difficult to disentangle these influences. To address this, we investigated cortical reinforcement learning by manipulating the reward-predictive sensory modality during learning tasks, while monitoring key regulators of cortical activity-local inhibitory neurons, and cholinergic inputs. We found that VIP interneurons are broadly recruited by reward-predictive cues via a modality-independent cholinergic signal. However, when task demands aligned with local computation, SST interneurons suppressed VIP recruitment through an inhibitory feedback loop. A computational model demonstrates that this cholinergic-VIP-SST interneuron circuit motif enables targeted reinforcement learning and region-specific credit assignment in the cortex. These results offer a neurobiologically-grounded framework for how the cortex uses global reinforcement signals to direct plasticity to task-relevant regions, enabling those regions to adapt and fine-tune their responses.

The Role of Predictive Processing and Perceptual Load in Selective Visual Attention: An Examination with Semantically Salient and Less Salient Distractors
Our attentional resources are allocated to the various aspects of the environment based on the context, and predictive coding has been used as a model to explain the interaction between sensory-based information and top-down expectations in visual attention (Spratling, 2008; Rauss et al., 2011). On the other hand, the saliency of the environmental stimuli is also hypothesized to be capturing the attentional resources of the individuals involuntarily, and thus, it is thought to be playing a crucial role in attentional resource allocation. The current study investigates the role of predictive processing of task difficulty in selective visual attention in the presence of various distractors. Utilizing a letter search task, we provided brief cues about the upcoming task's difficulty, and participants were asked to detect the target letters. We investigated whether predictive processing about task demands may cause a difference in behavioral measures in the presence of semantically less salient distractors in Experiment 1 (Gabor patches) and semantically more salient distractors in Experiment 2 (faces). Results showed that unmet expectations about the task demands caused longer reaction times in both studies. We observed that all independent variables, which are task difficulty, cue congruency, and distractor presence, affected reaction times in both experiments, but cue congruency interacted with distractor presence only in Experiment 2. Here, we argue that though predictive processing plays a role in attentional resource allocation and, distractors' characteristics are also crucial as the saliency level interacts with the cue congruency.

Outdoor Air Pollution Relates to Amygdala Subregion Volume and Apportionment in Early Adolescents
Background: Outdoor air pollution is associated with an increased risk for psychopathology. Although the neural mechanisms remain unclear, air pollutants may impact mental health by altering limbic brain regions, such as the amygdala. Here, we examine the association between ambient air pollution exposure and amygdala subregion volumes in 9-10-year-olds. Methods: Cross-sectional Adolescent Brain Cognitive DevelopmentSM (ABCD)(R) Study data from 4,473 participants (55.4% male) were leveraged. Air pollution was estimated for each participant's primary residential address. Using the probabilistic CIT168 atlas, we quantified total amygdala and 9 distinct subregion volumes from T1- and T2-weighted images. First, we examined how criteria pollutants (i.e., fine particulate matter [PM2.5], nitrogen dioxide, ground-level ozone) and 15 PM2.5 components related with total amygdala volumes using linear mixed-effect (LME) regression. Next, partial least squares correlation (PLSC) analyses were implemented to identify relationships between co-exposure to criteria pollutants as well as PM2.5 components and amygdala subregion volumes. We also conducted complementary analyses to assess subregion apportionment using amygdala relative volume fractions (RVFs). Results: No significant associations were detected between pollutants and total amygdala volumes. Using PLSC, one latent dimension (LD) (52% variance explained) captured a positive association between calcium and several basolateral subregions. LDs were also identified for amygdala RVFs (ranging from 30% to 82% variance explained), with PM2.5 and component co-exposure associated with increases in lateral, but decreases in medial and central, RVFs. Conclusions: Fine particulate and its components are linked with distinct amygdala differences, potentially playing a role in risk for adolescent mental health problems.

Stereotype of mouse social competency and status revealed by a novel competition paradigm in combination with available paradigms
With the acceleration of urbanization process, psychological, behavioral and biological studies on social organization and competition are boosting. The mouse has been recognized as valuable and economic model animal for biomedical research in social behaviors, but the application of reliable, valid and easily executable social competition paradigm for mouse is still limited. Moreover, discrepant paradigms containing different competitive factors such as muscular confrontation, threatening level, boldness or timidity tendency might lead to task-specific win-or-lose outcomes and confusing rankings. Here, we developed a mouse competition behavioral paradigm in which contenders were a pair of mice eager to take over the same food pellet hidden under a movable block in the middle of a narrow chamber where they were separated to the either right or left side. Our design mentality of this food pellet competition test (FPCT) allows experimenter to operate conveniently, avoids the direct violent competition between mice and facilitates to expose the psychological motivation of the contenders. Application of FPCT in combination with typically available paradigms, tube test and warm spot test (WST), discovered a stereotypic property of mouse social organization and competitivity in a given society of either males or females that were raised in an either 2- or 3-member cage, indicating that hierarchical sense of animals might be part of a comprehensive identify of self-recognition of individuals in an established society. More importantly, FPCT may largely facilitate the researches regarding the social organization and competition due to its reliability, validity and easy operability.

Uncovering locomotor learning dynamics in people with Parkinson's disease
Locomotor learning is important for improving gait and balance impairments in people with Parkinson's disease (PD). While PD disrupts neural networks involved in motor learning, there is a limited understanding of how PD influences the time course of locomotor learning and retention. Here, we used a virtual obstacle negotiation task to investigate whether the early stages of PD affect the acquisition and retention of locomotor skills. On Day 1, 15 participants with PD and 20 age-matched controls were instructed to achieve a specified level of foot clearance while repeatedly stepping over two different virtual obstacles on a treadmill. We assessed online performance improvement on Day 1 and overnight retention after at least 24 hours on Day 2. We used a hierarchical Bayesian state-space model to estimate the learning rate and the degree of interference between the two obstacles. There was a 93% probability that people with PD learned the locomotor skill faster than controls, but there was limited evidence of group differences in interference between the two heights of obstacles. Both groups improved their performance to a similar magnitude during skill acquisition and performed similarly during retention on Day 2. Notably, a slower learning rate was associated with greater online performance improvement, while lower interference was linked to better overnight retention, and this effect was strongest for the control group. These results highlight that people with early-stage PD retain the ability to use multisensory information to acquire and retain locomotor skills. In particular, our finding that people with early-stage PD learned faster than age-matched controls may reflect the emergence of compensatory motor learning strategies used to offset early motor impairments in people with PD.

Gut bacteria-derived succinate induces enteric nervous system regeneration
Enteric neurons control gut physiology by regulating peristalsis, nutrient absorption, and secretion. Disruptions in microbial communities caused by antibiotics or enteric infections result in the loss of enteric neurons and long-term motility disorders. However, the signals and underlying mechanisms of this microbiota-neuron communication are unknown. We studied the effects of microbiota on the recovery of the enteric nervous system after microbial dysbiosis caused by antibiotics. We found that both enteric neurons and glia are lost after antibiotic exposure, but recover when the pre-treatment microbiota is restored. Using murine gnotobiotic models and fecal metabolomics, we identified neurogenic bacterial species and their derived metabolite succinate as sufficient to rescue enteric neurons and glia. Unbiased single-nuclei RNA-seq analysis uncovered a novel neural precursor-like population marked by the expression of the neuronal gene Nav2. Genetic fate-mapping showed that Plp1+ enteric glia differentiate into neurons following antibiotic exposure. In contrast, Nav2+ neurons expand upon succinate treatment and indicate an alternative mode of neuronal regeneration under recovery conditions. Our findings highlight specific microbial species, metabolites, and the underlying cellular mechanisms involved in neuronal regeneration, with potential therapeutic implications for peripheral neuropathies.

Adhesion G protein-coupled receptor ADGRG1 promotes protective microglial response in Alzheimer's disease
Germline genetic architecture of Alzheimer's disease (AD) indicates microglial mechanisms of disease susceptibility and outcomes. However, the mechanisms that enable microglia to mediate protective responses to AD pathology remain elusive. Adgrg1 is specifically expressed in yolk-sac-derived microglia. This study reveals the role of yolk-sac-derived microglia in AD pathology, highlighting the function of ADGRG1 in modulating microglial protective responses to amyloid deposition. Utilizing both constitutive and inducible microglial Adgrg1 knockout 5xFAD models, we demonstrate that Adgrg1 deficiency leads to increased amyloid deposition, exacerbated neuropathology, and accelerated cognitive impairment. Transcriptomic analyses reveal a distinct microglial state characterized by downregulated genes associated with homeostasis, phagocytosis, and lysosomal functions. Functional assays in mouse models and human embryonic stem cells-derived microglia support that microglial ADGRG1 is required for efficient A{beta} phagocytosis. Together, these results uncover a GPCR-dependent microglial response to A{beta}, pointing towards potential therapeutic strategies to alleviate disease progression by enhancing microglial functional competence.

The infralimbic, but not the prelimbic cortex is needed for a complex olfactory memory task.
The medial prefrontal cortex (mPFC) plays a key role in memory and behavioral flexibility, and a growing body of evidence suggests that the prelimbic (PL) and infralimbic (IL) subregions contribute differently to these processes. Studies of fear conditioning and goal-directed learning suggest that the PL promotes behavioral responses and memory retrieval, while the IL inhibits them. Other studies have shown that the mPFC is engaged under conditions of high interference. This raises the possibility that the PL and IL play differing roles in resolving interference. To examine this, we first used chemogenetics (DREADDs) to suppress mPFC neuronal activity and tested subjects on a conditional discrimination task known to be sensitive to muscimol inactivation. After confirming the effectiveness of the DREADD procedures, we conducted a second experiment to examine the PL and IL roles in a high interference memory task. We trained rats on two consecutive sets of conflicting odor discrimination problems, A and B, followed by test sessions involving a mid-session switch between the problem sets. Controls repeatedly performed worse on Set A, suggesting that learning Set B inhibited the rats' ability to retrieve Set A memories (i.e. retroactive interference). PL inactivation rats performed similarly to controls. However, IL inactivation rats did not show this effect, suggesting that the IL plays a critical role in suppressing the retrieval of previously acquired memories that may interfere with retrieval of more recent memories. These results suggest that the IL plays a critical role in memory control processes needed for resolving interference.

Neuropeptide Dynamics Coordinate Layered Plasticity Mechanisms Adapting Drosophila Circadian Behavior to Changing Environment.
The Drosophila brain contains distinct sets of circadian oscillators responsible for generating the morning and evening bouts of locomotor activity, giving rise to a bimodal rest-activity pattern in light-dark cycles. We lack a mechanistic understanding of how environmental changes reshape this daily profile of rest-activity pattern. Here, we uncover a seasonal switch mechanism that remodels the evening bout of activity. Under summer-like conditions, an environment favored by fruit flies in temperate climates, levels of the PDF neuropeptide diminish, triggering a cascade. Lowered PDFR signaling disinhibits GSK3/SGG to advance the evening output. Upon sensing PDF loss, the neural activity weakens in the DN1p-SIFa circuit, responsible for promoting afternoon rest; leading to an earlier appearance of the evening peak. At the same time, the functional connections from DN1p to LNd oscillators strengthen, consequently handing over the evening pacemaker role to the DN1ps. Taken together, our findings elucidate how environment-induced changes in PDFR signaling tip the balanced output of the clock network, aligning daily rhythms with seasonal time. Neuropeptide-driven parallel adjustment of clock circuitry and clock protein functioning likely represents a conserved strategy across animal species, enabling them to adapt their daily behavior to seasonal changes throughout the year.

Integrated temporal profiling of iPSCs-derived motor neurons from ALS patients carrying C9orf72, FUS, TARDBP, and SOD1 mutations
Amyotrophic Lateral Sclerosis (ALS) is a lethal neurodegenerative disease that damages motor neurons in the central nervous system, causing progressive muscle weakness that ultimately leads to death. However, its underlying mechanisms still need to be fully understood, particularly the heterogeneity and similarity between various gene mutants during disease progression. In this study, we conducted temporal RNA-seq profiling in human induced pluripotent stem cells (hiPSCs) and iPSC-derived motor neurons (iMNs) carrying the C9orf72, FUS, TARDBP, and SOD1 mutations from both ALS patients and healthy individuals. We discovered dysregulated gene expression and alternative splicing (AS) throughout iMN development and maturation, and ALS iMNs display enrichment of cytoskeletal defects and synaptic alterations from premature stage to mature iMNs. Our findings indicate that synaptic gene dysfunction is the common molecular hallmark of fALS, which might result in neuronal susceptibility and progressive motor neuron degeneration. Analysis of upstream splicing factors revealed that differentially expressed RNA-binding proteins (RBPs) in ALS iMNs may cause abnormal AS events, suggesting the importance of studying RBP defects in ALS research. Overall, our research provides a comprehensive and valuable resource for gaining insights into the shared mechanisms of ALS pathogenesis during motor neuron development and maturation in iMN models.

Epigenetic derepression of H3K9me3 mitigates Alzheimer-related pathology and improves cognition via immunomodulation and Vgf induction
We investigated the role of histone 3 lysine 9 trimethylation (H3K9me3), an epigenetic mechanism involved in the repression of synaptic plasticity and memory-related genes, within aging and Alzheimer's disease (AD). Our study reveals that elevated cortical H3K9me3 strongly correlates with cognitive dysfunction in individuals with mild cognitive impairment (MCI) and AD. In old (18 months) and younger (14 months) APPSWE/PS1{Delta}E9 and 3xTg AD mouse models, inhibiting SUV39H1 methyltransferase with ETP69, substantially reduces cerebral H3K9me3 levels and attenuates amyloid-{beta} burden, tau pathology, and gliosis. Administration of ETP69 further promotes dendritic spine formation, leading to rapid and sustained improvements in cognitive function. Proteomics analysis indicates that a significant proportion of dysregulated proteins in the brains of AD-model mice are reversed by ETP69. These proteins are enriched for synaptic plasticity and learning-related pathways. ETP69 exerts its effects through multiple neuroprotective mechanisms, including regulation of neuroinflammation, induction of both blood and cerebral-infiltrating monocytes involved in cerebral A{beta} clearance. Moreover, ETP69 activates brain-derived neurotrophic factor (Bdnf) network, and particularly its downstream effector neurosecretory protein Vgf. These findings support the pharmacological inhibition of H3K9me3-mediated gene silencing to reverse AD-related pathology and cognitive decline.

IOP-induced blood-retinal barrier compromise contributes to RGC death in glaucoma
The integrity of the blood-retinal barrier (BRB) has been largely unexplored in glaucoma. We reveal that elevated intraocular pressure (IOP) partially compromises the BRB in two human-relevant inherited mouse models of glaucoma (DBA/2J and Lmx1bV265D). Experimentally increasing IOP in mouse eyes further confirms this. Notably, the compromise induces subtle leakage, happening without bleeding or detected endothelial cell junction disruption, and it precedes neurodegeneration. Leakage occurs from peripheral veins in the retinal ganglion cell layer with a concomitant loss of the transcytosis inhibitor MFSD2A. Importantly, stabilizing {beta}-catenin in retinal endothelial cells prevents both vascular leakage and neurodegeneration in the DBA/2J model. The occurrence of leakage in all 3 high IOP models indicates that BRB compromise may be a common, yet overlooked, mechanism in glaucoma. These findings suggest that IOP-induced BRB compromise plays a critical role in glaucoma, offering a new therapeutic target.

Glial cell derived pathway directs regenerating optic nerve axons toward the CNS midline
Several RGC intrinsic signaling pathways have been shown to enhance RGC survival and RGC axonal growth after optic nerve injury. Yet an unresolved challenge for regenerating RGC axons is to properly navigate the optic chiasm located at the Central Nervous System midline. Here, we use live-cell imaging in larval zebrafish to show that regrowing RGC axons initiate growth toward the midline and extend along a trajectory similar to their original projection. From a candidate genetic screen, we identify the glycosyltransferase Lh3 to be required during the process of regeneration to direct regrowing RGC axons toward the midline. Moreover, we find that mutants in collagen 18a1 (col18a1), a putative Lh3 substrate, display RGC axonal misguidance phenotypes similar to those we observe in lh3 mutants, suggesting that lh3 may act through col18a1 during regeneration. Finally, we show that transgenic lh3 expression in sox10+ presumptive olig2+ oligodendrocytes located near the optic chiasm restores directed axonal growth. Combined these data identify lh3 and col18a1 as part of a glial derived molecular pathway critical for guiding in vivo regenerating RGC axons towards and across the optic chiasm.

Distinct neuronal processes in the ventromedial prefrontal cortex mediate changes in attention load and nicotine pro-cognitive effects
The prefrontal cortex (PFC) plays a key role in attention. In particular, neuronal activity in the ventromedial PFC (vmPFC) has been implicated in the preparatory attentional period that immediately precedes cue presentation. However, whether vmPFC neuronal activity during this preparatory period is also sensitive to changes in task demand and to the pro-cognitive effects of nicotine remained to be investigated. Here, we used in vivo electrophysiology to record vmPFC neuronal activity during two distinct manipulations: a task manipulation that increased task demand by reducing the cue stimulus duration (from 1s to 0.5s), and a pharmacological manipulation by administrating an acute nicotine injection (10 ug/inj, i.v.) before the session. We found that increasing task demand decreased attentional performances and vmPFC precue neuronal activity, but had no effect on gamma oscillations. In contrast, nicotine injection increased attention and gamma oscillations, but almost abolished vmPFC phasic precue responses. Together, these findings indicate the existence of two distinct neuronal mechanisms operating at different timescales and suggests that allocation of attention could be achieved through multiple complementary neuronal mechanisms within the vmPFC.

Sensorimotor integration enhances temperature stimulus processing
Animals optimize behavior by integrating sensory input with motor actions. We hypothesized that coupling thermosensory information with motor output enhances the brain's capacity to process temperature changes, leading to more precise and adaptive behaviors. To test this, we developed a virtual "thermal plaid" environment where zebrafish either actively controlled temperature changes (sensorimotor feedback) or passively experienced the same thermal fluctuations. Our findings demonstrate that sensorimotor feedback amplifies the influence of thermal stimuli on swim initiation, resulting in more structured and organized motor output. We show that previously identified mixed-selectivity neurons that simultaneously encode thermal cues and motor activity enable the integration of sensory and motor feedback to optimize behavior. These results highlight the role of sensorimotor integration in refining thermosensory processing, revealing critical neural mechanisms underlying flexible thermoregulatory behavior. Our study offers new insights into how animals adaptively process environmental stimuli and adjust their actions, contributing to a deeper understanding of the neural circuits driving goal-directed behavior in dynamic environments.

Temporary cerebral ischaemia impairs thromboxane A2 constriction and induces hypertrophic remodelling in peripheral mesenteric arteries of hypertensive rats: limited reversal despite long-term suberoylanilide hydroxamic acid cerebroprotection
Stroke induces brain injury, especially severe in hypertensive patients, and elevates mortality rates through non-neurological complications. However, the potential effects of a transient ischaemic episode on the peripheral vasculature of hypertensive individuals remain unclear. Here, we investigated whether transient cerebral ischaemia (90 min)/reperfusion (1 or 8 days) induces alterations in mesenteric resistance artery (MRA) properties in adult male spontaneously hypertensive rats (SHR). In addition, we assessed whether the reported cerebroprotective effects of suberoylanilide hydroxamic acid (SAHA; 50 mg/kg; administered intraperitoneally at 1, 4, or 6 h after reperfusion onset) extend long-term and include beneficial effects on MRAs. Functional and structural properties of MRAs were examined at 1- and 8-days post-stroke. Nuclei distribution, collagen content, and oxidative stress were assessed. Ischaemic brain damage was evaluated longitudinally using magnetic resonance imaging. Following stroke, MRAs from SHR exhibited non-reversible impaired contractile responses to the thromboxane A2 receptor agonist U46619. Stroke increased the MRA cross-sectional area, wall thickness, and wall/lumen ratio due to augmented collagen deposition. These changes were partially sustained 8 days later. SAHA did not improve U46619-induced contractions but mitigated stroke-induced oxidative stress and collagen deposition, preventing MRA remodelling at 24 h of reperfusion. Furthermore, SAHA induced sustained cerebroprotective effects over 8 days, including reduced brain infarct and oedema, and improved neurological scores. However, SAHA had minimal impact on chronic MRA contractile impairments and remodelling. These findings suggest that stroke causes MRA changes in hypertensive subjects. While SAHA treatment offers long-term protection against brain damage, it cannot fully restore MRA alterations.

Human Astrocytes Synchronize Neural Organoid Networks
Biological neural networks exhibit synchronized activity within and across interconnected regions of the central nervous system. Understanding how these coordinated networks are established and maintained may reveal therapeutic targets for neurodegeneration and neuromodulation. Here, we tested the influence of astrocytes upon synchronous network activity using human pluripotent stem cell-derived bioengineered neural organoids. This study revealed that astrocytes significantly increase activity within individual organoids and across long distances among numerous rapidly merged organoids via influencing synapses and bioenergetics. Treatment of amyloid protein inhibited synchronous activity during neurodegeneration, yet this can be rescued by propagating activity from neighboring networks. Altogether, this study identifies critical contributions of human astrocytes to biological neural networks and delivers a rapid, reproducible, and scalable model to investigate long-range functional communication of the nervous system in healthy and disease states.

Primary cilia shape postnatal astrocyte development through Sonic Hedgehog signaling
Primary cilia function as specialized signaling centers that regulate many cellular processes including neuron and glia development. Astrocytes possess cilia, but the function of cilia in astrocyte development remains largely unexplored. Critically, dysfunction of either astrocytes or cilia contributes to molecular changes observed in neurodevelopmental disorders. Here, we show that a sub-population of developing astrocytes in the prefrontal cortex are ciliated. This population corresponds to proliferating astrocytes and largely expresses the ciliary protein ARL13B. Genetic ablation of astrocyte cilia in vivo at two distinct stages of astrocyte development results in changes to Sonic Hedgehog (Shh) transcriptional targets. We show that Shh activity is decreased in immature and mature astrocytes upon loss of cilia. Furthermore, loss of cilia in immature astrocytes results in decreased astrocyte proliferation and loss of cilia in mature astrocytes causes enlarged astrocyte morphology. Together, these results indicate that astrocytes require cilia for Shh signaling throughout development and uncover functions for astrocyte cilia in regulating astrocyte proliferation and maturation. This expands our fundamental knowledge of astrocyte development and cilia function to advance our understanding of neurodevelopmental disorders.

FBXW7 regulates MYRF levels to control myelin capacity and homeostasis in the adult CNS
Myelin, along with the oligodendrocytes (OLs) that produce it, is essential for proper central nervous system (CNS) function in vertebrates. Although the accurate targeting of myelin to axons and its maintenance are critical for CNS performance, the molecular pathways that regulate these processes remain poorly understood. Through a combination of zebrafish genetics, mouse models, and primary OL cultures, we found FBXW7, a recognition subunit of an E3 ubiquitin ligase complex, is a regulator of adult myelination in the CNS. Loss of Fbxw7 in myelinating OLs resulted in increased myelin sheath lengths with no change in myelin thickness. As the animals aged, they developed progressive abnormalities including myelin outfolds, disrupted paranodal organization, and ectopic ensheathment of neuronal cell bodies with myelin. Through biochemical studies we found that FBXW7 directly binds and degrades the N-terminal of Myelin Regulatory Factor (N-MYRF), to control the balance between oligodendrocyte myelin growth and homeostasis.

Differential reconfiguration of brain networks in children in response to standard versus rewarded go/no-go task demands
Response inhibition and sustained attention are critical for higher-order cognition and rely upon specific patterns of functional brain network organization. This study investigated how functional brain networks reconfigure to execute these cognitive processes during a go/no-go task with and without the presence of rewards in 26 children between the ages of 8 and 12 years. First, we compared task performance between standard and rewarded versions of a go/no-go task. We found that the presence of rewards reduced commission error rate, a measure considered to indicate improved response inhibition. Tau, thought to index sustained attention, did not change across task conditions. Next, changes in functional brain network organization were assessed between the resting state, the standard go/no-go task, and the rewarded go/no-go task. Relative to the resting state, integration decreased and segregation increased during the standard go/no-go task. A further decrease in integration and increase in segregation was observed when rewards were introduced. These patterns of reconfiguration were present globally and across several key brain networks of interest, as well as in individual regions implicated in the processes of response inhibition, attention, and reward processing. These findings align with patterns of brain network organization found to support the cognitive strategy of sustained attention, rather than response inhibition, during go/no-go task performance and suggest that rewards enhance this organization. Overall, this study used large-scale brain network organization and a within-subjects multi-task design to examine different cognitive strategies and the influence of rewards on response inhibition and sustained attention in late childhood.

Chronic recording of brain activity in awake toads
Background Amphibians represent an important evolutionary transition from aquatic to terrestrial environments and they display a large variety of complex behaviors despite a relatively simple brain. However, their brain activity is not as well characterized as that of many other vertebrates, partially due to physiological traits that have made electrophysiology recordings difficult to perform in awake and moving animals. New method We implanted flexible mesh electronic recording units in the cane toad (Rhinella marina) and performed extracellular recordings in the telencephalon of anesthetized toads and partially restrained, awake toads over multiple days. Results We recorded brain activity over five consecutive days in awake toads and over a 15 week period in a toad that was anesthetized during recordings. We were able to perform spike sorting and identified single- and multi-unit activity in all toads. Comparison with existing methods To our knowledge, this is the first report of a modern method to perform electrophysiology in non-paralyzed toads over multiple days, though there are historical references to short term recordings in the past. Conclusions Implementing flexible mesh electronics in amphibian species will allow for advanced studies of the neural basis of amphibian behaviors.

Prolonged Hyperactivity Elicits Massive and Persistent Chloride Ion Redistribution in Subsets of Cultured Hippocampal Dentate Granule Cells
Chloride ions play a critical role in neuronal inhibition through the activity of chloride-permeable GABAA receptor channels. Ion transporters, chloride channels, and immobile ion species tightly regulate intracellular chloride concentrations. Several studies related to epilepsy suggest that chloride extrusion function may decrease in an activity-dependent manner. Consequently, it is crucial to investigate whether intense neuronal activity, as observed during status epilepticus, could lead to sustained increases in intracellular chloride levels in neurons, which in turn could contribute to epilepsy-associated hyperexcitability. This study utilized the chloride sensitive indicator (6-Methoxyquinolinio) acetic acid ethyl ester bromide (MQAE) combined with fluorescence lifetime imaging (FLIM) to examine whether application of the convulsant, pilocarpine, a muscarinic acetylcholine receptor agonist, could induce synchronous epileptiform activity and elevate intracellular chloride concentrations in hippocampal slice cultures. Using a Gaussian mixture model, we identified a multimodal distribution of intracellular chloride levels among neurons, with a significant subset of these cells exhibiting massive and prolonged (days) chloride accumulation. The combination of multicellular imaging and statistical analysis served as a powerful tool for studying the emergence of multiple, distinct populations of neurons in pathological conditions, in contrast to homogeneous populations evident under control conditions.

Dark Microglia Are Abundant in Normal Postnatal Development, where they Remodel Synapses via Phagocytosis and Trogocytosis, and Are Dependent on TREM2
This study examined dark microglia-a state linked to central nervous system pathology and neurodegeneration-during postnatal development in the mouse ventral hippocampus, finding that dark microglia interact with blood vessels and synapses and perform trogocytosis of pre-synaptic axon terminals. Furthermore, we found that dark microglia in development notably expressed C-type lectin domain family 7 member A (CLEC7a), lipoprotein lipase (LPL) and triggering receptor expressed on myeloid cells 2 (TREM2) and required TREM2, differently from other microglia, suggesting a link between their role in remodeling during development and central nervous system pathology. Together, these results point towards a previously under-appreciated role for dark microglia in synaptic pruning and plasticity during normal postnatal development.

Real-cyber hybrid neural network for predicting neural circuits in mouse decision-making
A major function of the brain is to make decisions by moving the physical body according to sensory inputs. Previous studies have described the development of artificial neural networks (ANNs) to model decision-making circuits and compared the activity of artificial units with that of real neurons in animals. Here, we developed a real-cyber hybrid neural network (HNN) that directly uses the activity of real neurons as the inputs of an ANN to predict the body movements of head-fixed mice during a task. Using spike inputs from cortical or subcortical regions, especially the parietal cortex, the HNN predicted body movements better than the ANN did. The activities of the artificial units of the HNN were aligned with the onset of sounds and choices and decoded the choices of the mice, which was consistent with the behavior of the mouse neurons. The artificial units of the HNN compensated for unrecorded mouse neural activity. We propose that HNNs develop brain-like activity to predict animal movements by compensating for unrecorded neural activity.

Corticostriatal Maldevelopment in the R6/2 Mouse Model of Juvenile Huntington Disease
There is a growing consensus that brain development in Huntington disease (HD) is abnormal, leading to the idea that HD is not only a neurodegenerative but also a neurodevelopmental disorder. Indeed, structural and functional abnormalities have been observed during brain development in both humans and animal models of HD. However, a concurrent study of cortical and striatal development in a genetic model of HD is still lacking. Here we report significant alterations of corticostriatal development in the R6/2 mouse model of juvenile HD. We examined wildtype (WT) and R6/2 mice at postnatal (P) days 7, 14, and 21. Morphological examination demonstrated early structural and cellular alterations reminiscent of malformations of cortical development, and ex vivo electrophysiological recordings of cortical pyramidal neurons (CPNs) demonstrated significant age- and genotype-dependent changes of intrinsic membrane and synaptic properties. In general, R6/2 CPNs had reduced cell membrane capacitance and increased input resistance (P7 and P14), along with reduced frequency of spontaneous excitatory and inhibitory synaptic events during early development (P7), suggesting delayed cortical maturation. This was confirmed by increased occurrence of GABAA receptor-mediated giant depolarizing potentials at P7. At P14, the rheobase of CPNs was significantly reduced, along with increased excitability. Altered membrane and synaptic properties of R6/2 CPNs recovered progressively, and by P21 they were similar to WT CPNs. In striatal medium-sized spiny neurons (MSNs), a different picture emerged. Intrinsic membrane properties were relatively normal throughout development, except for a transient increase in membrane capacitance at P14. The first alterations in MSNs synaptic activity were observed at P14 and consisted of significant deficits in GABAergic inputs, however, these also were normalized by P21. In contrast, excitatory inputs began to decrease at this age. We conclude that the developing HD brain is capable of compensating for early developmental abnormalities and that cortical alterations precede and are a main contributor of striatal changes. Addressing cortical maldevelopment could help prevent or delay disease manifestations.

EEG markers of vigilance, task-induced fatigue and motivation during sustained attention: Evidence for decoupled alpha- and beta-signatures
Reduced vigilance can be captured in measures of attentional lapses in sustained attention tasks, but just how these lapses relate to task-induced fatigue and motivation to maintain optimal performance is unclear. We used the sustained attention to response task (SART) to induce fatigue, and manipulated motivation levels for the last block of the task in young and older participants (N = 34), while recording EEG to track electrophysiological markers of vigilance change, fatigue and motivation. Despite significant increases in subjective fatigue and mind wandering over 45 minutes, no vigilance decline was observed. However, the age groups differed markedly in their response strategies from the outset (adopting distinct speed-accuracy trade-off strategies) with faster/more erroneous responses in the younger and slower/more accurate responses in the older participants. The subjective rises in fatigue/mind wandering were coupled with an increase in pre-stimulus alpha-power, whereas the post-stimulus activity revealed two distinguishable beta signatures: a fronto-central topography as a marker of response strategy and a fronto-parietal distribution modulated by motivation per se. Our results thus show three distinct neural patterns underpinning the effects of fatigue, response strategy and motivation and suggest a (motivational) cognitive control mechanism behind resetting of performance decrement, independent of persistent fatigue.

Computational generation of long-range axonal morphologies
Long-range axons are fundamental to brain connectivity and functional organization, enabling communication between different regions of the brain. Recent advances in experimental techniques have yielded a substantial number of whole-brain axonal reconstructions. While most previous computational generative models of neurons have predominantly focused on dendrites, generating realistic axonal morphologies is challenging due to their distinct targeting. In this study, we present a novel algorithm for axon synthesis that combines algebraic topology with the Steiner tree algorithm, an extension of the minimum spanning tree, to generate both the local and long-range compartments of axons. We demonstrate that our computationally generated axons closely replicate experimental data in terms of their morphological properties. This approach enables the generation of biologically accurate long-range axons that span large distances and connect multiple brain regions, advancing the digital reconstruction of the brain. Ultimately, our approach opens up new possibilities for large-scale in-silico simulations, advancing research into brain function and disorders.

Stimulus-dependent delay of perceptual filling-in by microsaccades
Perception is a function of both stimulus features and active sensory sampling. The illusion of perceptual filling-in occurs when eye gaze is kept still: visual boundary perception may fail, causing adjacent visual features to remarkably merge into one uniform visual surface. Microsaccades--small, involuntary eye movements during gaze fixation--counteract perceptual filling-in, but the mechanisms underlying this process are not well understood. We investigated whether microsaccade efficacy for preventing filling-in depends on two boundary properties, color contrast and retinal eccentricity (distance from gaze center). Twenty-one participants fixated on a point until they experienced filling-in between two isoluminant colored surfaces. We found that increased color contrast independently extends the duration before filling-in but does not alter the impact of individual microsaccades. Conversely, lower eccentricity delayed filling-in only by increasing microsaccade efficacy. We propose that microsaccades facilitate stable boundary perception via a transient retinal motion signal that scales with eccentricity but is invariant to boundary contrast. These results shed light on how incessant eye movements integrate with ongoing stimulus processing to stabilize perceptual detail, with implications for visual rehabilitation and the optimization of visual presentations in virtual and augmented reality environments.

Macrophage crosstalk with neural progenitors and fibroblasts controls regenerative neurogenesis via Sema4ab after spinal cord injury in zebrafish
After spinal cord injury, interactions of multiple tissues inhibit neuronal regeneration in mammals, but not in anamniotes, such as zebrafish. These pivotal interactions are poorly understood. Here we analyse the role of the cell signalling molecule sema4ab in the cell communication network leading to regenerative neurogenesis after spinal injury in larval zebrafish. Sema4ab is expressed by macrophages and gene ablation doubles the rate of regenerative neurogenesis. Disruption of the sema4ab receptor plxnb1a/b, expressed by spinal progenitor cells, also moderately increases regenerative neurogenesis. In addition, single cell transcriptomics reveals altered interactions between macrophages and multiple additional cell types after sema4ab disruption. Pro-inflammatory cytokines are down-regulated and fibroblasts upregulate expression of the anti-inflammatory cytokine tgfb3. Inhibition of tgfb3 abolishes effects of sema4ab disruption on regenerative neurogenesis. This highlights sema4ab as a direct and indirect inhibitor of regenerative neurogenesis and as a potential therapeutic target in non-regenerating mammals.

CXCL10/CXCR3 Signaling Induces Neural Senescence and Cognitive Impairments
Chemokine receptors belong to the G-protein-coupled receptors family, and multiple lines of emerging evidence suggest that several chemokines are elevated in aging associated with central nervous system disorders. Increased level of CXCL10 in the central nervous system is reported in several neurodegenerative diseases, including Multiple sclerosis, Alzheimer's disease, and Virus-associated dementia. We also observed significantly increased expression of CXCL10 and CXCR3 in the prefrontal cortex and hippocampus of aged C57BL/6J mice (12- and 18-month-old mice). This leads us to hypothesize that CXCL10, being a component of SASPs, may aggravate/perpetuate the brain aging process and, finally, neurodegenerative diseases. To test this hypothesis, we administered CXCL10 (intracerebroventricular: ICV, 0.5 pg/ hrs, 28 days) in 8-month-old C57BL/6J mice. We observed increased expression of senescent marker proteins p16INK4a, p21Cip1, and p53 and decreased expression of pRB in the prefrontal cortex, which was blocked by CXCR3-specific antagonist AMG487. Furthermore, chronic infusion of CXCL10 induced learning and memory deficits in Y-maze, social recognition and contextual freeze tests, and c-FOS expression in the prefrontal cortex. To further determine the specificity of CXCL10/CXCR3 signaling, we treated the primary cortical neuron (Days in vitro: DIV 7-8) with CXCL10 and found increased senescence in CXCR3 dependent fashion. Using GFP-RFP-LC3{beta} transgenic mice, we also showed CXCL10/CXCR3 signaling attenuates autophagic flux in primary cortical neurons. Lastly, using a c-FOS-iRFP reporter, we observed that increased CXCL10/CXCR3 signaling impairs glutamatergic signaling in primary cortical neurons. These results support the hypothesis that increased CXCL10/CXCR3 facilitates brain aging and could be targeted for the management of aging-associated CNS disorders.

Astrocytic Ryk signaling coordinates scarring and wound healing after spinal cord injury
Wound healing after spinal cord injury involves highly coordinated interactions among multiple cell types, which is poorly understood. Astrocytes play a central role in creating a border against the non-neural lesion core. To do so, astrocytes undergo dramatic morphological changes by first thickening the processes and then elongating and overlap them. We show here show that the expression of a cell-surface receptor, Ryk, is induced in astrocytes after injury in both rodent and human spinal cord. Astrocyte-specific knockout of Ryk dramatically elongated the reactive astrocytes and accelerated the formation of the border and reduced the size of the scar. Astrocyte-specific knockout of Ryk also accelerated the injury responses of multiple cell types, including the resolution of neuroinflammation. Single cell transcriptomics analyses revealed a broad range of changes cell signaling among astrocytes, microglia, fibroblasts, endothelial cell, etc, after astrocyte-specific Ryk knockout, suggesting that Ryk not only regulates the injury response of astrocytes but may also regulate signals which coordinate the responses of multiple cell types. The elongation is mediated by NrCAM, a cell adhesion molecule induced by astrocyte-specific conditional knockout of Ryk after spinal cord injury. Our findings suggest a promising therapeutic target to accelerate wound healing and promote neuronal survival and enhance functional recovery.

Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment
Microglia continually surveil the brain allowing for rapid detection of tissue damage or infection. Microglial metabolism is linked to tissue homeostasis, yet how mitochondria are subcellularly partitioned in microglia and dynamically reorganize during surveillance, injury responses, and phagocytic engulfment in the intact brain are not known. Here, we performed intravital imaging of microglia mitochondria, revealing that microglial processes diverge, with some containing multiple mitochondria while others are completely void. Microglial processes that engage in minute-to-minute surveillance typically do not have mitochondria. Moreover, unlike process surveillance, mitochondrial motility does not change with animal anesthesia. Likewise, the processes that acutely chemoattract to a lesion site or initially engage with a neuron undergoing programmed cell death do not contain mitochondria. Rather, microglia mitochondria have a delayed arrival into the responding cell processes. Thus, there is subcellular heterogeneity of mitochondrial partitioning and asymmetry between mitochondrial localization and cell process motility or acute damage responses.

Sleep-Induced Vasomotor Pulsation is a Driver of Cerebrospinal Fluid and Blood-Brain Barrier Dynamics in the Human Brain
Sleep is crucial for restoring and maintaining brain tissue homeostasis, primarily through enhanced transport of cerebrospinal fluid (CSF) solutes. Infra-slow (<0.1 Hz) vasomotion, CSF flow, and the electrical potential of blood-brain barrier (BBB) all increase during sleep. While these phenomena have been linked to CSF solute transport, there is little understanding of their interaction as potentials drivers of CSF flow. Therefore, we recorded these three signals in a group of healthy volunteers across sleep-wake states with simultaneous 10 Hz functional magnetic resonance imaging (fMRI) of blood oxygen level dependent (BOLD) contrast, direct current-coupled electroencephalography (DC-EEG), and functional near-infrared spectroscopy (fNIRS). We next investigated the directed coupling patterns between these linked processes according to phase transfer entropy (TE). In the awake state, the electrophysiological BBB potential and water fluctuations predicted vasomotor waves uniformly throughout the brain. In sleep state, results showed a reversal of the direction of this coupling in cerebral cortex, as vasomotor BOLD waves started predicting both CSF and BBB potential shifts. Our findings indicate that vasomotor waves become the primary driver of CSF hydrodynamics and BBB electrical potential in human brain during sleep.

Noninvasive optical monitoring of cerebral hemodynamics in a preclinical model of neonatal intraventricular hemorrhage
Intraventricular hemorrhage (IVH) is a common complication in premature infants and is associated with white matter injury and long-term neurodevelopmental disabilities. Standard diagnostic tools such as cranial ultrasound and MRI are widely used in both preclinical drug development and clinical practice to detect IVH. However, these methods only provide endpoint assessments of blood accumulation and lack real-time information about dynamic changes in ventricular blood flow. This limitation could potentially result in missed opportunities to advance drug candidates that may have protective effects against IVH. In this pilot study, we aimed to develop a noninvasive optical approach using diffuse correlation spectroscopy (DCS) to monitor real-time hemodynamic changes associated with hemorrhagic and sub-hemorrhagic events in a preclinical rabbit model of IVH. DCS measurements were conducted during the experimental induction of IVH, and results were compared with ultrasound and histological analysis to validate findings. Significant changes in hemodynamics were detected in all animals subjected to IVH-inducing procedures, including those that did not show clear positive results on ultrasound. The study revealed progressively elevated coefficients of variation in blood flow, particularly driven by increased oscillations within the 0.05-0.1 Hz frequency band. These hemodynamic changes were more pronounced in animals that developed IVH, as confirmed by ultrasound. Our findings suggest that real-time optical monitoring with DCS can provide critical insights into pathological blood flow changes, offering a more sensitive and informative tool for evaluating potential therapeutics in the context of IVH.

The combination of optogenetic-induced protein aggregation and proximity biotinylation assays strongly implicates endolysosomal proteins in the early stages of α-synuclein aggregation
Alpha-synuclein (-syn) aggregation is a defining feature of Parkinson's disease (PD) and related synucleinopathies. Despite significant research efforts focused on understanding -syn aggregation mechanisms, the early stages of this process remain elusive, largely due to limitations in experimental tools that lack the temporal resolution to capture these dynamic events. Here, we introduce UltraID-LIPA, an innovative platform that combines the Light-Inducible Protein Aggregation (LIPA) system with the UltraID proximity-dependent biotinylation assay to identify -syn-interacting proteins and uncover key mechanisms driving its oligomerization. UltraID-LIPA successfully identified 38 -syn-interacting proteins, including both established and novel candidates, highlighting the accuracy and robustness of the approach. Notably, a strong interaction with endolysosomal and membrane-associated proteins was observed, supporting the hypothesis that interactions with membrane-bound organelles are pivotal in the early stages of -syn aggregation. This powerful platform provides new insights into dynamic protein aggregation events, enhancing our understanding of synucleinopathies and other proteinopathies.

Benchmarking Stroke Outcome Prediction through Comprehensive Data Analysis - NeuralCup 2023
Stroke is a significant cause of mortality and long-term disability worldwide, with variable recovery trajectories posing substantial challenges in anticipating post-event care and rehabilitation planning. The NeuralCup 2023 consortium was established to address these challenges by comparing the predictability of stroke outcome models through a collaborative, data-driven approach. This study presents the consortium's findings, which involved 15 participating teams worldwide. Using a comprehensive dataset, which included clinical and imaging data, we conducted an open competition to identify and compare predictors of motor, cognitive, and neuropsychological (emotional) outcomes one-year post-stroke. Analyses incorporated both traditional and novel methods, including machine learning algorithms. These efforts culminated in the search for 'optimal recipes' for predicting each domain through an exhaustive exploration of the features of all the approaches. Key predictors included lesion characteristics, T1-weighted MRI sequences, and demographic factors. Notably, integrating FLAIR imaging and white matter tract analysis emerged as crucial to improving the accuracy of cognitive and motor outcome predictions, respectively. These findings advocate for a tailored, multifaceted approach to stroke outcome prediction, underscoring the potential of collaborative data science in addressing complex neurological prognostication challenges. This study also sets a new benchmark methodology in stroke research, offering a foundational step toward personalized care strategies that could significantly impact recovery planning and quality of life for stroke survivors.

Coupling Between Functionality and Trafficking to the Axon Initial Segment in KCNQ2/3 K+ Channels
KCNQ2/3 are the predominant voltage-gated K+ channels localized at the axon initial segment (AIS), the critical site for the initiation of action potentials and the plasticity of excitability. Both the functionality and spatial distribution of KCNQ2/3 provide the basis for the regulation of neuronal excitability and the pathogenesis of various neurological disorders, including epilepsy. However, less is known about how functionality is coupled with trafficking regulation in KCNQ2/3. Here, we study the AIS localization of KCNQ2/3 by performing both multiple- and single-molecule imaging analyses. We found that low-activity mutations in the KCNQ3 subunit affect all of the 3D dynamics composed of lateral diffusion and exo/endocytosis processes through disruption of interaction with ankyrin-G, consequently suppressing the AIS targeting of KCNQ2/3. Thus, the functionality of KCNQ2/3 is coupled with its trafficking regulation, enhancing our understanding of the mechanisms underlying physiological and pathophysiological changes in neuronal excitability.

Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease
TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models of C9ORF72-related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimers disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, however, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a profound relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimers disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals essential considerations that must be taken when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.

An AI-Driven Model of Consciousness, Its Disorders, and Their Treatment
Understanding the neural signatures of consciousness and the mechanisms underlying its disorders, such as coma and unresponsive wakefulness syndrome, remains a critical challenge in neuroscience. In this study, we present a novel computational approach for the in silico discovery of neural correlates of consciousness, the mechanisms driving its disorders, and potential treatment strategies. Inspired by generative adversarial networks, which have driven recent advancements in generative artificial intelligence (AI), we trained deep neural networks to detect consciousness across multiple brain areas and species, including humans. These networks were then integrated with a genetic algorithm to optimize a brain-wide mean-field model of neural electrodynamics. The result is a realistic simulation of conscious brain states and disorders of consciousness (DOC), which not only recapitulates known mechanisms of unconsciousness but also predicts novel causes expected to lead to these conditions. Beyond simulating DOC, our model provides a platform for exploring therapeutic interventions, specifically deep brain stimulation (DBS), which has shown promise in improving levels of awareness in DOC in over five decades of study. We systematically applied simulated DBS to various brain regions at a wide range of frequencies to identify an optimal paradigm for reigniting consciousness in this cohort. Our findings suggest that in addition to previously studied thalamic and pallidal stimulation, high-frequency stimulation of the subthalamic nucleus, a relatively underexplored target in DOC, may hold significant promise for restoring consciousness in this set of disorders.

Partial Correlation as a Tool for Mapping Functional-Structural Correspondence in Human Brain Connectivity
Brain structure-function coupling has been studied in health and disease by many different researchers in recent years. Most of the studies have addressed functional connectivity matrices by estimating correlation coefficients between different brain areas, despite well-known disadvantages compared to partial correlation connectivity matrices. Indeed, partial correlation represents a more sensible model for structural connectivity since, under a Gaussian approximation, it accounts only for direct dependencies between brain areas. Motivated by this and following previous results by different authors, we investigate structure-function coupling using partial correlation matrices of functional magnetic resonance imaging (fMRI) brain activity time series under different regularization (a.k.a. noise-cleaning) algorithms. We find that, across different algorithms and conditions, partial correlation provides a higher match with structural connectivity retrieved from Density Weighted Imaging data than standard correlation, and this occurs at both subject and population levels. Importantly, we also show that the precise regularization and thresholding strategy are crucial for this match to emerge. Finally, we assess neuro-genetic associations in relation to structure-function coupling, which presents promising opportunities to further advance research in the field of network neuroscience, particularly concerning brain disorders.

Elucidating the neuropathological and molecular heterogeneity of amyloid-beta and tau in Alzheimer's disease through machine learning and transcriptomic integration
Discerning functional brain network variations related to neuropathological aggregates in Alzheimers disease (AD), including amyloid-{beta} (A{beta}) and phosphorylated tau (p-tau), is crucial for understanding their link to cognitive decline and underlying molecular mechanisms. However, these variations are often confounded by normal aging-related changes, complicating interpretation. To address this challenge, we first defined Alzheimers continuum cases (A{beta} positive (A+), n = 129) and normal elderly (A{beta} negative (A-), n = 160) using cerebral spinal fluid amyloid levels, and then applied a novel deep learning approach to resting-state connectivity using functional magnetic resonance imaging (fMRI) of the 289 subjects to disentangle A+-specific dimensions in brain network alterations from those shared with A- individuals. The identified A+-specific dimensions were further refined to predict individual A{beta} and p-tau levels separately. We observed that resulting brain signatures, defined from A+-specific dimensions for predicting these two CSF biomarkers, were both attributed to the right superior temporal and anterior cingulate cortices and associated with attention and memory domains. When linking the brain signatures to gene expression data from a public transcriptomic atlas, we found that the brain signatures were associated with molecular pathways involving synaptic dysfunction and disruptions in pathways containing activity of excitatory neurons, astrocytes, and microglia. For A--shared dimensions, the A{beta}-linked brain signature involved the left fusiform and right middle cingulate cortices, correlating with the language cognitive measurement and language-related molecular pathways. The p-tau-linked signature predominantly involved the right insula and inferior temporal cortices, correlating with the aging-related molecular pathways. Collectively, our findings provided new insights in understanding of Alzheimers continuum pathological biomarkers.

Development and validation of an open-source Hand Laterality Judgement Task for in-person and online studies
The Hand Laterality Judgement Task (HLJT) is considered a measure of the ability to manipulate motor images. The "biomechanical constraints" effect (longer reaction times for hand rotations towards anatomically difficult versus biomechanically easier movements) is considered the behavioural hallmark indicating motor imagery is being used. Previous work has used diverse HLJT paradigms, and there is no standardized procedure for the task. We developed an open-source, freely available version of the HLJT in PsychoPy2, which needs no programming skills and is highly customisable. Some studies suggest responding to the HLJT with the hands may interfere with performance, which would limit practical application of the task. We examined this potential issue using in-person and online versions. For the in-person version, 40 right-footed/handed individuals performed the HLJT with their feet or bimanually (N=20 each). For the online version, 60 right-handed individuals performed the task bimanually or unimanually (N=20 each). Bayesian mixed-effect analyses quantified the evidence for and against equivalence within and between the in-person and online versions. Both versions replicated previously described behavioural phenomena, including effects of angle, hand view, and the "biomechanical constraints" effect. While responding with different effectors modified overall reaction times, it did not interact with other factors analysed, and did not affect accuracy or the "biomechanical constraints" effect. There was also evidence for equivalence between in-person and online bimanual groups for all measures. We conclude that this open-source, standardized HLJT protocol (available at https://osf.io/8h7ec/) can reliably detect previously identified effects and works equally well in-person or online.

Abstract choice representations during stable choice-response associations
Perceptual decisions have long been framed in terms of the actions used to report a choice. Accordingly, studies of perceptual decision-making have historically relied on tasks with fixed choice-response mappings, in which choice and motor response are inextricably linked. Although several studies have since dissociated choice and response, they have typically involved dynamic switching of the choice-response mapping on a trial-by-trial basis. Thus, it remains unclear if abstract choice representations arise specifically when choice-response relationships change dynamically, or if they reflect a more general property of the decision-making process. Here, we show that in the human brain, choices are represented abstractly, even when the association between choice and motor response remains stable over time. We measured neural activity in humans using magnetoencephalography (MEG) while participants performed a motion discrimination task. Importantly, the associations between perceptual choice and motor response were balanced across experimental conditions and remained stable over many trials. We found neural information about the participants perceptual choice, independent of both the motor response and the visual stimulus. This abstract choice information increased during the stimulus period and peaked after the response had been made. Furthermore, choice and response information showed distinct cortical distributions, with strongest choice information in frontoparietal regions. Our results suggest that abstract choice representations are not restricted to action-independent contexts or those with dynamic choice-response associations and may therefore reflect a general role in perceptual decision-making.

Art's Hidden Topology: A window into human perception
Generations of researchers have sought a link between features of an artistic image and the audience's experience. However, a direct link between the properties of an image and the responses evoked has still not been established. Given the importance of shape to human perception and artistic creation, it can be assumed that one of the most important aspects of an artistic image is the use of different visual structures. We show that a method from the field of computational topology, persistent homology, can be used to analyse properties of image structures and composition at multiple scales. In order to determine the reliability of this method as a tool for analysing visual artworks, we analysed two different sets of abstract paintings that revealed significant discrepancies in the eye tracking and electroencephalography (EEG) activity of viewers. Our research showed that our newly developed method using persistent homology, not only clearly distinguished between two sets of images, which was not possible with common statistical image properties, but also allowed us to map topological features onto gaze fixation heat maps.

A brain-shuttled antibody targeting alpha synuclein aggregates for the treatment of synucleinopathies
Parkinson's disease and multiple system atrophy are members of a class of devastating neurodegenerative diseases called synucleinopathies, which are characterized by the presence of alpha-synuclein (-Syn) rich aggregates in the brains of patients. Passive immunotherapy targeting these aggregates is an attractive disease-modifying strategy. Such an approach must not only demonstrate target selectivity towards -Syn aggregates, but also achieve appropriate brain exposure to have the desired therapeutic effect. Here we present preclinical data for a next-generation antibody for the treatment of synucleinopathies. SAR446159 (ABL301) is a bispecific antibody composed of an -Syn-binding immunoglobulin (IgG) and an engineered insulin-like growth factor receptor 1 (IGF1R) binding single-chain variable fragment (scFv), acting as a shuttle to transport an antibody across the blood-brain barrier (BBB). SAR446159 binds tightly and preferentially to -Syn aggregates and prevents their seeding capacity in vitro and in vivo. Incubation with SAR446159 reduced -Syn preformed fibrils (PFFs) uptake in neurons and facilitated uptake and clearance by microglia. In wild type mice injected in the striatum with -Syn PFFs, treatment with SAR446159 reduced the spread of aSyn pathology as measured by phosphorylated -Syn staining and lessened the severity of motor phenotypes. Additionally, in 9-month-old transgenic mice overexpressing -Syn (mThy1--Syn, Line 61), repeated treatment with SAR446159 reduced markers of -Syn aggregation in the brain. SAR446159 had significantly higher brain and CSF penetration over a sustained period than its monospecific counterpart (1E4) in rats and monkeys. The binding properties of SAR446159 combined with its brain-shuttle technology make it a potent, next-generation immunotherapeutic for treating synucleinopathies

Simulation Insights on the Compound Action Potential in Multifascicular Nerves
Objective: Develop an efficient method for simulating evoked compound action potential (eCAP) signals from complex nerves to help optimize and interpret eCAP recordings; validate it through comparison with measured vagus nerve eCAP recordings; elucidate the subtle interplay giving rise to specific eCAP signal shapes and magnitudes. Approach: We developed an extended reciprocity theorem approach to model neuron signals in heterogeneous environments, and use it to study analytically the single fibre action potential. We then established a semi-analytic model that also uses hybrid electromagnetic-electrophysiological simulations to model eCAP signals from complex nerves populated with heterogeneous fiber populations of fibers. A cuff electrode was used to measure activity induced by vagus nerve stimulation in in vivo porcine experiments; these measurements were compared with signals produced by the model. Main Results: The semi-analytic model produces signals that approximate the shape and amplitude of in vivo measurements. Partially activated fascicles contribute substantially to the signal, as eCAP contributions from smoothly varying fiber calibers in fully activated ones partially cancel. As a result, eCAP magnitude does not depend monotonically on the stimulation current and recruitment level. Because the eCAP is sensitive to the degree of activation in individual fascicles, and to the location of the recording electrodes with respect to individual fascicles, the contributions of different fascicles to the recorded eCAP signals vary significantly with changes in the shape and placement of the stimulus and the recording electrodes. Significance: Our method can be used to rapidly assess new stimulation and recording setups involving complex nerves and neurovascular bundles, e.g., to maximize signal information content, for closed-loop control in bioelectronic medicine applications, and potentially to non-destructively reconstruct structural and functional nerve topologies through inverse problem solving.

Effects of non-invasive brain stimulation on effective connectivity during working memory task in Neurofibromatosis Type 1 patients
This study examined the effects of anodal transcranial direct current stimulation (atDCS) on effective connectivity during a working memory task. Eighteen adolescents with Neurofibromatosis Type 1 (NF1) completed a single{square}blind sham{square}controlled cross{square}over randomised atDCS trial. Dynamic causal modelling was used to estimate the effective connectivity between regions that showed working memory effects from the fMRI. Group-level inferences for between sessions (pre- and post-stimulation) and stimulation type (atDCS and sham) effects were carried out using the parametric empirical Bayes approach. A correlation analysis was performed to relate the estimated effective connectivity parameters of left dlPFC pre-atDCS and post-atDCS to the concentration of gamma-aminobutyric acid (GABA) measured via magnetic resonance spectroscopy (MRS-GABA). Next, correlation analysis was repeated using all working memory performance and all pre-atDCS and post-atDCS connectivity parameters. It was found that atDCS decreased average excitatory connectivity from left dorsolateral prefrontal cortex (dlPFC) to left superior frontal gyrus and increased average excitatory connectivity to left globus pallidus. Further, reduced average intrinsic (inhibitory) connectivity of left dlPFC was associated with lower MRS-GABA. However, none of the connectivity parameters of dlPFC showed any association with performance on a working memory task. These findings suggest that atDCS reorganised connectivity from frontal to fronto-striatal connectivity. As atDCS-related changes were not specific to the effect of working memory, they may have impacted general cognitive control processes. In addition, by reducing MRS-GABA, atDCS might make dlPFC more sensitive and responsive to external stimulation, such as performance of cognitive tasks.

Highlights- atDCS was applied to left dlPFC in NF1 patients during working memory
- After atDCS, no effect on modulatory connectivity
- Evidence for increased N-back average connectivity from dlPFC to globus pallidus
- Less dlPFC MRS-GABA was associated with less dlPFC inhibition

Failure to reproduce the effect of procedural memory interference on wakeful consolidation of episodic memory in younger and older adults
Brown and Robertson (2007) revealed that skill learning interferes with the wakeful consolidation of episodic memories in young adults. This finding is commonly used as evidence that episodic and procedural memories should not be learned in close temporal proximity but has not been reproduced by an independent laboratory. Additionally, older adults experience episodic memory deficits, but it is unknown whether this group is also vulnerable to this type of interference. We aimed to reproduce Brown and Robertson's (2007) finding in younger adults, while also comparing the magnitude of interference between younger and older adults. Forty younger (18-40 years; n =20) and older adults ([≥]55 years; n = 20) visited the laboratory in the morning and acquired episodic memories (a list of words) immediately before a procedural finger-tapping (procedural) task. Half of all participants were exposed to a learnable sequential structure. In the afternoon of the same day, participants were asked to recall the episodic memories from the morning session. We found weak evidence of interference for both age groups and no statistical difference in interference between groups. Our results suggest that the interfering effects of these memory types may be negligible or overestimated, and that these memory types can be acquired together without interference.