bioRxiv Subject Collection: Neuroscience's Journal
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Monday, July 14th, 2025
| Time |
Event |
| 4:33p |
IsoDGR-Induced Endothelial Cytoskeletal Disruption Drives Age-Related Blood-Brain Barrier Breakdown
Brain aging is characterized by progressive breakdown of the blood-brain barrier (BBB), which correlates with neuroinflammation and cognitive decline. Emerging evidence implicates degenerative modifications of the vascular proteins as a key driver of BBB dysfunction. In particular, spontaneous deamidation of Asp-Gly-Arg (NGR) motifs generates isoAsp-Gly-Arg (isoDGR) sequences that structurally mimic canonical Arg-Gly-Asp (RGD) integrin-binding ligands. Here, we show that age-associated accumulation of isoDGR in the brain cortex induces endothelial cytoskeletal collapse and tight junction disorganization, leading to BBB breakdown. Using mice lacking the L-isoaspartyl repair enzyme PCMT1 (which accelerates isoDGR accumulation) and wild type aged mice, we found markedly elevated isoDGR in brain tissues accompanied by focal microhemorrhages and increased BBB permeability. Recent whole-genome sequencing suggests that a common PCMT1 variant is linked to neurodegenerative disease risk, indicating potential clinical relevance in vascular aging. Remarkably, systemic treatment with an isoDGR-neutralizing antibody largely prevented capillary breaches and leakage, and even restored barrier integrity in aged wild-type mice. To uncover the molecular mechanism, we exposed brain endothelial cells to synthetic isoDGR-peptides, which recapitulated these effects. Unbiased RNA-sequencing reinforced these findings, revealing broad transcriptomic reprogramming of cytoskeletal, cell-cell junction, inflammatory, and stress-response pathways. Functional studies demonstrated that isoDGR triggered collapse of F-actin stress fibers, disrupted junctional ZO-1 and VE-cadherin, increased monolayer permeability to macromolecules, and impaired endothelial cell migration and proliferation. IsoDGR-treated endothelial cells exhibited increased oxidative stress, upregulation of ICAM-1/VCAM-1/CCL-2, and adopted a senescent phenotype. Our results suggest that isoDGR hijacks endothelial integrin signaling to destabilize the actin cytoskeleton and tight junctions, a process that breaches the BBB and subsequently activates inflammatory and senescence programs. In summary, we identify BBB disruption via isoDGR-induced cytoskeletal dysfunction as a central pathology of vascular aging, and demonstrate that targeting isoDGR damage preserves BBB integrity and attenuates neuroinflammation. | | 4:34p |
The selective amyloid-driven failure of cholinergic medial septal neurons in aging mice perturbs REM sleep, cognition and emotion, and broadcasts amyloid to other brain regions
Early degeneration of basal forebrain cholinergic neurons is a key feature of Alzheimer's Disease (AD). We expressed in mice of both sexes an AppNL-G-F allele, harboring familial AD mutations, specifically in cholinergic medial septum (MS) neurons, and compared the phenotype to mice with global AppNL-G-F expression. Over the course of 14 months, as mice reached late middle age, targeted expression led to the loss of about one-third of MS cholinergic neurons and widespread amyloid deposition in their terminal fields, especially in the hippocampus and, to a lesser extent, on blood vessels. This selective vulnerability of ageing cholinergic cells to amyloid, markedly reduced REM sleep and caused cognitive and emotional alterations resembling those in mice with the mutation expressed throughout the brain. Mice with global AppNL-G-F expression also had a previously unreported selective death of about 20% of their medial septal cholinergic cells. Although the broadcasting of amyloid by medial septal cholinergic cells is a notable feature, and potentially important in human pathology, selective genetic lesioning of about one third of the medial septal cholinergic cells, independently of amyloid, gave the same REM sleep, cognitive and emotional phenotypes. Thus, it is the killing of the cholinergic cells by amyloid, and therefore the missing acetylcholine, and not the secreted/deposited amyloid in the hippocampus and other areas that is the critical feature. These findings underscore the interest in revitalizing the classic cholinergic hypothesis of AD. Restricting pathological amyloid expression to MS cholinergic neurons, so that their health is compromised by amyloid, is sufficient to reproduce many AD-like symptoms, highlighting the critical role of these cells in early AD pathogenesis, REM sleep regulation, emotion and cognition. | | 4:34p |
Bridging local and global dynamics: a biologically grounded model for cooperative and competitive interactions in the brain
Functional brain networks exhibit both cooperative and competitive interactions, yet existing models--assuming purely excitatory long-range coupling--fail to account for the widespread anti-correlations observed in fMRI. Starting from a laminar neural mass framework, where each mass comprises distinct slow (alpha-band) and fast (gamma-band) oscillatory pyramidal subpopulations (P1 and P2), we show how laminar-specific long-range excitatory projections across neural mass parcels can give rise to both cooperation and competition via cross-frequency envelope coupling. We demonstrate that homologous connections across parcels (e.g., P1[->]P1 or P2[->]P2) induce positive correlations between the infra-slow amplitude fluctuations of alpha band envelopes in each parcel, as well as in the simulated fMRI BOLD signals. Conversely, heterologous connections (P1[->]P2) induce negative correlations. We tested this mechanism by building personalized whole-brain models for a cohort of 60 subjects in two steps. First, we inferred signed inter-parcel generative effective connectivity directly from resting-state fMRI using regularized maximum-entropy (Ising) models. Then we connected laminar neural masses to simulate BOLD dynamics by implementing positive and negative Ising connections via homologous and heterologous projections, respectively. Ising-derived cooperative/competitive connectivity modeling faithfully reproduced both static and dynamic functional connectivity patterns, as well as gamma power-BOLD correlation and partial alpha power-BOLD anticorrelation-outperforming structurally constrained and cooperative-only variants. This further demonstrates that functional data alone suffices to infer individualized connectivity. Together, these results provide a biologically grounded mechanistic model on how long-range excitatory circuits and local cross-frequency interactions shape the balance of cooperation and competition in large-scale brain dynamics. | | 4:34p |
Connectivity and function are coupled across cognitive domains throughout the brain
Decades of neuroimaging have revealed that the functional organization of the brain is roughly consistent across individuals and at rest it is resembles group-level task-evoked networks. A fundamental assumption in the field is that the functional specialization of a brain region arises from its connections to the rest of the brain, but limitations in the amount of data that can be feasibly collected in a single individual, leaves open the question: Is the association between task activation and connectivity consistent across the brain and many cognitive tasks? To answer this question, we fit ridge regressions models to activation maps from 33 cognitive domains (generated with NeuroQuery) using resting-state functional connectivity data from the Human Connectome Project as the predictor. We examine how well functional connectivity fits activation and find that all regions and all cognitive domains have a very robust relationship between brain activity and connectivity. The tightest relationship exists for higher-order, domain-general cognitive functions. These results support the claim that connectivity is a general organizational principle of brain function by comprehensively testing this relationship in a large sample of individuals for a broad range of cognitive domains and provide a reference for future studies engaging in individualized predictive models. | | 5:45p |
Temporal Dynamics of Sensorimotor Integration for Non-Visual Target Information During Movement Preparation and Online Control
Online movement variability in non-visual (auditory and proprioceptive) target reaching is modality-dependent. This study investigated whether such modality-specific effects emerge during movement preparation and whether this phase influences subsequent online control. Participants performed reaching movements toward auditory, proprioceptive, or audio-proprioceptive targets. Electromyography and movement kinematics were recorded to examine the effects of sensory modality on sensory encoding and motor coordination during movement preparation, as well as online control at 5%, 50%, and 100% of movement time. Results revealed a modality-dependent sensory encoding phase and a modality-independent motor coordination. Movement variability was greater for auditory targets than for proprioceptive and audio-proprioceptive targets at 50% and 100% of movement. Only motor coordination influenced early online control (5%), but this effect was modality-independent. These findings demonstrate that the influence of sensory modality extends beyond execution to the preparatory phase of movement. The results support a four-stage model of action control: a modality-dependent sensory encoding phase of preparation and late online control, alongside a modality-independent motor coordination phase and early online control. These findings offer new insight into the temporal dynamics of sensorimotor control without vision, indicating that non-visual sensory information is differentially used during distinct phases of movement preparation and execution. | | 5:45p |
Neural Representation of Associative Threat Learning in Pulvinar Divisions, Lateral Geniculate Nucleus, and Mediodorsal Thalamus in Humans
Understanding the neural mechanisms underlying associative threat learning is essential for advancing behavioral models of threat and adaptation. We investigated distinct activation patterns across thalamic pulvinar divisions, lateral geniculate nucleus (LGN), and mediodorsal thalamus (MD) during the acquisition of associative threat learning in the MRI. We revealed parallel thalamic learning systems within the anterior pulvinar and MD, supporting distinct mechanisms of automatic survival vs. more deliberate learning. Additionally, our findings support a novel hierarchical pulvinar model during fear conditioning: the medial pulvinar mediates basic threat information from the inferior and lateral divisions to the anterior pulvinar for integrative learning. Pulvinar divisions and MD support extinction learning. These regions also process salience and modulate safe/threat memory expression during extinction recall and threat renewal. The LGN sustains feedforward processing of anticipated visual input throughout all threat phases. This study extends dominant brain models of threat learning and memory, reframing our understanding of distinct thalamic roles in these psychological processes. | | 5:45p |
Responses of inferior colliculus neurons to notched noises in awake mice: putative neural correlates of auditory enhancement and Zwicker tone
Sensory systems are well adapted to constantly changing statistics of the environment and to process specific spectral features of sounds, such as spectral notch (i.e. low energy frequency band) embedded in broadband stimuli. Spectral notches can be added to the stimulus spectrum due to filtering by the outer ear, and can be used as monaural cues related to head or pinna position for localizing sound sources. In addition, broadband sounds with spectral notch are known to produce auditory enhancement, a perceptual phenomenon in which a target within a spectrally notched masker can become salient if preceded by a copy of the masker. Notched noise can also produce an auditory illusion, called Zwicker Tone (ZT), which is perceived immediately after stimulation and whose pitch corresponds to the spectral notch. The present study aimed to further investigate the mechanisms of auditory enhancement, including those of ZT, in the inferior colliculus of awake mice. We show that neural activity can be strongly suppressed during NN stimulation and enhanced immediately after NN stimulation. These effects depend on notch center frequency relative to the best frequency of neurons, stimulus level and notch width. Our results are consistent with the mechanisms described for post-inhibitory rebound in the central auditory system: NN could hyperpolarize the membrane potential, which can then activate several cationic conductances, leading to a rebound of neural activity. We discuss auditory enhancement and ZT as collateral effects of an essential neural mechanism aimed at enhancing the central representation of acoustic spectral contrasts. | | 5:45p |
Neurophysiological correlates of passive movements are speed- and type-dependent
Introduction: The supraspinal involvement in the control of passive movements remains elusive. Mechanoreceptor properties, their change in the context of ageing and the somatotopically organized supraspinal connections between sensory and motor systems provide a neuroanatomical basis for the prediction that cortical structures are involved in the control of passive movements. Previous electromyographic evidence indeed show movement speed and -type-dependent changes in muscle activity. This study aimed to provide electrophysiological evidence for the involvement of frontal cortex inhibition and corticomotor interactions in the control of passive movements. Methods: Continuous and discontinuous passive elbow movements were performed in healthy younger (n = 20, 22.5 +/- 2.31 y) and older (n = 20, 72.7 +/- 5.73 y) adults at three movement speeds (20, 60, and 100 bpm) while electro-encephalographic (EEG) and electromyographic (EMG) data were acquired. Alpha power and beta corticomuscular connectivity were used as measures of frontal cortex inhibition and brain-muscle connectivity, respectively. Results: Frontal cortex inhibition decreased (p = 0.036) and brain-muscle connectivity increased (p < 0.001) with increasing movement speeds. In addition, frontal cortex inhibition was 17% higher in the discontinuous condition as compared to the continuous condition (p = 0.005) while corticomuscular coherence was 25.9% higher in the continuous vs. the discontinuous condition (p < 0.001). These effects were independent of age. Conclusion: The present results provide insights into the control of passive movements and show that frontal cortex inhibition and brain-muscle interactions depend on movement speed and movement type. | | 5:45p |
A Sexually Dimorphic Neuronal Cluster in the Mouse Medial Amygdala Exhibits Binary Activation Mode Based on Male Sexual Status
Increasing scientific interest has been directed toward understanding sexual dimorphism in the brain. Although various brain structures exhibit masculine or feminine characteristics, no strictly binary anatomical feature, such as those seen in genitalia, has been identified. In this study, we identified a dense, sexually dimorphic cluster of neurons in the posterodorsal medial amygdala (MeApd), which we named DIMPLE, that exhibited a remarkable binary pattern of cFos activation. Using the TRAP2 (Targeted Recombination in Active Populations) transgenic mouse model, we found that it was consistently labeled in all females, regardless of age or sexual experience. In males, however, DIMPLE was not labeled in any of the adult virgins but was evident pre-weaning and following mating. Surgical removal of gonads (ovariectomy or orchiectomy) did not alter the labeling pattern of DIMPLE in either sex. Interestingly, a single intraperitoneal injection of prolactin, a hormone known to increase in males after mating, induced DIMPLE labeling in virgin males. However, treatment with cabergoline, a potent inhibitor of prolactin secretion, did not prevent DIMPLE labeling in females or in post-mating males. Given the established role of the MeApd in social and reproductive behaviors, we propose that DIMPLE may support neural mechanisms underlying female-typical behavior and potentially contribute to post-mating behavioral shifts in males. | | 6:18p |
Dynamic extracellular interactions with AMPA receptors
Synaptic plasticity in the central nervous system enables the encoding, storing, and integrating new information. AMPA-type glutamate receptors (AMPARs) are ligand-gated ion channels that mediate most fast excitatory synaptic transmission in the brain, and plasticity of AMPARs signaling underlies the long-lasting changes in synaptic efficacy and strength important for learning and memory.1,2 Recent work has indicated that the enigmatic N-terminal domain (NTD) of AMPARs may be a critical regulator of synaptic targeting and plasticity of AMPARs. However, few synaptic proteins have been identified that regulate AMPAR plasticity through interactions with AMPAR NTDs. Moreover, the scope of AMPAR NTD interactors that are important for synaptic plasticity remains unknown. Here, we present the dynamic, extracellular interactome for AMPARs during synaptic plasticity. Using surface-restricted proximity labeling and BioSITe-based proteomics, we identified 70 proteins that were differentially labeled by APEX2-tagged AMPARs after induction of chemical Long-term potentiation of synapses (cLTP) in cultured neurons. Included in this list, were four members of the IgLON family of GPI-anchored proteins (Ntm, OBCAM/Opcml, Negr1, Lsamp). We show OBCAM and NTM directly interact with the extracellular domains of AMPARs. Moreover, overexpression of NTM significantly attenuates the mobility of surface AMPARs in dendritic spines. These data represent a significant first step at uncovering the unexplored extracellular regulation of AMPARs, with broad implications for synapse function and synaptic plasticity. | | 10:33p |
Spatiotemporal Abstraction Theory: Re-Interpretation of Localized Cortical Networks
The brain excels at extracting meaning from noisy and degraded input, yet the computational principles that underlie this robustness remain unclear. We propose a theory of spatiotemporal abstraction (STA), in which localized cortical networks integrate inputs across space and time to produce multi-scale, concept-level representations that remain stable despite loss of detail. We demonstrate how this principle explains a long-standing paradox of how cochlear implant patients can understand speech despite severely scrambled neural patterns. STA provides a unified framework that explains fundamental questions: Why do we have so many neurons that respond very similarly in one cortical location? Why do we have different inhibitory neurons? It also forces us to re-examine long-standing explanations of memory, creativity, illusions, attractor dynamics, excitatory-to-inhibitory balance, and the structure and purpose of the ubiquitous canonical circuits seen throughout the brain. We conclude with STA implications for improving neural implants and artificial neural networks. | | 10:33p |
Recursive Entropic Time: A Neural Framework forthe Informational Construction of SubjectiveDuration
The conception of time as a universal and independent parameter is a foundational assumption in physical models. However, it does not address the subjective nature of temporal perception and leads to inconsistencies in complex systems. This paper introduces the Recursive Entropic Time framework, a theory proposing that subjective time is not fixed but instead emerges from neural systems involved in interpretation and association. We hypothesize that the brain uses a divided system for processing time. Primary sensory cortices handle objective clock-based time, while higher-order associative cortices construct subjective time through a mechanism in which the rate of temporal flow is inversely influenced by the amount of information being processed. To test this theory, we conducted a two-part investigation. In the first part, we used a public dataset involving brain scans of subjects under the influence of a hallucinogenic substance. This revealed that the Recursive Entropic Time model had greater effectiveness in associative regions of the brain compared to primary sensory areas. This finding suggested a region-specific effect rather than a global one. In the second part, we examined brain activity during a temporal reproduction task and analyzed two trials where participants produced nearly identical time durations. Despite the behavioral similarity, the information processing differed between the trials. The Recursive Entropic Time model accurately predicted these outcomes by reflecting internal durations derived from the information load. These findings support Recursive Entropic Time as a falsifiable and mechanistic explanation of how the brain constructs subjective time. We argue that time, as it is experienced, is not a simple reflection of external reality but a mental construction shaped by higher cognition. This framework provides a measurable and testable method for understanding subjective time and may lead to applications such as brain-based time atlases and insights into cognitive disorders. |
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