Biology subjects

Schreiber, S.

Publications and source records attributed to Schreiber, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Tonic pain revalues associative memories of phasic pain

Tonic pain is proposed to adapt protective behaviours during recovery from injury. A key untested prediction of this homeostatic model is that it appropriately reshapes internal representations of phasic pain. We investigated whether lateralised tonic pain modulates phasic pain-predictive cues on that side. Using a virtual-reality Pavlovian revaluation paradigm, we assessed physiological and neural conditioned responses with EEG in theta, alpha, and beta frequency bands. Pain-predictive cues elicited neural enhanced alpha and beta suppression and increased pupil diameter during conditioning acquisition. Critically, tonic pain revalued phasic conditioned responses during extinction, with reduced midfrontal theta synchronisation when the laterality of tonic pain was congruent with predicted phasic pain. Greater tonic pain unpleasantness also enhanced posterior beta suppression for congruent cues. These findings provide evidence for an internal representation of cue-pain associations that is topographically modulated by tonic pain, suggesting that tonic pain actively reconfigures pain predictions, enabling anticipatory protective behaviours.

neuroscience↗

bioRxiv2025

Dynamically rich states in balanced networks induced by single-neuron dynamics

Network states with rich dynamics and highly variable firing rates of individual neurons are prominent in experimental observations and thought to benefit complex information processing and learning. Such states have been proposed to arise from properties of network coupling, like a strong connectivity or slow synaptic dynamics. Here, we identify an alternative mechanism based on weak synaptic coupling and intrinsic cellular dynamics. We show that a switch in the cellular excitability class of action-potential generation (via a switch in the underlying mathematical bifurcation), further amplified by recurrent interactions, results in super-Poissonian spiking variability in random balanced networks. Information encoding is shifted to higher frequency bands and collective chaos in the network is enhanced when intrinsic cellular dynamics follow a saddle homoclinic orbit (HOM) bifurcation. The robust effect links the biophysics of individual neurons to collective dynamics of large random networks, highlighting the relevance of single-cell dynamics for computation in physiological and artificial networks.

neuroscience↗

bioRxiv2025

Inhibition of acute lung inflammation by a neuroimmune circuit induced by vagal nerve stimulation.

Vagus nerve stimulation (VNS) has been shown to limit immune cell activity across several pathologies ranging from sepsis to auto-immune diseases. While stimulation of vagal efferent neurons has been previously demonstrated to reduce maladaptive host responses during endotoxemia, only selective stimulation of vagal afferent neurons was able to inhibit TLR7-induced macrophage activation and neutrophil recruitment in the lung. These anti-inflammatory actions are facilitated by systemic increases in epinephrine, as VNS significantly increased epinephrine in the serum and bronchoalveolar lavage fluid, and inhibition of epinephrine production eliminated the protection afforded by VNS. Selective afferent VNS induced activation in the nucleus tractus solitarius and the rostral ventrolateral medulla. Inhibition of neuronal activity in this brain region that controls peripheral sympathetic nervous system activity rendered VNS ineffective. Activation of the {beta}2-adrenergic receptor ({beta}2AR) is critical for innate immune cell suppression, as the anti-inflammatory effects of VNS were eliminated in {beta}2AR-knock out mice, and with pharmacological inhibition of the {beta}2AR. Analysis of the immune cells responding to R848 critically identified that plasmacytoid dendritic cells were refractive to inhibition by VNS, and this corresponded to lack of {beta}2AR expression. These findings demonstrate a novel neuro-immune circuit elicited by VNS that can control acute lung inflammation. SummaryWe have identified a novel neuro-immune circuit activated by afferent vagus nerve stimulation to reduce acute lung inflammation. This effect was dependent on vagal-induced adrenal gland-derived epinephrine release that initiates anti-inflammatory {beta}2-adrenergic receptor signaling in innate immune cells within the lung.

immunology↗

bioRxiv2025

Individualized Phenotyping of Functional ALS Pathology in Sensorimotor Cortex

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons in primary motor cortex (MI), leading to muscle weakness, atrophy, and death within a median of three years. Even though ALS is characterized by different disease subtypes affecting different body parts, individiualized phenotyping of functional ALS pathology has so far not been achieved. We recorded 7 Tesla functional MRI (7T-fMRI) data while ALS patients and matched controls moved affected and non-affected body parts in the MR scanner. We applied robust Shared Response Modeling (rSRM) for capturing ALS-specific shared responses for group classification, and Partial Least Squares (PLS) regression for relating the latent variables to clinical subtypes and the degree of disease progression. We show that both functional connectivity and functional activation in MI are a predictor for disease onset site. However, disease severity could best be predicted by functional connectivity rather than pure activation changes. Critically, we show that functionally disease-defining information in MI is not strongest in the area that is behaviorally first-affected, deviating from the behavioral phenotype of the patients. When computing the models weight distribution of the King stage classification and projecting them back into voxel space, the highest mean weights are present in the foot and tongue/face regions that seem to drive disease progress. Our data highlight the importance of 7T-fMRI task-based functional connectivity measures for classifying ALS-patients, and provide evidence that a single 7T-MRI scan can be used for identifying a disease signature of each individual ALS patient.

neuroscience↗

bioRxiv2024

The electrogenicity of the Na+/K+-ATPase poses challenges for computation in highly active spiking cells

1The evolution of the Na+/K+-ATPase laid the foundation for ion homeostasis and electrical signalling. While not required for restoration of ionic gradients, the electrogenicity of the pump (resulting from its 3:2 stoichiometry) is useful to prevent runaway activity. As we show here, electrogenicity could also come with disadvantageous side effects: (1) an activity-dependent shift in a cells baseline firing and (2) interference with computation, disturbing network entrainment when inputs change strongly. We exemplify these generic effects in a mathematical model of the weakly electric fish electrocyte, which spikes at hundreds of Hz and is exposed to abrupt rate changes when producing behaviorally-relevant communication signals. We discuss biophysical strategies that may allow cells to mitigate the consequences of electrogenicity at additional metabolic cost and postulate an interesting role for a voltage-dependence of the Na+/K+-ATPase. Our work shows that the pumps electrogenicity can open an additional axis of vulnerability that may play a role in brain disease.

neuroscience↗

bioRxiv2024

Spatial and morphological organization of mitochondria across a connectome

Neuronal function depends critically on the cell biological organization of mitochondria, which regulate calcium signals and produce energy, among other roles. However, little is known about how mitochondria are organized within the circuits of neurons that make up each brain. To uncover the systematic rules that govern mitochondria shape and position in a connectome, we analyzed the morphological and spatial organization of more than 100,000 mitochondria in over 1,000 visual projection neurons in the Drosophila connectome. We found that mitochondrial shape and size differ systematically between cell types, and are distinct enough between cell types to serve as an identifying fingerprint. Moreover, we derived three quantitative rules that describe how mitochondria are positioned within neurons relative to synapses and other subcellular features: (1) they are positioned with a precision of 2-3 microns; (2) their relative preference for pre- and postsynaptic sites and other subcellular features differs between axons and dendrites; (3) their positions were specialized to different cell types. These organizing rules correlated with functional and anatomical properties of the cells, including visual responses and input connectivity. We also find that, in the flys olfactory associative learning circuits, mitochondria are enriched at presynapses to particular postsynaptic cells by accumulating in functional sub-compartments of axons. Overall, our findings reveal a robust set of organizing principles for mitochondria within and between cells, uncovering cell biology that maps onto the organization of the connectome and adding new dimensions for understanding circuit function in the connectome.

neuroscience↗

bioRxiv2024

Neolithic introgression of IL23R-related protection against chronic inflammatory bowel diseases in modern Europeans

BackgroundThe hypomorphic variant rs11209026-A in the IL23R gene provides significant protection against immune-related diseases in Europeans, notably inflammatory bowel disease (IBD). Today, the A-allele occurs with an average frequency of 5% in Europe. MethodsThis study comprised 251 ancient genomes from Europe spanning over 14,000 years. In these samples, the investigation focused on admixture informed analyses and selection scans of rs11209026-A and its haplotypes. Findingsrs11209026-A was found at high frequencies in Anatolian Farmers (AF, 18%) where it was likely under weak positive selection. AF later introduced the allele into the ancient European gene-pool. Subsequent admixture caused its frequency to decrease and formed the current southwest-to-northeast allele frequency cline in Europe. The geographic distribution of rs11209026-A may influence the gradient in IBD incidence rates that are highest in northern and eastern Europe. InterpretationGiven the dramatic changes from hunting and gathering to agriculture during the Neolithic, AF might have been exposed to selective pressures from a pro-inflammatory lifestyle and diet. Therefore, the protective A-allele may have increased survival by reducing intestinal inflammation and microbiome dysbiosis. The adaptively evolved function of the variant likely contributes to the high efficacy and low side-effects of modern IL-23 neutralization therapies for chronic inflammatory diseases. This study highlights how evolutionary informed research can provide promising targets for new therapeutic strategies. FundingDeutsche Forschungsgemeinschaft (DFG German Research Foundation) under Germanys Excellence Strategy - EXC 2167 390884018 and EXC 2150 390870439.

evolutionary biology↗

bioRxiv2024

Antigen-driven expansion of public clonal T cell populations in inflammatory bowel diseases

BackgroundInflammatory Bowel Diseases (IBDs), including Crohns disease (CD) and ulcerative colitis (UC), are known to involve shifts in the T-cell repertoires of affected individuals. These include a reduction in regulatory T cells in both diseases, increase in TNF production in CD, expansion of an unconventional T-cell population in CD, and clonal expansion of abundant T-cell populations in CD mucosal tissue. There are also differential HLA risk and protective alleles between CD and UC, implying CD- and UC-specific repertoire changes that have not yet been identified. MethodsWe performed ImmunoSequencing on blood samples from 3,853 CD cases, 1,803 UC cases, and 5,596 healthy controls. For each sample we imputed HLA type and cytomegalovirus (CMV) infection status based on public T-cell receptor {beta} (TCRB) usage and identified public TCRBs enriched in CD or UC cases. FindingsWe determine that there is more expansion across clonotypes in CD, but not UC, compared with healthy controls. We also identify novel interactive effects of HLA-DQ heterodimers with CD and UC risk. Strikingly, from blood we identify public TCRBs specifically expanded in CD or UC. These sequences are more abundant in intestinal mucosal samples, form groups of similar CDR3 sequences, and can be associated to specific HLA alleles. Although the prevalence of these sequences is higher in ileal and ileocolonic CD than colonic CD or UC, the TCRB sequences themselves are shared across CD and not between CD and UC. InterpretationThere are peptide antigens that commonly evoke immune reactions in IBD cases and rarely in non-IBD controls. These antigens differ between CD and UC. CD, particularly ileal CD, also seems to involve more substantial changes in clonal population structure than UC, compared to healthy controls.

immunology↗

bioRxiv2024

Pericytes mediate neurovascular remodeling in chronic arterial hypertension

Chronic arterial hypertension restructures the vascular architecture of the brain, leading to a series of pathological responses that culminate in cerebral small vessel disease. Pericytes respond dynamically to vascular challenges; however, how they manifest under the continuous strain of hypertension has not been elucidated. Therefore, in this study, we characterized pericyte behavior alongside hypertensive states in the spontaneously hypertensive stroke-prone rat (SHRSP) model, emphasizing their phenotypic and metabolic transformation. Our results reveal an early transition in PDGFR{beta}+ pericytes toward increased NG2 and CD13 co-expressing subtypes, signaling enhanced pericyte reactivity in an effort to stabilize vascular structures and an inflammatory engagement within the vascular niche in response to hypertensive stress. Gene expression profiling of microvessels revealed altered expression within crucial pathways i.e., angiogenesis, blood-brain barrier integrity, hypoxia and inflammation. Furthermore, we detected that circulating extracellular vesicles from SHRSP alter pericyte mitochondrial membrane potential, highlighting their ability to transmit pathogenic signals that exacerbate vascular remodeling. Detailed metabolic analysis revealed a significant shift toward glycolytic metabolism in pericytes already in initial hypertension, alongside a dysregulation of ATP production pathways. These findings emphasize the transformative influence of hypertension on cerebral pericytes and the extensive consequences on cerebral vascular health.

neuroscience↗

bioRxiv2024

Epithelial Hexokinase 2 expression is a marker for intestinal inflammation

BackgroundInflammation is characterized by a metabolic switch promoting glycolysis and lactate production. Hexokinases (HK) catalyze the first reaction of glycolysis and inhibition of epithelial HK2 protected from colitis in mice. HK2 expression has been described as elevated in patients with intestinal inflammation, however there is conflicting data from few cohorts especially with severely inflamed individuals, thus systematic studies linking disease activity with HK2 levels are needed. MethodsWe examined the relationship between HK2 expression and inflammation severity using bulk transcriptome data derived from the mucosa of thoroughly phenotyped patients suffering from intestinal inflammation of two independent cohorts. Analyzing publicly available single cell RNA sequencing data and performing immunofluorescence on colonic biopsies of unrelated patients with intestinal inflammation confirmed the RNA-based findings on cellular and protein level. ResultsHK2 expression gradually increased from mild to intermediate inflammation, yet strongly declined at high inflammation scores. Expression of epithelial marker genes also declined at high inflammation scores, whereas that of candidate immune marker genes increased, indicating a cellular remodeling of the mucosa during inflammation with an infiltration of HK2-negative immune cells and a loss of the apical epithelium - the main site of HK2 expression. Normalizing for the enterocyte loss clearly identified epithelial HK2 expression as gradually increasing with disease activity and remaining elevated at high inflammation scores. HK2 protein expression was mostly restricted to brush border enterocytes and these cells along with HK2 levels vanished with increasing disease severity. ConclusionsOur findings clearly define dysregulated epithelial HK2 expression as an indicator of disease activity in intestinal inflammation and suggest targeted HK2-inhibition as a potential therapeutic avenue.

immunology↗

bioRxiv2024

Chemical tools to expand the ligandable proteome: diversity-oriented synthesis-based photoreactive stereoprobes

Chemical proteomics enables the global assessment of small molecule-protein interactions in native biological systems and has emerged as a versatile approach for ligand discovery. The range of small molecules explored by chemical proteomics has, however, been limited. Here, we describe a diversity-oriented synthesis (DOS)-inspired library of stereochemically-defined compounds bearing diazirine and alkyne units for UV light-induced covalent modification and click chemistry enrichment of interacting proteins, respectively. We find that these photo-stereoprobes interact in a stereoselective manner with hundreds of proteins from various structural and functional classes in human cells and demonstrate that these interactions can form the basis for high-throughput screening-compatible nanoBRET assays. Integrated phenotypic analysis and chemical proteomics identified photo-stereoprobes that modulate autophagy by engaging the mitochondrial serine protease CLPP. Our findings show the utility of photo-stereoprobes for expanding the ligandable proteome, furnishing target engagement assays, and discovering and characterizing bioactive small molecules by cell-based screening.

biochemistry↗

bioRxiv2024

scRNA-seq reveals persistent aberrant differentiation of nasal epithelium driven by TNFα and TGFβ in post-COVID syndrome

Post-COVID syndrome (PCS) currently affects approximately 3-17% of people following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and has the potential to become a significant global health burden. PCS presents with various symptoms, and methods for improved PCS assessment are presently developed to guide therapy. Nevertheless, there are few mechanistic insights and treatment options. Here, we performed single-cell RNA transcriptomics on nasal biopsies from 33 patients suffering from PCS with mild, moderate, or severe symptoms. We identified 17 different cell clusters representing 12 unique cell populations, including all major epithelial cell types of the conducting airways and basal, secretory, and ciliated cells. Severe PCS was associated with decreased numbers of ciliated cells and the presence of immune cells. Ensuing inflammatory signaling upregulated TGF{beta} and induced an epithelial-mesenchymal transition, which led to the high abundance of basal cells and a mis-stratified epithelium. We confirmed the results in vitro using an air-liquid interface culture and validated TNF as the causal inflammatory cytokine. In summary, our results show that one mechanism for sustained PCS is not through continued viral load, but through the presence of immune cells in nasal tissue leading to impaired mucosal barrier function and repeated infections. These findings could be further explored as a therapeutic option akin to other chronic inflammatory diseases by inhibiting the TNF-TGF{beta} axis, restoring the nasal epithelium, and reducing respiratory tract-related infections.

genomics↗

bioRxiv2023

Age-Related Differences in Human Cortical Microstructure Depend on the Distance to the Nearest Vein

Age-related differences in cortical microstructure are used to understand the neuronal mechanisms that underlie human brain ageing. The cerebral vasculature contributes to cortical ageing, but its precise interaction with cortical microstructure is poorly understood. In a cross-sectional study, we combine venous imaging with vessel distance mapping (VDM) to investigate the interaction between venous distances and age-related differences in the microstructural architecture of the primary somatosensory cortex (S1), the primary motor cortex (M1), and additional areas in frontal cortex as non-sensorimotor control regions. We scanned 18 younger adults and 17 older adults using 7T-MRI to measure age-related changes in quantitative T1 (qT1) values, positive QSM (pQSM) values, and negative QSM (nQSM) values at 0.5 mm isotropic resolution. We modelled different cortical depths using an equi-volume approach and assessed the distance of each voxel to its nearest vein using VDM. Our data reveal a dependence of cortical qT1 and pQSM values on venous distance. In addition, there is an interaction between venous distance and age on qT1 values, driven by lower qT1 values in older compared to younger adults in voxels that are closer to a vein. Together, our data show that the local venous architecture explains a significant amount of variance in standard measures of cortical microstructure and should be considered in neurobiological models of human brain organisation and cortical ageing.

neuroscience↗

bioRxiv2023

Slow rhythmic activity from an interplay of voltage and extracellular concentration dynamics: a minimal biophysical mechanism for neuronal bursting

Slow brain rhythms, for example during slow-wave sleep or pathological conditions like seizures and spreading depolarization, can be accompanied by synchronized oscillations in extracellular potassium concentration. Slow brain rhythms typically have longer periods than tonic action-potential firing. They are assumed to arise from network-level mechanisms, involving synaptic interactions and delays, or from intrinsically bursting neurons equipped with ion channels of slow dynamics. Here, we demonstrate that both mechanisms are not necessarily required and that slow rhythms can also be generated from an interplay of fast neuronal voltage dynamics and changes in extracellular ionic concentrations alone in any neuron with type excitability. The coupling of fast-spiking neuron dynamics and a slow extracellular potassium transient is regulated by the Na+/K+-ATPase. We use bifurcation analysis and the slow-fast method to reveal that this coupling suffices to generate a hysteresis loop organized around a bistable region that emerges from a saddle-node loop bifurcation - a common feature of type excitable neurons. Moreover, the Na+/K+-ATPase not only plays a key role in burst generation by shearing the bifurcation diagram but also modulates tonic spiking and depolarization block by its density and pump rate. These dynamics of bursting, tonic spiking and depolarization block, accompanied by the fluctuation of extracellular potassium, are likely to be relevant for pathological conditions. We suggest that these dynamics can result from any disturbance in extracellular potassium regulation, such as glial malfunction or hypoxia. The identification of a minimal mechanistic requirement for producing these dynamics adds to a better understanding of pathologies in brain rhythms may direct attention to alternative pharmacological targets for therapy. Author SummaryThe brain can produce slow rhythms, such as those observed during sleep or epilepsy. These rhythms are much slower than the neuronal electrical signals, and their origins are still under debate. Mechanisms discussed so far are based on the connection delays in neural networks or on neuronal ion channels with particularly slow kinetics. We show that neurons with specific spiking dynamics - allowing them to fire at arbitrarily low frequencies (type neurons) - can produce slow rhythmic patterns without requiring synaptic connectivity or special ion channels. In these cells, slow rhythmic activity arises from the interplay of slow changes in extracellular potassium concentration and the cells voltage dynamics, mediated by the Na+/K+-ATPase pump. The latter, found in all neurons, regulates the concentrations of sodium and potassium ions across the cell membrane. The core mechanism is not idiosyncratic, rather mathematical analysis shows under which conditions slow rhythmic activity can arise generically from the pump-based coupling in a broad class of neurons. We demonstrate that the pump is relevant for the creation of different firing patterns, which can be associated with various diseases. A better understanding these complex dynamics is important for the development of more effective treatments for concentration-dependent pathologies.

neuroscience↗

bioRxiv2023

Partitioning the Impacts of Spatial-Temporal Variation in Demography and Dispersal on Metapopulation Growth Rates

AO_SCPLOWBSTRACTC_SCPLOWSpatial-temporal variation in environmental conditions is ubiquitous in nature. This variation simultaneously impacts survival, reproduction, and movement of individuals and, thereby, the rate at which metapopulations grow. Using the tools of stochastic demography, the metapopulation growth rate is decomposed into five components corresponding to temporal, spatial, and spatial-temporal variation in fitness, and spatial and spatial-temporal covariation in dispersal and fitness. While temporal variation in fitness always reduces the metapopulation growth rate, all other sources of variation can either increase or reduce the metapopulation growth rate. Increases occur either by reducing the impacts of temporal variation or by generating a positive fitness-density covariance where individuals tend to concentrate in higher-quality patches. For example, positive auto-correlations in spatial-temporal variability in fitness generate this positive fitness-density covariance for less dispersive populations, but decrease it for highly dispersive populations, e.g. migratory species. Negative auto-correlations in spatialtemporal variability have the opposite effects. Positive covariances between movement and future fitness, on short or long time scales, increase growth rates. These positive covariances can arise is unexpected ways. For example, the win-stay, lose-shift dispersal strategy in negatively autocorrelated environments can generate positive spatial covariances that exceed negative spatial-temporal covariances. This decomposition of the metapopulation growth rate provides a way to quantify the relative importance of fundamental sources of variation on metapopulation persistence.

ecology↗

bioRxiv2023

Tryptophan wasting and disease activity as a systems phenomenon in inflammation - an analysis across 13 chronic inflammatory diseases.

Chronic inflammatory diseases (CID) are systems disorders affecting various organs including the intestine, joint and skin. The essential amino acid tryptophan (Trp) is not only used for protein synthesis but can also be catabolized to various bioactive derivatives that are important for cellular energy metabolism and immune regulation. Increased Trp catabolism via the kynurenine pathway is seen across individual CID entities1-5. Here, we assessed the levels of Trp and tryptophan derivatives across 13 CID to investigate the extent and nature of Trp wasting as a systems phenomenon in CID. We found reduced serum Trp levels across the majority of CID and a prevailing negative relationship between Trp and systemic inflammatory marker C-reactive protein (CRP). Increases in the kynurenine-to-Trp ratio (Kyn:Trp) indicate that the kynurenine pathway is a major route for CID-related Trp wasting. However, the extent of Trp depletion and its relationship with disease activity varies by disease, indicating potential differences in Trp metabolism. In addition, we find that amino acid catabolism in chronic inflammation is specific to tryptophan wasting, whereas other proteinogenic amino acids are not affected. Hence, our results suggest that increased Trp catabolism is a common metabolic occurrence in CID that may directly affect systemic immunity. Grant supportThis work was supported by the DFG Cluster of Excellence 1261 "Precision medicine in chronic inflammation" (KA, SSchr, PR, BH, SWa), the BMBF (e:Med Juniorverbund "Try-IBD" 01ZX1915A and 01ZX2215, the e:Med Network iTREAT 01ZX2202A, and GUIDE-IBD 031L0188A), DFG RU5042 (PR, KA), and Innovative Medicines Initiative 2 Joint Undertakings ("Taxonomy, Treatments, Targets and Remission", No. 831434, "ImmUniverse", grant agreement No. 853995, "BIOMAP", grant agreement No. 821511).

immunology↗

bioRxiv2023

Spatio-temporal dynamics of microglia phenotype in human and murine cSVD: impact of acute and chronic hypertensive states

Vascular risk factors such as chronic hypertension are well established major modifiable factors for the development of cerebral small vessel disease (cSVD). In the present study, our focus was the investigation of cSVD-related phenotypic changes in microglia in human disease and in the spontaneously hypertensive stroke-prone rat (SHRSP) model of cSVD. Our examination of cortical microglia in human post-mortem cSVD cortical tissue revealed distinct morphological microglial features specific to cSVD. We identified enlarged somata, an increase in the territory occupied by thickened microglial processes, and an expansion in the number of vascular-associated microglia. In parallel, we characterized microglia in a rodent model of hypertensive cSVD along different durations of arterial hypertension, i.e., early chronic and late chronic hypertension. Microglial somata were already enlarged in early hypertension, whereas at late-stage chronic hypertension they further exhibited elongat ed branches, thickened processes, and a reduced ramification index, mirroring the findings in human cSVD. An unbiased multidimensional flow cytometric analysis revealed phenotypic heterogeneit y among microglia cells within the hippocampus and cortex. At early-stage hypertension, hippocampal microglia exhibited upregulated CD11b/c, P2Y12R, CD200R, and CD86 surface markers. Detailed analysis of cell subpopulations revealed a unique microglial subset expressing CD11b/c, CD163, and CD86 exclusively in early hypertension. Notably, even at early-stage hypertension, microglia displayed a higher association with cerebral blood vessels. We identified several profound clusters of microglia expressing distinct marker profiles at late chronic hypertensive states. We further detected a temporal hypertension-related disturbances in blood-brain barrier integrity, accompanied by increased recruitment of leukocytes to the brain parenchyma in early hypertension. In summary, our findings demonstrate a higher vulnerability of the hippocampus, stage-specific microglial signatures based on morphological features, and cell surface protein expression in response to chronic arterial hypertension. These results indicate the diversity within microglia sub-populations and implicate the subtle involvement of microglia in cSVD pathogenesis.

neuroscience↗

bioRxiv2023

Multimodal layer modeling reveals in-vivo pathology in ALS

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterised by the loss of motor control. Current understanding of ALS pathology is largely based on post-mortem investigations at advanced disease stages. A systematic in-vivo description of the microstructural changes that characterise early-stage ALS, and their subsequent development, is so far lacking. Recent advances in ultra-high field (7T) MRI data modelling allow us to investigate cortical layers in-vivo. Given the layer-specific and topographic signature of pathology in ALS, we combined submillimeter structural 7T-MRI data (qT1, QSM), functional localisers of body parts (upper limb, lower limb, face) and automated layer modelling to systematically describe pathology in the primary motor cortex (M1), in 12 living ALS-patients with reference to 12 age-, gender-, handedness- and education-matched controls. Longitudinal sampling was performed for a subset of patients. We calculated multimodal pathology maps for each layer (superficial layer, layer 5a, layer 5b, layer 6) of M1 to identify hotspots of demyelination, iron and calcium accumulation in different cortical fields. We show preserved mean cortical thickness and layer architectures of M1, despite significantly increased iron in layer 6 and significantly increased calcium in layer 5a and superficial layer, in patients compared to controls. The behaviorally first-affected cortical field shows significantly increased iron in L6 compared to other fields, while calcium accumulation is atopographic and significantly increased in the low-myelin borders between cortical fields compared to the fields themselves. A subset of patients with longitudinal data shows that the low-myelin borders are particularly disrupted, and that calcium hotspots but to a lesser extent iron hotspots precede demyelination. Finally, we highlight that a very-slow progressing patient (P4) shows a distinct pathology profile compared to the other patients. Our data shows that layer-specific markers of in-vivo pathology can be identified in ALS-patients with a single 7T-MRI measurement after first diagnosis, and that such data provide critical insights into the individual disease state. Our data highlight the non-topographic architecture of ALS disease spread, and the role of calcium rather than iron accumulation in predicting future demyelination. We also highlight a potentially important role of low-myelin borders, that are known to connect to multiple areas within the M1 architecture, in disease spread. Importantly, the distinct pathology profile of a very-slow progressing patient (P4) highlights a distinction between disease duration and pathology progression. Our findings demonstrate the importance of in-vivo histology for the diagnosis and prognosis of neurodegenerative diseases such as ALS.

neuroscience↗