Biology subjects

van den Berg, M.

Publications and source records attributed to van den Berg, M..

11 recordsLinked to original sources

bioRxiv2026

Age-specific pediatric templates improve EEG source-reconstructed biomarkers in children

EEG source reconstruction requires an anatomical head model, ideally constructed from individual magnetic resonance imaging (MRI) scans. In developmental studies of children and adolescents, however, MRIs are rarely available. Researchers therefore routinely rely on adult templates, such as the FreeSurfer average (fsaverage), despite substantial anatomical changes throughout development. How much this reliance on adult models biases downstream EEG biomarkers remains unclear. Here, we investigated whether age-specific pediatric templates offer a better alternative to fsaverage for EEG-derived biomarkers in children and adolescents, using individual MRI-based reconstruction as the reference. We analyzed eyes-closed resting-state EEGs from 384 Healthy Brain Network participants aged 5.5 to 17.5 years. For each participant, we tested three anatomical models: their individual MRI, an age-specific pediatric template from a series spanning ages 6-17 at one-year intervals, and the adult fsaverage template. We compared four EEG biomarkers in childhood and adolescence: absolute power, relative power, long-range temporal correlations quantified with detrended fluctuation analysis (DFA), and functional excitation-inhibition (fE/I) ratio. Pediatric templates agreed more closely with individual MRI-based biomarkers in both developmental groups and had fewer parcels with significantly different biomarker values than the adult template, except for absolute power in older adolescents. We conclude that when individual MRI is not available, age-specific pediatric templates match individual MRI-based EEG biomarker values more closely than the adult template across all four biomarkers up to approximately 12 years of age and should be the preferred choice at least up to this age.

neuroscience↗

bioRxiv2025

Long-term dietary interventions fail to mitigate functional connectivity loss and cognitive decline in the TgF344-AD rat model of Alzheimers Disease

IntroductionAlzheimers disease (AD) is a complex neurodegenerative disorder, characterized by altered brain functional connectivity and network activity, detectable using resting-state functional MRI (rsfMRI). Caloric restriction (CR) and its mimetic resveratrol (Rsv) have shown potential in reducing AD-related pathology and preserving brain function, though research on long-term efficacy is limited. Therefore, we aimed to assess the effects of short- term CR and Rsv administrations on resting-state (rs) functional connectivity (FC), after which we assessed the effects of long-term CR and Rsv interventions on rs-FC, spatial memory, amyloid burden, and neuroinflammation in TgF344-AD rats (Tg) and wild-type (WT) littermates. Materials and MethodsWe used rsfMRI to investigate rs-FC changes after CR (40%) or daily Rsv supplementation (10 mg/kg, oral) in male and female, WT and TgF344-AD (Tg) rats at the age of 4 months and 11 months, after, respectively, 1 month (short-term) and 8 months (long- term) of either Rsv supplementation, control (Ctrl) or CR diet. Additionally, spatial memory was assessed utilizing the Morris Water Maze (MWM), followed by histological validation of amyloid plaque load (X34), astrogliosis (GFAP) and microgliosis (IBA-1) at 11 months of age. ResultsBoth long-term CR or Rsv supplementation exert limited effects in the TgF344-AD model on the known AD-related pathological hallmarks. Short-term CR led to a reduction in rs-FC in female TgF344-AD rats compared to Rsv Tg supplemented rats for connections primarily within and between the hippocampal network, while between other connections, CR reduced rs-FC compared to Ctrl in females, irrespective of genotype. Rsv increased rs-FC compared to CR for only a few connections in females, again irrespective of genotype. Long- term CR decreased rs-FC in male Tg CR rats, compared to Tg Ctrl and WT CR rats, primarily for connections within the lateral cortical network (LCN). For other connections, CR reduced rs- FC when compared to Ctrl, irrespective of genotype. Overall, Rsv supplementation showed negligible effects on rs-FC. Moreover, long-term CR yielded modest cognitive improvements in male Tg rats, as evidenced by enhanced performance in the MWM but not in females. Histological validation after long-term dietary intervention revealed region-specific increase or decrease of amyloid burden after CR or Rsv supplementation, respectively. Additionally, CR reduced IBA-1 levels in males, irrespective of genotype, GFAP levels were unaffected by long- term dietary intervention. ConclusionAltogether, our findings indicate that long-term CR and Rsv exert distinct and limited effects on AD-related pathology in the TgF344-AD model, with CR demonstrating a modest but greater effect on functional and cognitive measures compared to Rsv. This study underscores the difficulty of altering key disease processes with these long-term dietary approaches, highlighting the need for more comprehensive long-term studies to elucidate the potential modulatory role of dietary interventions on AD pathophysiology.

neuroscience↗

bioRxiv2024

Short-term caloric restriction or resveratrol supplementation alters large-scale brain network connectivity in male and female rats

IntroductionDietary interventions such as caloric restriction (CR) exert positive effects on brain health. Unfortunately, poor compliance hinders the success of this approach. A proposed alternative is resveratrol (Rsv), a CR-mimetic known to promote brain health. Direct comparison between the effects of Rsv and CR on brain health is lacking, with limited knowledge on their sex-specific effects. Therefore, we aimed to compare and unravel the sex-specific impact of these dietary interventions on spontaneous brain activity. MethodsHere, we used resting-state fMRI to investigate functional connectivity (FC) changes in five prominent resting-state brain networks (RSNs) in healthy four month old male and female F344 rats supplemented to either 40% CR or daily Rsv supplementation (10 mg/kg, oral) for the duration of one month. ResultsOur results demonstrated a decreased body weight (BW) in CR rats, as well as an increase in body weight in male Rsv supplemented rats, compared to female Rsv supplemented rats, whereas this difference between sexes was not observed in the control or CR groups. Furthermore, we found that both CR or Rsv supplementation induce a female-specific decrease of FC between the subcortical network and hippocampal network, and between the subcortical network and lateral cortical network. Moreover, Rsv supplementation lowered FC within the hippocampal network and between the hippocampal and the default mode like network, the lateral cortical network and the sensory network - an effect not observed for the CR rats. Finally, we observed an overall lower FC in male rats compared to females, irrespective of dietary intervention, within the subcortical network and between the subcortical, the sensory and default mode like network. DiscussionOur findings reveal that both CR and Rsv induce a similar female-specific decrease of FC in RSNs associated with memory and emotion, all the while CR and Rsv induce dissimilar changes in body weight and other within- and between RSN FC measures. Altogether, this study provides insight into the effects and comparability of short-term CR and Rsv supplementation on brain connectivity within and between RSNs in both male and female F344 rats, providing a FC reference for future research of dietary effects.

neuroscience↗

bioRxiv2024

A Spike Trimer Dimer-Inducing Nanobody with Anti-Sarbecovirus Activity

The continued emergence and zoonotic threat posed by coronaviruses highlight the urgent need for effective antiviral strategies with broad reactivity to counter new emerging strains. Nanobodies (or single-domain antibodies) are promising alternatives to traditional monoclonal antibodies, due to their small size, cost-effectiveness and ease of bioengineering. Here, we describe 7F, a llama-derived nanobody, targeting the spike receptor binding domain of sarbecoviruses and SARS-like coronaviruses. 7F demonstrates potent neutralization against SARS-CoV-2 and cross-neutralizing activity against SARS-CoV and SARS-like CoV WIV16 pseudoviruses. Structural analysis reveals 7Fs ability to induce the formation of spike trimer dimers by engaging with two SARS-CoV-2 spike RBDs, targeting the highly conserved class IV region. Bivalent 7F constructs substantially enhance neutralization potency and breadth, up to more recent SARS-CoV-2 variants of concern. Furthermore, we demonstrate the therapeutic potential of 7F against SARS-CoV-2 in the fully differentiated 3D tissue cultures mirroring the epithelium of the human airway ex vivo. The broad sarbecovirus activity and distinctive structural features of 7F underscore its potential as promising antiviral against emerging and evolving sarbecoviruses.

microbiology↗

bioRxiv2024

Early altered directionality of resting brain network state transitions in the TgF344-AD rat model of Alzheimer's disease

Alzheimers disease (AD) is a progressive neurodegenerative disease resulting in memory loss and cognitive decline. Synaptic dysfunction is an early hallmark of the disease whose effects on whole-brain functional architecture can be identified using resting-state functional MRI (rsfMRI). Insights into mechanisms of early, whole-brain network alterations can help our understanding of the functional impact of ADs pathophysiology. Here, we obtained rsfMRI data in the TgF344-AD rat model at the pre- and early-plaque stages. This model recapitulates the major pathological and behavioural hallmarks of AD. We used co-activation pattern (CAP) analysis to investigate if and how the dynamic organization of intrinsic brain functional networks states, undetectable by earlier methods, is altered at these early stages. We identified and characterized six intrinsic brain states as CAPs, their spatial and temporal features, and the transitions between the different states. At the pre-plaque stage, the TgF344-AD rats showed reduced co-activation of hub regions in the CAPs corresponding to the default mode-like and lateral cortical network. Default mode-like network activity segregated into two distinct brain states, with one state characterised by high co-activation of the basal forebrain. This basal forebrain co-activation was reduced in TgF344-AD animals mainly at the pre-plaque stage. Brain state transition probabilities were altered at the pre-plaque stage between states involving the default mode-like network, lateral cortical network, and basal forebrain regions. Additionally, while the directionality preference in the network-state transitions observed in the wild-type animals at the pre-plaque stage had diminished at the early-plaque stage, TgF344-AD animals continued to show directionality preference at both stages. Our study enhances the understanding of intrinsic brain state dynamics and how they are impacted at the early stages of AD, providing a nuanced characterization of the early, functional impact of the diseases neurodegenerative process.

neuroscience↗

bioRxiv2023

Evolution of aberrant brain-wide spatiotemporal dynamics of resting-state networks in a Huntington's disease mouse model

Distinct resting-state networks (RSNs) are differentially altered in the course of Huntingtons disease (HD). However, these RSN changes are depicted using traditional functional connectivity analyses which ignore the dynamic brain states that constitute these RSNs and their time-dependent relationship. Dynamic states are represented by recurring spatiotemporal patterns of propagating cortical and subcortical brain activity observed in low-frequency BOLD fluctuations, called quasi-periodic patterns (QPPs). In this study, we used resting-state fMRI to investigate QPPs in the zQ175DN mouse model of HD at 3, 6 and 10 months of age. We identified age- and genotype-specific short (3s) QPPs, representative of the lateral cortical network (LCN) and the default mode-like network (DMLN), and a long (10s) QPP, the homolog of the human primary QPP, exhibiting the propagation of activity between the LCN and the DMLN. Hyperactivity was present in the caudate putamen and the somatosensory cortex in zQ175DN mice at 3 and 6 months of age. Moreover, DMLN-wide reduction in activation was observed at all ages, where at 6 and 10 months of age the reduced activity gradually advanced into a breakdown of the LCN-to-DMLN propagation. We then investigated the relationship in the timing of peak activity of six brain regions involved in the long QPPs and found that the retrosplenial cortex, a transmodal region which orchestrates multisensory integration, has a premature peak of BOLD activation in zQ175DN mice at 6 months of age, as compared to age-matched controls. Irrespective of either LCN or DMLN activation, this resulted in an asynchrony of the retrosplenial cortex in the peak timing relationships relative to other regions during the long (10s) QPPs. Finally, the normative, age-dependent, wild-type QPPs were significantly decreased in occurrence in the zQ175DN group at each age, indicating the presence of phenotypically-driven LCN and DMLN states as captured with QPPs. As BOLD-dependent variations result from neurovascular coupling, we assessed mutant huntingtin (mHTT) deposition in astrocytes and pericytes, known components of the neurogliovascular unit. These analyses showed increased cell-type dependent deposition starting at 6 months in the caudate putamen, somatosensory and motor cortex, regions that are prominently involved in HD pathology as seen in humans. Our findings provide meaningful insights into the development and progression of altered functional brain dynamics in this HD model, opening potential new avenues for its application in clinical HD research. SUMMARYHuntingtons disease (HD) is marked by irreversible loss of neuronal function for which currently no availability for disease-modifying treatment exists. Advances in the understanding of disease progression can aid biomarker development, which in turn can accelerate therapeutic discovery. We characterized the progression of altered dynamics of whole-brain network states in the zQ175DN mouse model of HD using a dynamic functional connectivity (FC) approach to resting-state fMRI and identified quasi-periodic patterns (QPPs) of brain activity constituting the most prominent resting-state networks. The occurrence of the normative QPPs, as observed in healthy controls, was reduced in the HD model as the phenotype progressed. This uncovered progressive cessation of synchronous brain activity with phenotypic progression, which is not observed with the conventional static FC approaches. This work opens new avenues in assessing the dynamics of whole brain states, through QPPs, in clinical HD research.

neuroscience↗

bioRxiv2022

Cholinergic modulation supports DMN suppression during resting state

Brain activity during the resting state is widely used to examine brain organization, cognition and alterations in disease states. While it is known that neuromodulation and the state of alertness impact resting-state activity, neural mechanisms behind such modulation of resting-state activity are unknown. In this work, we used a computational model to demonstrate that change in excitability and recurrent connections, due to cholinergic modulation, impacts resting-state activity. The results of such modulation in the model match closely with experimental work on direct cholinergic modulation of Default Mode Network (DMN) in rodents. We further extended our study to the human connectome derived from diffusion-weighted MRI. In human resting-state simulations, an increase in cholinergic input resulted in a brain-wide reduction of functional connectivity. Furthermore, selective cholinergic modulation of DMN closely captured experimentally observed transitions between the baseline resting state and states with suppressed DMN fluctuations associated with attention to external tasks. Our study thus provides insight into potential neural mechanisms for the effects of cholinergic neuromodulation on resting-state activity and its dynamics.

neuroscience↗

bioRxiv2022

Early Electrophysiological Aberrations in the Hippocampus of the TgF344-AD Rat Model as a Potential Biomarker for Alzheimer's Disease Prognosis

The hippocampus is thought to guide navigation and has an essential contribution to learning and memory. Hippocampus is one of the brain regions impaired in Alzheimers disease (AD), a neurodegenerative disease with progressive memory impairments and cognitive decline. Although successful treatments for AD are still not available, developing new strategies to detect AD at early stages before clinical manifestation is crucial for timely interventions. Here, we investigated in the TgF344-AD rat model the classification of AD-transgenic rats versus Wild-type littermates (WT) from electrophysiological activity recorded in the hippocampus of freely moving subjects at an early, pre-symptomatic stage of the disease (6 months old). To this end, recorded signals were filtered in two separate frequency regimes namely low frequency LFP signals and high frequency spiking activity and passed to machine learning (ML) classifiers to identify the genotype of the rats (TG vs. WT). For the low frequency analysis, we first filtered the signals and extracted the power spectra in different frequency bands known to carry differential information in the hippocampus (delta, theta, slow- and fast-gamma) while for the high frequency analysis, we extracted spike-trains of neurons and calculated different distance metrics between them, including Van Rossum (VR), Inter Spike Interval (ISI), and Event Synchronization (ES). These measures were then used as features for classification with different ML classifiers. We found that both low and high frequency signals were able to classify the rat genotype with a high accuracy with specific signals such as the gamma band power, providing an important fraction of information. In addition, when we combined information from both low and high frequency the classification was boosted indicating that independent information is present across the two bands. The results of this study offer a better insight into how different regions of the hippocampus are affected in earlier stages of AD.

neuroscience↗

bioRxiv2020

Mono-ubiquitination of Rabphilin 3A by UBE3A serves a non-degradative function

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by brain-specific loss of UBE3A, an E3 ubiquitin protein ligase. A substantial number of possible ubiquitination targets of UBE3A have been identified, although evidence of being direct UBE3A substrates is often lacking. Here we identified the synaptic protein Rabphilin-3a (RPH3A), an effector of the RAB3A small GTPase involved in axonal vesicle priming and docking, as a ubiquitination target of UBE3A. We found that the UBE3A and RAB3A binding sites on RPH3A partially overlap, and that RAB3A binding to RPH3A interferes with UBE3A binding. We confirmed previous observations that RPH3A levels are critically dependent on RAB3A binding but, rather surprisingly, we found that the reduced RPH3A levels in the absence of RAB3A are not mediated by UBE3A. Indeed, while we found that RPH3A is ubiquitinated in a UBE3A-dependent manner in mouse brain, UBE3A mono-ubiquitinates RPH3A and does not facilitate RPH3A degradation. Moreover, we found that an AS-linked UBE3A missense mutation in the UBE3A region that interacts with RPH3A, abrogates the interaction with RPH3A. In conclusion, our results identify RPH3A as a novel target of UBE3A and suggest that UBE3A-dependent ubiquitination of RPH3A serves a non-degradative function.

neuroscience↗

bioRxiv2020

Identification and antimicrobial properties of bacteria isolated from naturally decaying wood

Research on wood decay in forest ecosystems has traditionally focused on wood-rot fungi, which lead the decay process through attack of the lignocellulose complex. The role of bacteria, which can be highly abundant, is still unclear. Wood-inhabiting bacteria are thought to be nutritionally dependent on decay activities of wood-rot fungi. Therefore, we hypothesized that these bacteria are not antagonistic against wood-rot fungi whereas antagonistic activity against other bacteria may be high (resource competition). This was examined for decaying wood in temperate forests. We found that the abundance of cultivable bacteria in decaying wood can be highly variable. The general pattern is an increase of bacteria with progressive decay, but we also identified several fungi that were apparently able to exclude bacteria from their woody territory. We established a bacterial collection which is highly representative for decaying wood with typical wood-inhabiting taxa: Xanthomonadaceae, Acetobacteraceae, Caulobacteraceae, Methylovirgula, Sphingomonas, Burkholderia and Granulicella. In vitro antagonistic activity against other bacteria and fungi was evaluated. In contrast to our hypothesis, we found surprisingly low antagonistic activity against bacteria (<2% of isolates), while antagonism against fungi was more prevalent. These results may point at a prominent role of mycophagy (growth at the expense of living fungi) among wood-inhabiting bacteria.

microbiology↗

bioRxiv2018

Excitatory GABAergic signalling is associated with acquired benzodiazepine resistance in status epilepticus

Status epilepticus (SE) is defined as a state of unrelenting seizure activity. It is associated with a rapidly rising mortality rate, and thus constitutes a medical emergency. Benzodiazepines, which act as positive modulators of chloride (Cl-) permeable GABAA receptors, are indicated as the first line of treatment, but this is ineffective in many cases. We found that 48% of children presenting with SE were unresponsive to benzodiazepine treatment, and critically, that the duration of SE at the time of treatment is an important predictor of non-responsiveness. We therefore investigated the cellular mechanisms that underlie acquired benzodiazepine resistance, using rodent organotypic brain slices. Removing Mg2+ ions leads to an evolving pattern of epileptiform activity, and eventually to a persistent state of repetitive discharges that strongly resembles clinical EEG recordings of SE. We show that the persistent SE-like activity is associated with a reduction in GABAA receptor conductance and Cl- extrusion capability. We explored the effect on intraneuronal Cl- using both gramicidin, perforated-patch clamp recordings and Cl- imaging. This showed that during SE-like activity, reduced Cl- extrusion capacity was further exacerbated by activity-dependent Cl- loading, resulting in a persistently high intraneuronal Cl-. Consistent with these results, we found that optogenetic stimulation of GABAergic interneurons in the SE-like state, actually enhanced epileptiform activity in a GABAAR dependent manner. Together our findings describe a novel potential mechanism underlying benzodiazepine-resistant SE, with relevance to how this life-threatening condition should be managed in the clinic.

neuroscience↗