bioRxiv Subject Collection: Neuroscience's Journal

Axon collateral pattern of a sparse locus coeruleus norepinephrine neuron in mouse cerebral cortex.
The locus coeruleus (LC) contains predominantly norepinephrine (NE) neurons with widespread axonal projections throughout the brain and plays a critical role in the control of behavior, particularly arousal. Historically, the LC-NE system was thought to perform this function by releasing NE uniformly throughout most brain regions. However, recent evidence suggests that the cortical projections of the LC are modularly organized, allowing coordination of diverse and sometimes opposing functions, such as fear memory formation and extinction. However, many details remain unclear, and answers require data from axon collaterals of sparse neurons. We modified a viral tracing protocol using a dual recombinase system to trace the axonal collaterals of sparse LC neurons projecting to the cingulate cortex (CgC). Our results show that even a small number of LC neurons still have broad cortical projections, but the pattern is not uniform. There are a few major projections with dense fibers and numerous minor projections with sparse innervation. Notably, the major projections, including the rostrosplenial cortex, dorsal hippocampus, somatosensory cortex, and CgC (the injection site for retrograde viral labeling), are functionally related and may coordinate goal-directed navigation. In conclusion, our results suggest that a single LC neuron projects divergently and non-uniformly to the cortex, with major projections coordinating related cortical areas to regulate specific functions, while minor projections appear less functionally specific. Its likely that these minor projections contribute to the overall maintenance of arousal throughout the brain.

Spatial coding supports auditory conceptual navigation
Grid cells in human entorhinal cortex encode spatial layouts for real-world navigation, yet their role in conceptual navigation remains unclear. Here we show that mentally transforming tones within a purely auditory pitch-duration space engages spatial circuits, and that such resources are causally necessary. In Experiment 1, participants trained for five days to navigate through a purely conceptual pitch-duration auditory space, then underwent fMRI on Day 6. We observed a six-fold modulation of entorhinal BOLD signals aligned to each participants trajectory angles, similar to grid-cell firing in physical space. Stronger grid-like coding predicted larger training-related gains. In Experiment 2, a new cohort performed the same task under either a spatial or non-spatial interference load. Only the spatial condition selectively disrupted performance on trials requiring mental "movement," indicating a causal reliance on spatial resources. These findings provide evidence that auditory conceptual transformations recruit--and depend on--spatial grid-like computations in the entorhinal-hippocampal system, pointing to a domain-general role for spatial coding in organizing new knowledge along continuous dimensions.

Hexagonal modulation of theta rhythmic attentional sampling of visual space
Spatial attention improves visual perception by selecting behaviorally relevant sensory signals. Traditionally, attention has been conceptualized as a static spotlight, while recent evidence posited that attention operates as a moving spotlight that samples visual space sequentially in discrete snapshots that are clocked by theta rhythms ([~]3-8 Hz). While theta rhythmic attentional sampling has mainly been observed in fronto-parietal and occipital areas, theta oscillations also hallmark entorhinal-hippocampal grid-cell networks, which encode physical space in hexagonal patterns that guide overt exploration and navigation. We hypothesized that visual attention might rely on the same underlying principles and sample visual space in a hexagonal, grid-like configuration. To test this hypothesis, twenty participants performed a cue-guided attention task that probed behavioral performance as a function of space and time. Reaction times were assessed as a function of spatial location and varying cue-target intervals, which revealed prominent, spatially-structured theta rhythms. Specifically, higher theta power was evident at spatial locations that were aligned to multiples of 60{degrees}, consistent with an underlying hexagonal organization. Participants that exhibited stronger hexagonal sampling relied less on the spatial cue to guide their attentional allocation. In sum, these findings suggest that covert visual attention relies on an underlying hexagonal grid-like structure known from the entorhinal-hippocampal system and highlight that theta rhythms reflect a common organizing principle for spatial cognition.

Significance StatementAttention prioritizes sensory inputs to optimize behavior. But how does attention sample the environment in space and time? Here, we demonstrate that attentional sampling of visual space is not uniform, but preferentially explores locations that are oriented along a hexagonal pattern, reminiscent of the spatial configuration of entorhinal-hippocampal grid cells. Moreover, covert attentional sampling was clocked by theta oscillations (3-8 Hz). In sum, these findings provide evidence for a shared neural basis of underlying spatial attention and navigation and reveal that theta rhythms orchestrate sampling behaviors in space and time as a unifying principle underlying spatial cognition.

Targeted ubiquitination of NaV1.8 reduces sensory neuronal excitability
Chronic pain and addiction are a significant global health challenge. Voltage-gated sodium channel NaV1.8, a pivotal driver of pain signaling, is a clinically validated target for the development of novel, non-addictive pain therapeutics. Small molecule inhibitors against NaV1.8 have shown promise in acute pain indications, but large clinical effect sizes have not yet been demonstrated and efficacy in chronic pain indications are lacking.

An alternative strategy to target NaV1.8 channels for analgesia is to reduce the number of channels that are present on nociceptor membranes. We generated a therapeutic heterobifunctional protein, named UbiquiNaV, that contains a NaV1.8-selective binding module and the catalytic subunit of the NEDD4 E3 Ubiquitin ligase. We show that UbiquiNav significantly reduces channel expression in the plasma membrane and reduces NaV1.8 currents in rodent sensory neurons. We demonstrate that UbiquiNaV is selective for NaV1.8 over other NaV isoforms and other components of the sensory neuronal electrogenisome. We then show that UbiquiNaV normalizes the distribution of NaV1.8 protein to distal axons, and that UbiquiNaV normalizes the neuronal hyperexcitability in in vitro models of inflammatory and chemotherapy-induced neuropathic pain. Our results serve as a blueprint for the design of therapeutics that leverage the selective ubiquitination of NaV1.8 channels for analgesia.

rTCT: Rodent Triangle Completion Task to facilitate translational study of path integration
Path integration is navigation in the absence of environmental landmarks and is a primary cognitive mechanism underlying spatial memory. Path integration performance is primarily assessed in humans using the Triangle Completion Task (TCT). In humans, TCT has shown promise for the early diagnosis of Alzheimers disease. In rodents, however, path integration is assessed using a wide variety of tasks but none of which currently provide a homologue for the TCT. As rodents are routinely used as preclinical models, homologous path integration tasks that result in comparable performance metrics between species are important. In the present study we developed and tested a novel rodent version of the triangle completion task to enhance cross species comparability of path integration performance. Rats were able to comprehend and perform the task. A group of Alzheimers disease model rats (TgF344-AD) exhibited similar path integration performance to their wild-type littermates; however, analysis of behavioural structure suggests use of differing behavioural strategies. This work establishes a novel rodent homologue of the triangle completion task, facilitating enhanced reverse translational study of human path integration.

AAV serotype PHP.eB achieves superior neuronal transduction efficiency compared to AAV9 in pigtail macaques following intracerebroventricular administration
Adeno-associated virus (AAV) vectors are pivotal in gene therapy for neurological disorders due to their ability to enable long-term gene expression in the central nervous system (CNS). However, transducing larger brains, such as those of non-human primates (NHPs), remains challenging, necessitating alternative delivery routes and optimized capsids. This study directly compares the transduction efficiency and biodistribution of the benchmark AAV9 and its engineered derivative, AAV-PHP.eB, following intracerebroventricular (ICV) administration in juvenile Macaca nemestrina. Employing a neuron-specific promoter and nuclear-localized reporter, we systematically quantified transduction across cortical, subcortical, and spinal regions. AAV-PHP.eB demonstrated significantly higher transduction rates in cortical and spinal regions compared to AAV9, despite similar expression patterns. Both vectors exhibited limited subcortical penetration and significant peripheral leakage, highlighting key challenges in CNS targeting. This is the first study to quantitatively compare AAV-PHP.eB and AAV9 in NHPs, providing valuable insights into the advantages and limitations of engineered AAV capsids for CNS gene therapy. These findings lay a critical foundation for optimizing vector designs and delivery strategies to improve outcomes in clinical applications for neurodegenerative and neurodevelopmental disorders.

Developmental Variations in Recurrent Spatiotemporal Brain Propagations from Childhood to Adulthood
The brain undergoes profound structural and functional transformations from childhood to adolescence. Convergent evidence suggests that neurodevelopment proceeds in a hierarchical manner, characterized by heterogeneous maturation patterns across brain regions and networks. However, the maturation of the intrinsic spatiotemporal propagations of brain activity remains largely unexplored. This study aims to bridge this gap by delineating spatiotemporal propagations from childhood to early adulthood. By leveraging a recently developed approach that captures time-lag dynamic propagations, we characterized intrinsic dynamic propagations along three axes: sensory-association (S-A), task-positive to default networks (TP-D), and somatomotor-visual (SM-V) networks, which progress towards adult-like brain dynamics from childhood to early adulthood. Importantly, we demonstrated that as participants mature, there is a prolonged occurrence of the S-A and TP-D propagation states, indicating that they spend more time in these states. Conversely, the prevalence of SM-V propagation states declines during development. Notably, top-down propagations along the S-A axis exhibited an age-dependent increase in occurrence, serving as a superior predictor of cognitive scores compared to bottom-up S-A propagation. These findings were replicated across two independent cohorts (N = 677 in total), emphasizing the robustness and generalizability of these findings. Our results provide new insights into the emergence of adult-like functional dynamics during youth and their role in supporting cognition.

Hippocampus responds to mismatches with predictions based on episodic memories but not generalised knowledge
Prediction errors drive learning by signalling a mismatch between our expectations and reality. The hippocampus plays a key role in mismatch detection, but it is not known what information the hippocampus uses to form expectations. Here we show that the human hippocampus bases its expectations on episodic memories and not generalised schematic knowledge. Across three fMRI experiments, we demonstrate that the hippocampus is selectively engaged by mismatches with episodic memories of specific events. In contrast, mismatches with schematic knowledge activate regions of the Semantic Control and Multiple Demand Networks, as well as subcortical regions involved in prediction error signalling. Notably, mismatches with episodic memories also engage the Default Mode Network. Overall, our findings provide direct support for some models of learning via mismatch detection and refute models that propose the hippocampus plays a wider role as a more generalised mismatch detector.

Distinct Structural Connectivity Patterns Associated with Variations in Language Lateralisation
Hemispheric asymmetries in white matter tracts are proposed key determinants of language lateralisation, yet evidence in healthy individuals remains inconsistent. This suggests that simple tractography techniques might not be sensitive enough to identify language dominance. Significant insights into the functional organization of the human brain may be achieved by considering networks and brain connectivity, providing more information about discrepancies in people with different hemispheric language dominance. In this study, we examined 285 healthy participants compare their structural connectomes at the whole-brain level and determine the networks responsible for the three different functional language lateralisation groups (typical, atypical and strongly atypical). Probabilistic tractography generated whole-brain tractograms, and white matter fibres were filtered according to anatomical Boolean guidelines. Connectivity matrices with nodes corresponding to supramodal sentence areas in the language atlas and edges weighted by fractional anisotropy (FA) were generated to compare the groups using graph theory and network-based statistic (NBS) approaches. We demonstrated that both atypical (bilateral) and strongly atypical (right-lateralised) lateralisation are characterised by heightened interhemispheric temporal connectivity. Post-hoc analyses showed that strongly atypical individuals exhibited increased temporo-frontal connectivity, while atypical individuals had enhanced temporal and frontal connectivity but lacked temporo-frontal connections. These connectivity patterns diverge from traditional models of hemispheric dominance, suggesting a reliance on integrated bilateral networks in atypically lateralised individuals. This reflects distinct neural mechanisms underlying atypical language organisation, departing from developmental trajectory of typical lateralisation and offering insights into cognitive flexibility and clinical applications.

APOE4 exacerbates glucocorticoid stress hormone-induced tau pathology via mitochondrial dysfunction
APOE4 is the leading genetic risk factor for Alzheimers disease, and chronic stress is a leading environmental risk factor. Studies suggest that APOE4 confers vulnerability to the behavioral and neuropathological effects of chronic stress, representing a potential mechanism by which this genetic variant accelerates Alzheimers onset and progression. Whether and how APOE4-mediated stress vulnerability manifests in neurons of the hippocampus, a brain region particularly susceptible to stress and Alzheimers pathology, remains unexplored.

Using a combination of in vivo and in vitro experiments in humanized APOE4 and APOE3 knockin mice and primary hippocampal neurons from these animals, we investigate whether and how APOE4 confers sensitivity to glucocorticoids, the main stress hormones.

We find that a major hallmark of stress/glucocorticoid-induced brain damage, tau pathology (i.e., tau accumulation, hyperphosphorylation, and spreading) is exacerbated in APOE4 versus APOE3 mice. Moreover, APOE4 animals exhibit underlying mitochondrial dysfunction and enhanced glucocorticoid receptor activation in the hippocampus, factors that likely contribute to tau pathogenesis in both the presence and absence of stress/glucocorticoids. Supporting this concept, we show that opening of the mitochondrial permeability transition pore drives mitochondrial dysfunction and tau pathology in APOE4 mice, and that pharmacological inhibition of pore opening is protective against ApoE4-mediated mitochondrial damage, tau phosphorylation and spreading, and downstream hippocampal synapse loss. These findings shed light on the mechanisms of stress vulnerability in APOE4 carriers and identify the mitochondrial permeability transition pore as a potential therapeutic target for ameliorating Alzheimers pathogenesis in this population.

Coordinated representational drift supports stable place coding in hippocampal CA1
The phenomenon of representational drift (i.e., changing neuronal tuning during repeated exposure to the same stimuli), is a fundamental paradox in neuroscience that raises the question how stable behaviour can emerge from unstable neural representations. Place cells in CA1 of the hippocampus are crucial for spatial navigation and memories1 but show gradual changes in their preferred firing location over time when exposed to the same environment2-9. This drift occurs despite the fact that the animal maintains the ability to navigate and to perform spatial tasks, suggesting a complex relationship between neural activity and behaviour. Here, we show that while the spatial tuning functions of individual CA1 neurons drift over time, stable space coding prevails at the population level: Representational drift is not random but can be described as a translation and rotation in population state space, which preserves the internal geometry of population activity over time. Compensating for the coordinated translation and rotation allows for drift correction and a recovery of spatial tuning on future days. Moreover, the preserved internal geometry stabilises downstream readout under noisy conditions. We propose that the conserved population geometry might serve as a mechanism by which downstream reader networks achieve effective drift correction and, thus, ameliorate the readout of stable information.

Information Shielding Through Neural Deactivation: A Fundamental Mechanism of Human Information Processing
Information processing is a core issue in cognitive neuroscience. The brain can either accept or shield information. However, information shielding has traditionally been regarded as a byproduct of other cognitive processes that prepare brain areas for activation, with the accompanying brain deactivation seen as merely supportive. Here, we offer an alternative perspective, demonstrating that people can directly perform information shielding without engaging other cognitive processes. Using information shielding as a novel investigative lens, we provide direct evidence that deactivation serves as a primary mechanism in its own right. We found that information shielding was characterized by a deactivation-dominant neural dynamic, with initial executive control region activation giving way to increased sensory region deactivation, especially after a 3-second boundary. Neural decoding results further confirmed this deactivation trend. This deactivation pattern was consistent across both auditory and visual modalities. Furthermore, non-invasive brain stimulation demonstrated a causal relationship between the deactivation pattern and information shielding, and we found that this deactivation mechanism extended to general unnecessary information processing, regardless of whether the necessity was determined objectively or subjectively. This challenges the conventional emphasis on activation as the primary mode of information processing and opens new fundamental avenues for understanding inhibitory cognitive processes.

Early life adversity and White Matter Microstructural Organization - a systematic review.
Early life adversity, defined as exposure to stressful events during childhood, is a significant risk factor for the development of psychiatric disorders. Diffusion tensor imaging studies employing tract-based spatial statistics have shown microstructural abnormalities in white matter among individuals exposed to early life adversity; however, robust conclusions are yet to be drawn. This systematic review synthesizes findings of previous tract-based spatial statistics studies to identify the white matter alterations in adult brains exposed to early life adversity, in papers with methodological consistency. The literature search (April 2024) was conducted to identify tract-based spatial statistics studies that compared diffusion metrics between adults exposed to early life adversity and adults not. Embase, Pubmed, and PsycInfo were searched, retrieving 2458 articles. Following deduplication, 1739 titles and/or abstracts were screened. 1699 articles were excluded, and 40 full texts were reviewed. Seven articles, reporting on 764 subjects, met the inclusion criteria and were included in the narrative synthesis. Compared to controls, adults exposed to early life adversity showed lower fractional anisotropy values in white matter tracts of the limbic and visual processing systems, specifically the anterior thalamic radiation, inferior longitudinal fasciculus, corona radiata, uncinate fasciculus, inferior fronto-occipital fasciculus, and cingulum bundle. This systematic review highlights that early life adversity may underlie emotional dysregulation and contribute to an increased risk of psychopathology in later life and explores the potential neurobiological mechanisms that underpin these structural changes. Understanding these associations is crucial for developing targeted interventions aimed at mitigating the long-term impact of early life adversity.

Reduced inter-subject functional connectivity during movies in autism: Replicability across cross-national fMRI datasets
Background: Autism is a neurodevelopmental disorder characterized by repetitive behaviors and difficulties in social communication and interaction. Previous research has shown that these symptoms are linked to idiosyncratic behavioral and brain activity patterns while viewing natural social events in movies. This study aimed to investigate the replicability of brain activity idiosyncrasy in autistic individuals by comparing their inter-subject functional connectivity (ISFC) with that of neurotypical individuals. Methods: We tested for ISFC differences between autism and neurotypical groups using functional magnetic resonance imaging (fMRI) data from two independent datasets from Germany (Nneurotypical = 25, 7 Males, 18 Females; Nautism = 22, 12 Males, 10 Females) and Finland (Nneurotypical = 19, Nautism = 18; All males). Participants watched short movie stimuli, and pairwise ISFCs were computed across 273 brain regions. Group differences were evaluated using subject-wise permutation tests for each dataset. Results: In both datasets, the autism group showed lower ISFCs compared to the neurotypical group, specifically between visual regions (e.g., occipital gyrus, cuneus) and parietal regions (e.g.,superior and inferior parietal lobules), as well as between visual regions and frontal regions (e.g.,inferior frontal gyrus, precentral gyrus). ISFC was higher in the Finnish autism group in temporal regions associated with sound and speech processing. Conclusions: The study confirmed the replicability of reduced ISFCs in autistic individuals during naturalistic movie-watching, especially between visual and parietal/frontal brain regions. These findings reinforce the utility of ISFC and naturalistic movie-watching paradigm in studying neural connectivity alterations in autism.

Master control genes in the regeneration of rod photoreceptors from endogenous progenitor cells in zebrafish retina
Retinitis Pigmentosa is a chronic retinal degenerative disease characterized by the gradual loss of rod, and later, cone photoreceptors until the individual is completely blind. Regeneration of photoreceptors from endogenous progenitor cells is a possible therapeutic approach, but mammals do not do this naturally. Mammalian models can be induced to generate retinal progenitors from Muller glial cells, but there has been limited success in rod photoreceptor specific regeneration. Unlike mammals, zebrafish have the natural ability to regenerate neurons after injury or disease and can provide insight into the molecular mechanisms of regeneration. In this study, we used a zebrafish model of Retinitis Pigmentosa to investigate the class of progenitors responsible for rod photoreceptor regeneration in the context of chronic disease. Using bioinformatic analyses of single-cell RNA sequencing datasets, we identified master regulator genes responsible for proliferation of retinal progenitors, differentiation of progenitors into rod photoreceptors, and maturation of the new rod photoreceptors. Using transient knockdown of gene expression in adult regenerating retina we determined that e2f1, e2f2, e2f3 and aurkb are critical for proliferation of progenitors, and prdm1a is critical for differentiation of progenitors into rod photoreceptors. This study provides a list of master regulators responsible for the specific regeneration of rod photoreceptors during chronic retinal degeneration.

Impact StatementIdentification of master regulating genes that drive the proliferation of progenitor cells and their differentiation specifically into rod photoreceptors provides insight that can be used to develop regenerative therapies for retinal degenerative diseases.

Remote Cortical Network for Frontal Cognitive Symptoms derived from Tau Accumulation in Progressive Supranuclear Palsy
Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder characterized by movement impairments and frontal cognitive dysfunctions. While motor symptoms are linked with subcortical tau deposits, mechanisms underlying the frontal cognitive symptoms remain unclear due to limited tau accumulation in the frontal cortex and heterogeneous tau distribution. Here, we combined high-contrast tau PET with normative connectome to identify a common network extended from tau deposits underlying the frontal cognitive symptoms in PSP. Regions with tau deposition were connected to a common cortical network that was not detectable through atrophy-based analyses. This network was primarily overlapped with canonical action-mode and frontoparietal networks. While the degree of subcortical tau deposition or atrophy correlated with motor symptoms, only connectivity between tau deposition sites and the derived cortical network explained the frontal cognitive deficits. These findings propose network mechanisms underlying frontal cognitive impairments in PSP, emphasizing the role for remote effects of pathological tau deposits.

Genetic and environmental contributions to ReHo and fALFF in early adolescence vary across brain regions
Research on genetic and environmental influences on brain function generally focuses on connections between brain areas. A different yet unexplored approach is to examine activity within local brain regions. We investigated the influence of genes and environmental effects on two specific measures of local brain function: Regional Homogeneity (ReHo) and fractional Amplitude of Low-Frequency Fluctuations (fALFF). Participants were drawn from a sample of adolescent twins on two occasions (mean ages 11.5 and 13.2 years, N = 278 and 248). Results showed that genetic and environmental factors influenced brain function in almost all 210 cortical regions examined. Moreover, genetic and common environmental factors influencing ReHo and fALFF values at wave 1 (9-14 years) also influenced values at wave 2 (10-16 years) for many regions. However, the influence of genetic and common environmental factors varied across the cortex, exhibiting different patterns in different regions. Furthermore, we found new (i.e., independent) genetic and environmental influences on brain activity at wave 2, again with regional patterns. Exploratory analyses found weak associations between anxiety and depressive symptoms and local brain function in several regions of the temporal lobe. These findings are consistent with similar studies of other resting-state functional MRI metrics (i.e., functional connectivity).

SurfNet: Reconstruction of Cortical Surfaces via Coupled Diffeomorphic Deformations
To achieve fast and accurate cortical surface reconstruction from brain magnetic resonance images (MRIs), we develop a method to jointly reconstruct the inner (white-gray matter interface), outer (pial), and midthickness surfaces, regularized by their interdependence. Rather than reconstructing these surfaces separately without taking into consideration their interdependence as in most existing methods, our method learns three diffeomorphic deformations jointly to optimize the midthickness surface to lie halfway between the inner and outer cortical surfaces and simultaneously deforms it inward and outward towards the inner and outer cortical surfaces, respectively. The surfaces are encouraged to have a spherical topology by regularization terms for non-negativeness of the cortical thickness and symmetric cycle-consistency of the coupled surface deformations. The coupled reconstruction of cortical surfaces also facilitates an accurate estimation of the cortical thickness based on the diffeomorphic deformation trajectory of each vertex on the surfaces. Validation experiments have demonstrated that our method achieves state-of-the-art cortical surface reconstruction performance in terms of accuracy and surface topological correctness on large-scale MRI datasets, including ADNI, HCP, and OASIS.

Automated assessment of the mouse body-language reveals pervasive behavioral disruption in a two-hit model of psychiatric vulnerability
The influence of early-life experiences is widely acknowledged as a crafting tool that sculpts complex behavioral patterns and well-being of living organisms. The use of preclinical models can provide invaluable insight into how a negative environmental push interplays with genetic make-up in shaping psychiatric vulnerability. However, the assessment of psychiatric traits in cross-species studies often relies on the use of surrogate metrics as a proxy for the internal state, limiting the interpretation to context-dependent outcomes. In this work, we exploited a validated computational tool for digitalized ethological screening to identify spontaneous hallmarks of altered behavioral functioning in a dual-hit mouse model of psychiatric vulnerability. To do so, mice carrying heterozygous deletion of the gene coding for Contactin-associated protein-like 2 (Cntnap2+/-) and their wild-type (WT) littermates were raised with limited bedding and nesting (LBN). These animals were compared to both WT and Cntnap2+/- mice raised in standard conditions, mapping their spontaneous behavior during freely-moving exploration. Our data show that descriptors of motility state or surrogate anxiety indicators largely failed in detecting subtle diversion from control conditions. By contrast, automated segmentation of the body-language revealed a significant impact of both genotype and early-life experience in shaping the spontaneous behavioral programming. Thus, using unsupervised clustering, we unveiled two alternative neurobehavioral profiles within our dataset. We found that one of the identified profiles largely overlapped with Cntnap2+/- mice raised with LBN, while the other was equally shared among controls. We conclude that the coincidence of early-life adversity and Cntnap2 haploinsufficiency drastically reshapes behavioral structure in rodents.

Subjective sleep quality in healthy young adults moderates associations of sensitivity to punishment and reward with functional connectivity of regions relevant for insomnia disorder
Chronic unhealthy sleeping behaviours are a major risk factor for the emergence of mood and anxiety disorders. Nevertheless, we are still lacking understanding why some individuals are more prone than others to affective dysregulation caused by sleep disruption. With preliminary evidence suggesting that brain activity during positive and negative emotional processing might play an important modulating role, we conducted whole-brain resting-state functional connectivity analyses in a large cohort of healthy young adults (N = 155). Using regions consistently affected in insomnia disorder as seeds, we investigated sleep quality-related neural connectivity patterns that were both insensitive and sensitive to the interactions with individual measures of reward and punishment processing, additionally assessing the links with indices of emotional health. Majority of the findings reflected interactions between sleep quality and reinforcement sensitivity, with the opposite associations reported in the good and poor sleepers. One of such connections, the coupling between precentral gyrus and posterior insula, was additionally negatively linked to trait anxiety, with the lowest connectivity values observed in poor sleepers with higher sensitivity to punishment. In turn, the only finding associated solely with sleep quality, i.e. coupling between subgenual anterior cingulate cortex and thalamus, was also related to the habitual use of emotion suppression strategies. As such, the present study provides evidence that affective functioning plays an essential role in determining the effects of poor sleep quality on brain connectivity and emotional health, providing a plausible mechanism for why certain individuals are more susceptible to sleep-related affective dysregulation than others.

Viral-mediated fluorescent labeling of hyaluronan reveals extracellular matrix dynamics in the mouse brain in vivo
The extracellular matrix (ECM) of the brain is primarily composed of the glycan polymer hyaluronan (HA), a core scaffold that nucleates proteoglycans forming a self-assembled matrix that acts as structural framework and signaling hub. Since most of the neural matrix is composed of sugars, development of genetically encoded tags has been limited. Therefore, although several staining protocols exist for ECM in fixed tissue, there are no reliable matrix labels for live imaging. Here we report a viral-mediated fluorescent probe that binds to HA and labels the mouse brain ECM. The vector encodes the HA binding domain from neurocan fused to GFP and an externalization tag (AAV-Ncan-GFP), enabling transduced cells to secrete the fluorescent hyalectan into the extracellular space, thereby labeling HA. We demonstrate stable probe expression in organotypic brain slices, as well as in vivo in the mouse cortex, where it labels both perineuronal nets and interstitial matrix. We validate HA labeling through colocalization with HABP and sensitivity to hyaluronidase, and confirm the probe extracellular localization by shadow imaging. As a proof of concept, we combine AAV-Ncan-GFP with dendritic spine imaging ex vivo and calcium transient imaging in vivo, providing a real-time map of local ECM alongside neural function. The probe enables time-lapse imaging of ECM dynamics in live mice, facilitating longitudinal studies across a wide range of timescales, from minutes to days. The results establish AAV-Ncan-GFP as a valuable tool for real-time observation of brain ECM and a promising resource to explore ECM dynamics and brain function in vivo.

Oscillatory impact of Transcranial Magnetic Stimulation at very weak-intensity on the primary motor cortex: A TMS-EEG study in the human brain
BackgroundVery weak transcranial magnetic stimulation (TMS, 10 mT, [~]0.05-10 V/m) has been explored in animal models showcasing potential for effective neuromodulation. However, the physiological effects of these type of pulsed fields remain rather unexplored in humans.

ObjectiveWe here aimed to characterize the neural effects of very weak TMS pulsed fields ([~]6V/m, [~]6% of the resting motor threshold, rMT) and explore their ability to evoke and/or modulate local oscillatory activity generated on human primary motor regions.

MethodsNeuronavigated TMS was employed in a cohort of healthy participants (n=18) to deliver single pulses and short bursts of rhythmic (20 Hz) TMS at very weak intensity and at conventional levels (here referred as high intensity) usually employed in human applications ([~]113V/m, [~]77% rMT), to the left primary motor cortex (M1). In parallel, their potential to evoke brain activity such as Transcranial Evoked Potentials (TEPs), and to entrain or modulate local ongoing oscillations was explored with scalp EEG recordings.

ResultsBoth, single TMS pulses and 4-pulse rhythmic TMS beta (20 Hz) bursts delivered at conventional intensity elicited consistent Transcranial Evoked Potentials (TEPs) and beta-synchronized Event Related Spectral Perturbations (ERSP) around the left M1 area. Most interestingly, very-weak-intensity TMS modulated in this same area oscillatory activity at a mu-alpha frequency (7-13 Hz) only for rhythmic TMS bursts time-locked to -the troughs of the local ongoing beta oscillations.

ConclusionsOur data provide first time support for the modulation of oscillatory signals with TMS delivered at an unprecedentedly weak intensity on the human primary motor cortex. This evidence enriches current knowledge on the impact of weak pulsed magnetic fields in humans, paving the way for future neurotherapeutics with a new generation of portable and autonomous low-intensity multichannel TMS devices.

HIGHLIGHTSO_LIVery weak-intensity 20Hz TMS rhythmic patterns evoked significant mu-alpha central activity (7-13Hz) when bursts were aligned with the troughs of local ongoing beta oscillatory activity.
C_LIO_LIConventional high-intensity single pulse and 20Hz TMS patterns elicited consistent TMS evoked potentials (TEP) and beta-synchronized local changes of Event Related Spectral Perturbations (ERSPs) in the left M1.
C_LIO_LIFulfilling established criteria of TMS entrainment, the effects driven by high-intensity stimulation on M1 were TMS pattern- and oscillation-phase-dependent. Differences featured by very weak vs. conventional intensity TMS on entrained oscillatory activity suggests these two modalities operate on distinct physiological mechanisms.
C_LI

A Meta-analysis of Perceptual Pseudoneglect reveals the Functional Anatomy of Perceptual Judgements
Major evidence for a right-hemisphere dominance of the brain in spatial and/or attentional tasks comes from lesion studies in patients with spatial neglect. However, the neuroanatomy of the different forms of neglect remains a matter of debate, and it remains unclear how dysfunctions in neglect relate to intact processes. In the healthy brain, perceptual pseudoneglect is the equivalent of neglect as observed in paradigms such as the line bisection task. Therefore, the current study investigated the intact functional anatomy of perceptual pseudoneglect using a meta-analysis to compensate for some of the limitations of individual imaging studies. We collated the data from 24 articles that tested 952 participants with a range of paradigms (landmark task, line bisection, grating-scales task, and number line task) obtaining 337 foci. Using Activation Likelihood Estimation (ALE) we identified a right-hemisphere biased network of cortical areas, including superior and intraparietal regions, the intraoccipital sulcus together with other occipital regions, as well as inferior frontal areas that were associated with perceptual pseudoneglect in partial agreement with lesion studies in patients with neglect. The present results are consistent with a framework of neural computations that explains the neural and behavioural asymmetries of perceptual pseudoneglect as due the need for to an integrated representation of spatial information during perceptual judgments.

Neural correlates of boundary extension during visual imagination
People typically remember seeing a greater expanse of a scene than was visible in a studied close-up (boundary extension, BE). Multivoxel pattern analysis was used to test the neural correlates of BE. Classifiers were trained using a whole-brain searchlight method to discriminate between close-up and wider-angle versions of 16 scenes during repeated perceptual exposures. Earlier, each subject studied either the close or wide version of each scene and then visually imagined it from memory. If a brain region reflects BE, then unlike classification during perception, visual images of close views should sometimes be misclassified as wide (capturing false memory beyond the view), whereas visual images of wide views should be correctly classified. BE-consistent patterns during imagery were found in high-level visual regions, including posterior superior parietal cortex. This pattern did not reflect a brain-wide bias toward better classification of wider-angle views: the pattern reversed (better classification of close views) in the early visual cortex, presenting a novel distinction between early and late visual representations in imagery. We propose that this method reflects active maintenance of boundary-extended scene representations in memory and that it holds promise as a general purpose tool for decoding false memory in the brain.