Biology subjects

Schulz, E.

Publications and source records attributed to Schulz, E..

At least 19 recordsLinked to original sources

bioRxiv2026

Neuroinflammation is an early pathological process in a mouse model of prodromal Parkinsons disease

Approximately 90% of Parkinson's disease (PD) patients exhibit olfactory deficits, which often precedes motor symptoms by years, and are a robust predictor for PD and subsequent cognitive decline. Pathological changes in the PD olfactory system, particularly synuclein (Syn) pathology in the olfactory bulb (OB) and severe involvement of the anterior olfactory nucleus (AON), are distinct from normal aging. However, the causal link between Syn aggregation and functional impairment, potentially involving cytotoxicity and neuroinflammation, remains elusive. To investigate these early pathological events, we utilized a prodromal PD model that we have previously characterized, involving the unilateral OB injection of Syn preformed fibrils (PFF) in wild-type mice. This triggers the transneuronal spread of pathogenic Syn, and olfactory dysfunction starting at 1-month post-injections. Here we report on neuropathological and inflammatory events 1-3 month following injection of PFFs into the OB. Following PFF injection, Syn pSer129 pathology progressively accumulated bilaterally in the AON and ipsilateral in the piriform cortex (PCX) over three months. Stereological quantification revealed no significant neuronal loss in the AON or PCX during this 1-3 month interval, indicating that olfactory impairment precedes overt neurodegeneration. Instead, we identified the upregulation of pro-inflammatory genes (Il-1{beta} ; and Il-6), significant microglial reactivity, and sustained astrogliosis within olfactory structures. These findings identify neuroinflammation as a key early mediator linking Syn pathology to olfactory dysfunction in the absence of neuronal loss. This suggests a critical window for therapeutic intervention and highlights neuroinflammatory markers as potential biomarkers for the prodromal phase of PD.

neuroscience↗

bioRxiv2026

A combination of EWSR1-FLI1 with loss of one EWSR1 allele promotes damage in the mitotic spindle and sensitization to microtubule-destabilizing agent

Microtubule-destabilizing agents (MDAs) and microtubule-stabilizing agents (MSAs) are commonly used chemotherapeutic agents due to its activity to induce cell death by compromising the dynamics of spindles during mitosis. Ewing sarcoma, the second most common pediatric bone cancer, is known to selectively respond to MDAs as a first-line treatment, but not to MSAs. Ewing sarcoma cells carry an aberrant EWSR1-FLI1 fusion gene and only one wildtype EWSR1 allele. To investigate the origin of this MDA sensitivity, we used an (AID-EWSR1/wt: EWSR1-FLI1-mCherry/wt) cell line that enables conditional induction of EWSR1-FLI1 expression (Tet-On system) and EWSR1 knockdown derived from one EWSR1 allele (auxin-degron system). A combination of EWSR1-FLI1 expression and EWSR1 knockdown induces apoptosis upon nocodazole treatment, a type of MDA. Our study revealed that the mitotic spindles of Ewing sarcoma cells (A673, RD-ES and SK-ES1) contain elevated levels of tubulin damage, visualized with GTP-tubulin, compared to mesenchymal stem cells (MSC). Consistently, the combination of EWSR1-FLI1 expression and EWSR1 knockdown in (AID-EWSR1/wt: EWSR1-FLI1-mCherry/wt) cell line also leads to an increased incidence of damage in mitotic spindles. Together, we propose that the sensitivity of Ewing sarcoma cells is derived from the increased levels of damage to mitotic spindles caused by EWSR1-FLI1 expression and EWSR1 knockdown.

Cancer Biology↗

bioRxiv2025

Modulating Brain Perfusion, Functional Connectivity, and Metabolite Patterns through Theta Burst Transcranial Focused Ultrasound Stimulation

BackgroundTranscranial ultrasonic stimulation (TUS) is an emerging non-invasive neuromodulation technique with the potential to target both cortical and subcortical brain regions. This study investigates the effects of theta-burst TUS (tb-TUS), a neuromodulatory pattern characterized by bursts of pulses repeated at a theta frequency, on cerebral blood flow, functional connectivity, and metabolite concentrations in the primary motor cortex (M1). The aim of this study is to take a first step towards the mechanistic and methodological feasibility of tb-TUS at the M1 using multimodal neuroimaging. MethodsSeventeen healthy participants underwent a double-blind, sham-controlled crossover design, receiving both active and sham tb-TUS to the left M1 over three days. Multimodal MRI, including pseudo-continuous arterial spin labeling (PCASL), resting-state functional MRI (rs-fMRI), and magnetic resonance spectroscopy (MRS), was conducted at baseline, pre-, and post-stimulation. Acoustic simulations and finger-tapping BOLD-peak signal guided individualized TUS targeting. ResultsActive tb-TUS significantly reduced cerebral blood flow (p < .001) and within-region functional connectivity (p < .001) in the M1 compared to sham stimulation. A non-significant trend towards decreased GABA was observed, with no significant session x condition interaction found for GABA, Glutamate, or Glx concentrations. ConclusionThis pilot study demonstrates that tb-TUS of the M1 induces reductions in cerebral blood flow and functional connectivity in healthy participants. Our findings indicate that tb-TUS may be mitigating neural hyperactivity patterns, but preliminary studies so far arrive at differing results, highlighting the need for further research to replicate our findings, elucidate the underlying mechanisms, and optimize stimulation protocols.

physiology↗

bioRxiv2024

The hippocampus supports interpolation into new states during category abstraction

The hippocampus forms concepts by integrating multi-feature relations into a unified representation. A common yet unconfirmed assumption is that such cognitive maps afford interpolations to never-experienced states. We approach this question as a category-learning problem in which prototypes are omitted from training but guide category-based decisions in a subsequent feature-inference task. Consistent with behavior, missing inferred stimulus features were represented at prototypical values in neocortex. This cortical completion effect correlated with hippocampal responses, which in turn reflected the distance between imagined prototypes and experienced exemplars. This was paralleled by a learning-dependent grid-like representation of the underlying conceptual space in entorhinal cortex. Our results suggest that abstracted prototypes correspond to interpolated central states in a cognitive map that guide cortical pattern completion during category-based decisions.

neuroscience↗

bioRxiv2024

An inductive bias for slowly changing features in human reinforcement learning

Identifying goal-relevant features in novel environments is a central challenge for efficient behaviour. We asked whether humans address this challenge by relying on prior knowledge about common properties of reward-predicting features. One such property is the rate of change of features, given that behaviourally relevant processes tend to change on a slower timescale than noise. Hence, we asked whether humans are biased to learn more when task-relevant features are slow rather than fast. To test this idea, 295 human participants were asked to learn the rewards of two-dimensional bandits when either a slowly or quickly changing feature of the bandit predicted reward. Across two experiments and one preregistered replication, participants accrued more reward when a bandits relevant feature changed slowly, and its irrelevant feature quickly, as compared to the opposite. We did not find a difference in the ability to generalise to unseen feature values between conditions. Testing how feature speed could affect learning with a set of four function approximation Kalman filter models revealed that participants had a higher learning rate for the slow feature, and adjusted their learning to both the relevance and the speed of feature changes. The larger the improvement in participants performance for slow compared to fast bandits, the more strongly they adjusted their learning rates. These results provide evidence that human reinforcement learning favours slower features, suggesting a bias in how humans approach reward learning. Author summaryLearning experiments in the laboratory are often assumed to exist in a vacuum, where participants solve a given task independently of how they learn in more natural circumstances. But humans and other animals are in fact well known to "meta learn", i.e. to leverage generalisable assumptions about how to learn from other experiences. Taking inspiration from a well-known machine learning technique known as slow feature analysis, we investigated one specific instance of such an assumption in learning: the possibility that humans tend to focus on slowly rather than quickly changing features when learning about rewards. To test this, we developed a task where participants had to learn the value of stimuli composed of two features. Participants indeed learned better from a slowly rather than quickly changing feature that predicted reward. Computational modelling of participant behaviour indicated that participants had a higher learning rate for slowly changing features from the outset. Hence, our results support the idea that human reinforcement learning reflects a priori assumptions about the reward structure in natural environments.

neuroscience↗

bioRxiv2023

Delay of human early development via in vitro diapause

Many mammals can control the timing of gestation and birth by pausing embryonic development at the blastocyst stage. It is unknown whether the capacity to pause development is conserved, in general across mammals, and more specifically in humans. Activity of the growth regulating mTOR pathway governs developmental pausing in the mouse (1). Here we show a stage-specific capacity to delay the progression of human development via mTOR inhibition. In this context, human blastoids and pluripotent stem cells in naive and naive-like, but not primed, states can be induced to enter a dormant state, which is reversible at the functional and molecular level. Comparative analysis of mouse and human naive cells longitudinal response to mTORi revealed distinct temporal dynamics and metabolic requirements of dormancy in each species. Mouse and human blastocysts show similar tissue-specific patterns of mTOR pathway activity, suggesting that the mTOR pathway may be a conserved regulator of blastocyst development and timing in both species. Our results raise the possibility that the developmental timing of the human embryo may be controllable, with implications for reproductive therapies.

developmental biology↗

bioRxiv2022

CasTuner: a degron and CRISPR/Cas-based toolkit for analog tuning of endogenous gene expression

Certain cellular processes are dose-dependent, requiring a specific quantity of gene products or a defined stoichiometry between them. This is exemplified by haploinsufficiency or by the need for dosage compensation for X-linked genes between the sexes in many species. Understanding dosage-sensitive processes requires the ability to perturb endogenous gene products in a quantitative manner. Here we present CasTuner, a CRISPR-based toolkit that allows analog tuning of endogenous gene expression. In the CasTuner system, activity of Cas-derived repressors is controlled through a FKBP12F36V degron domain and can thereby be quantitatively tuned by titrating the small molecule degrader dTAG-13. The toolkit can be applied at the transcriptional level, using the histone deacetylase hHDAC4 fused to dCas9, or at the post-transcriptional level, using the RNA-targeting CasRx. To optimise efficiency, inducibility and homogeneity of repression we target a fluorescently tagged endogenous gene, Esrrb, in mouse embryonic stem cells. Through flow cytometry, we show that CasTuner allows analog tuning of the target gene in a homogeneous manner across cells, as opposed to the widely used KRAB repressor domain, which exhibits a digital mode of action. We quantify repression and derepression dynamics for CasTuner and use it to measure dose-response curves between the pluripotency factor NANOG and several of its target genes, providing evidence for target-specific dose dependencies. CasTuner thus provides an easy-to-implement tool to perturb gene expression in an inducible, tunable and reversible manner and will be useful to study dose-responsive processes within their physiological context.

genetics↗

bioRxiv2022

Context-dependent choice and evaluation in real-world consumer behavior

A body of work spanning neuroscience, economics, and psychology indicates that decisionmaking is context-dependent, which means that the value of an option depends not only on the option in question, but also on the other options in the choice set--or the context. While context effects have been observed primarily in small-scale laboratory studies with tightly constrained, artificially constructed choice sets, it remains to be determined whether these context effects take hold in real-world choice problems, where choice sets are large and decisions driven by rich histories of direct experience. Here, we investigate whether valuations are context-dependent in real-world choice by analyzing a large restaurant rating dataset (Yelp.com) as well as two independent replication datasets which provide complementary operationalizations of restaurant choice. We find that users make fewer ratings-maximizing choices in choice sets with higher-rated options--a hallmark of context-dependent choice-- and that post-choice restaurant ratings also varied systematically with the ratings of unchosen restaurants. Furthermore, in a follow-up laboratory experiment using hypothetical choice sets matched to the real-world data, we find further support for the idea that subjective valuations of restaurants are scaled in accordance with the choice context, providing corroborating evidence for a general mechanistic-level account of these effects. Taken together, our results provide a potent demonstration of context-dependent choice in real-world choice settings, manifesting both in decisions and subjective valuation of options.

neuroscience↗

bioRxiv2022

A novel automated morphological analysis of microglia activation using a deep learning assisted model

There is growing evidence for the key role of microglial activation in brain pathophysiology. Consequently, there is a need for efficient automated methods to measure the morphological changes distinctive of microglia functional states in research settings. Currently, many commonly used automated methods can be subject to sample representation bias, time consuming imaging, specific hardware requirements, and difficulty in maintaining an accurate comparison across research environments. To overcome these issues, we use commercially available deep learning tools (Aiforia(R) Cloud (Aifoira Inc., Cambridge, United States) to quantify microglial morphology and cell counts from histopathological slides of Iba1 stained tissue sections. We provide evidence for the effective application of this method across a range of independently collected datasets in mouse models of viral infection and Parkinsons disease. Additionally, we provide a comprehensive workflow with training details and annotation strategies by feature layer that can be used as a guide to generate new models. In addition, all models described in this work are shared within the Aiforia(R) platform and are available for study-specific adaptation and validation.

neuroscience↗

bioRxiv2022

Investigation on How Dynamic Effective Connectivity Patterns Encode the Fluctuating Pain Intensity in Chronic Migraine

Chronic migraine is characterised by persistent headaches for more than 15 days per month; the intensity of the pain is fluctuating over time. Here, we explored the dynamic interplay of connectivity patterns between regions known to be related to pain processing and their relation to the ongoing dynamic pain experience. We recorded EEG from 80 sessions (20 chronic migraine patients in 4 separate sessions of 25 minutes). The patients were asked to continuously rate the intensity of their endogenous headache. On different time-windows, a dynamic causal model (DCM) of cross spectral responses was inverted to estimate connectivity strengths. For each patient and session, the evolving dynamics of effective connectivity were related to pain intensities and to pain intensity changes by using a Bayesian linear model. Hierarchical Bayesian modelling was further used to examine which connectivity-pain relations are consistent across sessions and across patients. The results reflect the multi-facetted clinical picture of the disease. Across all sessions, each patient with chronic migraine exhibited a distinct pattern of pain intensity-related cortical connectivity. The diversity of the individual findings are accompanied by inconsistent relations between the connectivity parameters and pain intensity or pain intensity changes at group level. This suggests a rejection of the idea of a common neuronal core problem for chronic migraine.

neuroscience↗

bioRxiv2021

Individual Stability of Pain- and Touch-Related Neuronal Gamma Oscillations

BackgroundThe processing of brief pain and touch stimuli has been associated with an increase of neuronal oscillations in the gamma range (40-90 Hz). However, some studies report divergent gamma effects across single participants. MethodsIn two repeated sessions we recorded gamma responses to pain and touch stimuli using EEG. Individual gamma responses were extracted from EEG channels and from ICA components that contain a strong gamma amplitude. ResultsWe observed gamma responses in the majority of the participants. If present, gamma synchronisation was always bound to a component that contained a laser-evoked response. We found a broad variety of individual cortical processing: some participants showed a clear gamma effect, others did not exhibit any gamma. For both modalities, the effect was reproducible between sessions. In addition, participants with a strong gamma response showed a similar time-frequency pattern across sessions. ConclusionsOur results indicate that current measures of reproducibility of research results do not reflect the complex reality of the diverse individual processing pattern of applied pain and touch. The present findings raise the question of whether we would find similar quantitatively different processing patterns in other domains in neuroscience: group results would be replicable but the overall effect is driven by a subgroup of the participants.

neuroscience↗

bioRxiv2021

Hippocampal spatio-temporal cognitive maps adaptively guide reward generalization

The brain forms cognitive maps of relational knowledge, an organizing principle thought to underlie our ability to generalize and make inferences. However, how can a relevant map be selected in situations where a stimulus is embedded in multiple relational structures? Here, we find that both spatial and temporal cognitive maps influence generalization in a choice task, where spatial location determines reward magnitude. Mirroring behavior, the hippocampus not only builds a map of spatial relationships but also encodes temporal distances. As the task progresses, participants choices become more influenced by spatial relationships, reflected in a strengthening of the spatial and a weakening of the temporal map. This change is driven by orbitofrontal cortex, which represents the evidence that an observed outcome is generated from the spatial rather than the temporal map and updates hippocampal representations accordingly. Taken together, this demonstrates how hippocampal cognitive maps are used and updated flexibly for inference.

neuroscience↗

bioRxiv2021

Increased Functional Connectivity Characterises the Prodromal Phase of the Migraine Cycle

IntroductionEpisodic migraine is reflected by cyclic changes in behaviour and cortical processing. We aimed to identify how Functional connectivities change over the entire migraine cycle. MethodsBy using longitudinal neuroimaging and a whole-brain connectivity analysis approach, we tested 12 episodic migraine patients across 82 FMRI recordings during spontaneous headache attacks with Follow-up measurements over the pain-free interval without any external stimulation. ResultsWe Found that Functional connectivities linearly increased over the interictal interval. In the prodromal phase, we observed the strongest connections between the anterior agranular insula and the posterior orbitofrontal cortex with sensory, motor, and cingulate areas. The strengths of the connections dropped during the headache. Peak connectivity during the prodromal phase and its collapse during the headache can be regarded as a mechanism of normalising cortical processing. ConclusionsThe strongest connections during the ictal phase of the migraine cycle may contribute to the variety of symptoms of migraine attacks including headache, sensory hypersensitivity, and autonomous symptoms. We speculate about a malfunction at the molecular level in agranular frontal and insular regions, which needs to be addressed in subsequent studies. Article highlightsO_LIWe investigated functional connectivities over an entire migraine cycle. C_LIO_LIWe found cycle-related connectivity changes for two proximate agranular regions. C_LIO_LIThe prodromal increase and the collapse of connectivity during the headache may reflect normalising cortical processing. C_LI

neuroscience↗

bioRxiv2021

Individually Unique Dynamics of Cortical Connectivity Reflect the Ongoing Intensity of Chronic Pain

BackgroundChronic pain diseases are characterised by an ongoing and fluctuating endogenous pain, yet it remains to be elucidated how this is reflected by the dynamics of ongoing functional cortical connections. The present study addresses this disparity by taking the individual perspective of pain patients into account, which is the varying intensity of endogenous pain. MethodsTo this end, we investigated the cortical encoding of 20 chronic back pain patients and 20 chronic migraineurs in four repeated fMRI sessions. During the recording, the patients were asked to continuously rate their pain intensity. A brain parcellation approach subdivided the whole brain into 408 regions. A 10 s sliding-window connectivity analysis computed the pair-wise and time-varying connectivity between all brain regions across the entire recording period. Linear mixed effects models were fitted for each pair of brain regions to explore the relationship between cortical connectivity and the observed trajectory of the patients fluctuating endogenous pain. ResultsTwo pain processing entities were taken into account: pain intensity (high, middle, low pain) and the direction of pain intensity changes (rising vs. falling pain). Overall, we found that periods of high and increasing pain were predominantly related to low cortical connectivity. For chronic back pain this applies to the pain intensity-related connectivity for limbic and cingulate areas, and for the precuneus. The change of pain intensity was subserved by connections in left parietal opercular regions, right insular regions, as well as large parts of the parietal, cingular and motor cortices. The change of pain intensity direction in chronic migraine was reflected by decreasing connectivity between the anterior insular cortex and orbitofrontal areas, as well as between the PCC and frontal and ACC regions. ConclusionsInterestingly, the group results were not mirrored by the individual patterns of pain-related connectivity, which is suggested to deny the idea of a common neuronal core problem for chronic pain diseases. In a similar vein, our findings are supported by the experience of clinicians, who encounter patients with a unique composition of characteristics: personality traits, various combinations of symptoms, and a wide range of individual responses to treatment. The diversity of the individual cortical signatures of chronic pain encoding results adds to the understanding of chronic pain as a complex and multifaceted disease. The present findings support recent developments for more personalised medicine.

neuroscience↗

bioRxiv2021

Pain and the Emotional Brain: Affective Rather than Cognitive Processes Drive the Cortical Encoding of Pain

BackgroundThe experience of pain has been dissociated into two interwoven aspects: a sensory-discriminative aspect and an affective-motivational aspect. We aimed to explore which of the pain descriptors is more deeply rooted in the human brain. FindingsParticipants were asked to evaluate applied cold pain. The majority of the trials showed distinct ratings: some were rated higher for unpleasantness and others for intensity. We compared the relationship between functional data recorded from 7 tesla MRI with unpleasantness and intensity ratings and revealed a stronger relationship between cortical data and unpleasantness ratings. ConclusionsThe present study underlines the importance of the emotional-affective aspects of pain-related cortical processes in the brain. The findings corroborate previous studies showing a higher sensitivity to pain unpleasantness compared to ratings of pain intensity. For the processing of pain in healthy subjects, this effect may reflect the more direct and intuitive evaluation of emotional aspects of the pain system, which is to prevent harm and to preserve the physical integrity of the body.

neuroscience↗

bioRxiv2021

Intrinsic Network Activity Reflects the Fluctuating Experience of Tonic Pain

Although we know sensation is continuous, research on long-lasting and continuously changing stimuli is scarce and the dynamic nature of ongoing cortical processing is largely neglected. In a longitudinal study with 152 fMRI sessions, participants were asked to continuously rate the intensity of applied tonic heat pain for 20 minutes. Using group independent component analysis and dual-regression, we extracted the subjects time courses of intrinsic network activity. The relationship between the dynamic fluctuation of network activity with the varying time courses of three pain processing entities was computed: pain intensity, the direction of pain intensity changes and temperature. We were able to dissociate the spatio-temporal patterns of objective (temperature) and subjective (pain intensity/changes of pain intensity) aspects of pain processing in the human brain. We found two somatosensory networks with distinct functions: one network which encodes the small fluctuations in temperature and consists mainly of bilateral SI. A second right-lateralised network that encodes the intensity of the subjective experience of pain consists of SI, SII, the PCC, and the thalamus. We revealed the somatosensory dynamics that build up towards a current subjective percept of pain. The timing suggests a cascade of subsequent processing steps towards the current pain percept.

neuroscience↗

bioRxiv2021

Intrinsic Network Connectivity Reflects the Cyclic Trajectory of Migraine Attacks

BackgroundEpisodic migraine is considered to be cyclic in nature, triggered by the hypothalamus. To assess the natural trajectory of intrinsic networks over an entire migraine cycle, we designed a longitudinal intra-individual study using functional magnetic resonance imaging (fMRI). MethodsIntrinsic network connectivity was assessed for 12 migraineurs in 82 sessions including spontaneous, untriggered headache attacks and follow-up recordings towards the next attack. ResultsWe found cyclic changes in the visual, auditory, and somatosensory networks, in limbic networks (e.g. thalamo-insular, parahippocampal), and in the salience network (anterior insula and dorsal anterior cingulate cortex). Connectivity changes also extended to further cortical networks, such as the central executive network, the default mode network, as well as subcortical networks. Almost all of these network connectivity changes followed the trajectory of a linear increase over the pain-free interval that peaked immediately prior to the headache, and "dropped" to the baseline level during the headache. These network alterations are associated with a number of cortical functions that may explain the variety of ictal and pre-ictal physiological and psychological migraine symptoms. ConclusionOur results suggest that migraine disease is associated with widespread cyclic alterations of intrinsic networks that develop before the headache is initiated, i.e. during the interictal and premonitory phase. The increasing magnitude of connectivity within these networks towards the next attack may reflect an increasing effort to maintain network integrity.

neuroscience↗

bioRxiv2021

Intrinsic Network Activity Reflects the Ongoing Experience of Chronic Pain

Analyses of intrinsic network activity have been instrumental in revealing cortical processes that are altered in chronic pain patients. However, such studies have not accounted for variable time courses of network activity and subjective pain experience. In a novel approach, we aimed to elucidate how intrinsic functional networks evolve in regard to the fluctuating intensity of the experience of chronic pain. In a longitudinal study with 156 fMRI sessions, 20 chronic back pain patients and 20 chronic migraine patients were asked to continuously rate the intensity of their endogenous pain. Using group independent component analysis and dual-regression, we extracted the time courses of 100 independent components separately for chronic back pain and chronic migraine. We investigated the relationship between the fluctuation of intrinsic network activity with the time course of subjective pain ratings. For chronic back pain, we found increased cortical network activity for the salience network and a local pontine network, as well as decreased network activity in the anterior and posterior default mode network for higher pain intensities. Higher pain intensities in chronic migraine were accompanied with lower activity in a prefrontal cortical network. By taking the perspective of the individual, we focused on the processes that matter for each patient, which are phases of relatively low pain and more straining phases of relatively high pain. The present design of ongoing assessment of the endogenous pain can be a powerful and promising tool to assess the signature of a patients endogenous pain encoding over weeks and months.

neuroscience↗