Biology subjects

Jaeger, D.

Publications and source records attributed to Jaeger, D..

At least 19 recordsLinked to original sources

bioRxiv2026

Behavior Differentially Shapes Spontaneous Cortical Network Dynamics Across Frequencies

The rapid and coordinated propagation of neural activity across a network of distributed brain regions underpins complex behavior and cognition. Yet how multiple distributed processes are facilitated in parallel across timescales and behavioral states remains unclear. Using simultaneous fast wide-field voltage and hemodynamic imaging in awake mice, we show that behavior differentially shapes cortical network dynamics across frequencies and signal types. Although static functional connectivity preserved canonical networks across frequencies, the underlying dynamics diverged. Low-frequency and hemodynamic activity were dominated by behavior-dependent persistence of network states, whereas higher-frequency activity exhibited stable network structure with modulation through changes in state expression. Despite these differences, shared network organization was preserved across timescales and signal types. This indicates that similar functional connectivity can arise from distinct temporal dynamics. These findings reveal that cortical networks are governed by frequency-dependent principles through which behavior shapes the persistence and expression of large-scale brain states.

neuroscience↗

bioRxiv2026

Hierarchical classification of immune cell transcriptomes at population-scale

Accurate immune cell classification is essential for interpreting single-cell RNA sequencing (scRNA-seq) data. However, progress in automating cell type annotation is constrained by the lack of independent, high-resolution benchmarks, as routine data integration introduces statistical dependencies that inflate model generalizability. Here, we present the single-cell universal classification omnibus (Suco), a resource of independent, uniform expert annotations, and Compocyte, a modular hierarchical classifier. Together, they establish a framework that substantially outperforms existing classifiers while facilitating expert review of ambiguous annotations. Applying Compocyte across 50 studies, including three newly generated datasets, we classified 15.6 million leukocytes from 3,965 patients. Within this cohort, we identified a new tumor-associated resorptive macrophage phenotype, a non-canonical monocyte subtype in subclinical cytokine release syndrome, and the programmatic erosion of T cell memory stemness across metastatic sites. Suco and Compocyte thus provide a generalizable framework to uncover the principles governing human immunity at population scale. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/728980v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@13a6e4borg.highwire.dtl.DTLVardef@11f1626org.highwire.dtl.DTLVardef@1e72bd4org.highwire.dtl.DTLVardef@1ee799b_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefThe single-cell universal classification omnibus and the modular hierarchical classifier Compocyte enable annotating single cell RNA sequencing data from 3,965 patients, revealing novel resorptive macrophage and vaccination-associated monocyte states, alongside the erosion of T cell memory stemness as a hallmark of solid tumor metastases. HighlightsO_LISuco, a benchmark enabling novel single cell artificial intelligence models C_LIO_LICompocyte, a hierarchical cell type classifier outperforming current architectures C_LIO_LIMacrophages adopt osteoclast-like gene expression states across cancer types C_LIO_LIStem-like programs erode in metastasis-infiltrating T memory cells across tumors C_LI

bioinformatics↗

bioRxiv2026

An integrated platform for simultaneous wide-field voltage/calcium imaging and fMRI (EPI & ZTE) reveals neuronal infraslow dynamics underlying functional connectivity

Wide-field optical imaging acquired simultaneously with functional MRI (fMRI) has the ability to provide unprecedented insight into the neural origins of time-varying whole-brain activity. Simultaneously linking cellular-scale activity to whole-brain fMRI remains challenging due to optical access, RF coil placement, and transmission constraints in the MRI environment. We present an integrated platform that combines a long-distance tube-lens optical path (>98% transmission), a chronically stable optically-fused cranial window, and a subject-conformal RF surface coil compatible with both echo planar imaging (EPI) and zero-echo-time (ZTE) fMRI. The system supports concurrent wide-field imaging of genetically encoded voltage or calcium indicators concurrently with intrinsic hemoglobin signals. In individual mice, wide-field optical and fMRI measures yield concordant functional connectivity, and cross-modal timing analyses demonstrate that neuronal infraslow dynamics (<0.1 Hz) underlie the majority of fMRI connectivity, after removing hemodynamic crosstalk. The platform's sensitivity, chronic stability, and sequence flexibility broaden access to cellular-to-whole-brain investigations across basic and translational neuroimaging.

neuroscience↗

bioRxiv2025

Cortex-wide voltage imaging in a sensory cued reaching task reveals fast subnetwork dynamics

Oscillatory activities and network dynamics are fundamental to sensorimotor processing, motor control, and cognitive functions. Capturing the fast cortical dynamics underlying sensorimotor behaviors demands temporal resolution beyond conventional imaging methods. We employed pan-cortical JEDI-1P voltage imaging of layer 2/3 activity in a skilled reaching task to reveal previously inaccessible rapid networks dynamics. Our approach uncovered distinct spectral signatures including reward-related gamma oscillations in M2, global low-frequency suppression during movement execution, and 8 Hz large-amplitude oscillations in sensorimotor cortex during task disengagement. Using independent component analysis, we were able to separate multiplexed functional networks with fast temporal features shared among sensorimotor regions and slower dynamics such as a global preparatory ramp. These distributed activity patterns successfully predicted both sensorimotor parameters and trial outcomes. Our study bridges critical gaps in understanding rapid temporal organization of cortical networks during complex behaviors, revealing how fast neural dynamics coordinate to produce motor actions across distributed cortical regions.

neuroscience↗

bioRxiv2025

Tuft dendrites in frontal motor cortex enable flexible learning

Flexible learning relies on integrating sensory and contextual information to adjust behavioral output in different environments. The anterolateral motor cortex (ALM) is a frontal area critical for action selection in rodents. Here we show that inputs critical to decision-making converge on the apical tuft dendrites of L5b pyramidal neurons in ALM. We therefore investigated the role of these dendrites in a rule-switching paradigm. Activation of dendrite-inhibiting layer 1 interneurons impaired relearning, without affecting previously learned behavior. Remarkably, this inhibition profoundly suppressed calcium activity selectively in dendritic shafts but not spines while reducing burst firing. Moreover, excitatory synaptic inputs to tuft dendrites exhibited rule-dependent clustering. We conclude that active dendritic integration is a key computational component of flexible learning.

neuroscience↗

bioRxiv2025

Image-based screens identify regulators of endogenous Dvl2 biomolecular condensates

Dishevelled (Dvl) proteins are essential transducers in Wnt signaling pathways, which have been implicated in development, stem cell maintenance, and human diseases such as cancer. Several studies have shown that Dvl proteins form dynamic biomolecular condensates. However, how cellular signals and cell states influence the formation of biomolecular condensates remains poorly understood. Here, we analyzed cells with endogenous Dvl2 condensates using image-based cell sorting in combination with phosphoproteomics and identified protein enrichment for Wnt/PCP signaling and the G2/M cell cycle transition. We then performed an image-based high-throughput screen to identify small molecule kinase inhibitors that affect Dvl2 liquid-liquid phase separation. Strikingly, CK1{delta}/{varepsilon} inhibition blocked Dvl2 condensate formation. Its effect on Wnt signaling was modulated in genetic epistasis experiments with loss-of-function alleles of APC, Axin1, and MCC. Our study highlights the interplay between post-translational modifications and condensate dynamics, opening new avenues for research on their role in cellular signaling and disease intervention.

cell biology↗

bioRxiv2023

Modeling synaptic integration of bursty and beta oscillatory inputs in ventromedial motor thalamic neurons in normal and parkinsonian states

The Ventromedial Motor Thalamus (VM) is implicated in multiple motor functions and occupies a central position in the cortico-basal ganglia-thalamocortical loop. It integrates glutamatergic inputs from motor cortex (MC) and motor-related subcortical areas, and it is a major recipient of inhibition from basal ganglia. Previous experiments in vitro showed that dopamine depletion enhances the excitability of thalamocortical cells (TC) in VM due to reduced M-type potassium currents. To understand how these excitability changes impact synaptic integration in vivo, we constructed biophysically detailed VM TC models fit to normal and dopamine-depleted conditions, using the NEURON simulator. These models allowed us to assess the influence of excitability changes with dopamine depletion on the integration of synaptic inputs expected in vivo. We found that VM TCs in the dopamine-depleted state showed increased firing rates with the same synaptic inputs. Synchronous bursting in inhibitory input from the substantia nigra pars reticulata (SNR), as observed in parkinsonian conditions, evoked a post-inhibitory firing rate increase with a longer duration in dopamine-depleted than control conditions, due to different M-type potassium channel densities. With beta oscillations in the inhibitory inputs from SNR and the excitatory inputs from drivers and modulators, we observed spike-phase locking in the activity of the models in normal and dopamine-depleted states, which relayed and amplified the oscillations of the inputs, suggesting that the increased beta oscillations observed in VM of parkinsonian animals are predominantly a consequence of changes in the presynaptic activity rather than changes in intrinsic properties. Significance StatementThe Ventromedial Motor Thalamus is implicated in multiple motor functions. Experiments in vitro showed this area undergoes homeostatic changes following dopamine depletion (parkinsonian state). Here we studied the impact of these changes in vivo, using biophysically detailed modeling. We found that dopamine depletion increased firing rate in the ventromedial thalamocortical neurons and changed their responses to synchronous inhibitory inputs from substantia nigra reticulata. All thalamocortical neuron models relayed and amplified beta oscillations from substantia nigra reticulata and cortical/subcortical inputs, suggesting that increased beta oscillations observed in parkinsonian animals predominantly reflect changes in presynaptic activity.

neuroscience↗

bioRxiv2023

Brain rhythms control microglial response and cytokine expression via NFkappaB signaling

Microglia, the brains primary immune cells, transform in response to changes in sensory or neural activity, like sensory deprivation. However, little is known about how specific frequencies of neural activity, or brain rhythms, impact microglia and cytokine signaling. Using visual noninvasive flickering sensory stimulation (flicker) to induce electrical neural activity at different frequencies, 40Hz, within the gamma band and 20Hz, within the beta band, we discovered these brain rhythms differentially affect microglial morphology and cytokine expression in healthy animals. We found that flicker induced expression of certain cytokines, including IL-10 and M-CSF, that was independent of microglia. Because NF{kappa}B is activated by synaptic activity and regulates cytokines, we hypothesized this pathway plays a causal role in frequency-specific cytokine and microglial responses. Indeed, we found that after flicker, phospho-NF{kappa}B co-labeled with neurons more than microglia. Furthermore, inhibition of NF{kappa}B signaling by a small molecule inhibitor down-regulated flicker-induced cytokine expression and attenuated flicker-induced changes in microglia morphology. These results reveal a new mechanism through which brain rhythms affect brain function by altering microglia morphology and cytokines via NF{kappa}B. TeaserFrequency-specific brain rhythms regulate cytokine expression, microglia morphology, and microglia-independent expression of M-CSF and IL10 via NF{kappa}B.

neuroscience↗

bioRxiv2022

Cortical networks relating to arousal are differentially coupled to neural activity and hemodynamics

Even in the absence of specific sensory input or a behavioral task, the brain produces structured patterns of activity. This organized activity is modulated by changes in arousal. Here, we use wide-field voltage imaging to establish how arousal relates to cortical network voltage and hemodynamic activity in spontaneously behaving head-fixed male and female mice expressing the voltage-sensitive fluorescent FRET sensor Butterfly 1.2. We find that global voltage and hemodynamic signals are both positively correlated with changes in arousal with a maximum correlation of 0.5 and 0.25 respectively at a time lag of 0 seconds. We next show that arousal influences distinct cortical regions for both voltage and hemodynamic signals. These include a broad positive correlation across most sensory-motor cortices extending posteriorly to the primary visual cortex observed in both signals. In contrast, activity in prefrontal cortex is positively correlated to changes in arousal for the voltage signal while it is a slight net negative correlation observed in the hemodynamic signal. Additionally, we show that coherence between voltage and hemodynamic signals relative to arousal is strongest for slow frequencies below 0.15 Hz and is near zero for frequencies greater than 1Hz. We finally show that coupling patterns are dependent on the behavioral state of the animal with correlations being driven by periods of increased orofacial movement. Our results indicate that while hemodynamic signals show strong relations to behavior and arousal, these relations are distinct from those observed by voltage activity. Significance StatementWe leverage wide-field voltage imaging to examine the relation between cortical changes in membrane potential dynamics and hemodynamics. These two signals are then examined with respect to changes in arousal, as measured by pupil diameter, in awake head fixed mice. Our results show similarities as well as important differences in the correlation of arousal with neuronal population activity dynamics and the hemodynamic signal. Further, the spatial activity correlation maps with arousal depended differentially on the behavioral state of the animal in a frequency dependent manner. Our results indicate that the modulation of brain networks by arousal is dynamically regulated, and only partly overlap between functional networks determined from hemodynamic or voltage activity.

neuroscience↗

bioRxiv2022

Detecting rapid pan-cortical voltage dynamics in vivo with a brighter and faster voltage indicator

Widefield imaging with genetically encoded voltage indicators (GEVIs) is a promising approach for understanding the role of large cortical networks in the neural coding of behavior. However, the slow kinetics of current GEVIs limit their deployment for single-trial imaging of rapid neuronal voltage dynamics. Here, we developed a high-throughput platform to screen for GEVIs that combine fast kinetics with high brightness, sensitivity, and photostability under widefield one-photon illumination. Rounds of directed evolution produced JEDI-1P, a green-emitting fluorescent indicator whose performance is improved for all metrics. Next, we optimized a neonatal intracerebroventricular delivery method to achieve cost-effective and wide-spread JEDI-1P expression in mice. We also developed an approach to effectively correct optical measurements from hemodynamic and motion artifacts. Finally, we achieved stable brain-wide voltage imaging and successfully tracked gamma-frequency whisker and visual stimulations in awake mice in single trials, opening the door to investigating the role of high-frequency signals in brain computations.

neuroscience↗

bioRxiv2021

Input to layer 1 of somatosensory cortex: Local input outweighs long-range and can modulate the activity of layer 1 interneurons

Neocortical Layer (L) 1 has been proposed to be at the center for top-down and bottom-up integration. It is a locus for interactions between long-range inputs, L1 interneurons and apical tuft dendrites of pyramidal neurons. While input to L1 has been studied intensively, the level and effect of input to this layer has still not been completely characterized. Here we examined the input to L1 of mouse somatosensory cortex with retrograde tracing and optogenetics. Our assays reveal that local input to L1 is predominantly from L2/3 and L5 pyramidal neurons and interneurons, and that subtypes of local L5 and L6b neurons project to L1 with different probabilities. Long-range input from sensory-motor cortices to L1 of S1 arose predominantly from L2/3 neurons. Our optogenetic experiments showed that intra-telencephalic L5 pyramidal neurons drive L1 interneurons but have no effect locally on L5 apical tuft dendrites. Dual retrograde tracing revealed that a fraction of local and long-range neurons were both presynaptic to L5 neurons and projected to L1. Our work highlights the prominent role of local inputs to L1 and shows the potential for complex interactions between long-range and local inputs which are both in position to modify the output of somatosensory cortex.

neuroscience↗

bioRxiv2021

Thalamic state controls timing and synchronization of primary somatosensory cortical representations in the awake mouse

The thalamus controls transmission of sensory signals from periphery to cortex, ultimately shaping perception. Despite this significant role, dynamic thalamic gating and the consequences for downstream cortical sensory representations have not been well studied in the awake brain. We optogenetically modulated the ventro-posterior medial thalamus in the vibrissa pathway of the awake mouse, and measured spiking activity in the thalamus, and activity in primary somatosensory cortex (S1) using extracellular electrophysiology and genetically encoded voltage imaging. Thalamic hyperpolarization significantly enhanced thalamic sensory-evoked bursting, yet surprisingly the S1 cortical response was not amplified, but instead timing precision was significantly increased, spatial activation more focused, and there was an increased synchronization of cortical inhibitory neurons. A thalamocortical network model implicates the modulation of precise timing of feedforward thalamic population spiking, presenting a highly sensitive, timing-based gating of sensory signaling to cortex.

neuroscience↗

bioRxiv2021

Langerhans islets induce anti-tumor immunity at the expense of glycemic control and predict chemotherapy response in pancreatic cancer

Induction of anti-tumor immunity in pancreatic ductal adenocarcinoma (PDA) is an unresolved challenge. Systematic investigation of the microenvironment of primary pancreatic tumors revealed a role of endocrine Langerhans islets in the coordination of immune activation. We found that intratumoral {beta}-cells, regulated via STAT3, secrete C-C motif chemokine ligand 27 (CCL27) and thereby promote a TH1 phenotype in the microenvironment resulting in an enhanced T cell infiltration and prolonged patient survival. The local effect can be abrogated in a patient-based human explant model by inhibition of the CCL27 receptor CCR10. This defense mechanism is paralleled by an impaired metabolic function of Langerhans islets with reduced insulin levels resulting in a dysregulation of glycemic control in patients. Based on these findings, screening of PDA cases (n= 2264) led to the identification of type 2 diabetes mellitus (T2DM) and extractable glycated haemoglobin (HbA1c) levels as response markers for neoadjuvant chemotherapy with fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). Collectively these data provide insights into the interconnection of T2DM and PDA, and link declining glycemic control to therapeutic efficacy, which can be utilized as a tool for clinical decision-making and improve patient management.

cancer biology↗

bioRxiv2020

Changes in excitability properties of ventromedial motor thalamic neurons in 6-OHDA lesioned mice

The activity of basal ganglia input receiving motor thalamus (BGMT) makes a critical impact on motor cortical processing, but modification in BGMT processing with Parkinsonian conditions have not be investigated at the cellular level. Such changes may well be expected due to homeostatic regulation of neural excitability in the presence of altered synaptic drive with dopamine depletion. We addressed this question by comparing BGMT properties in brain slice recordings between control and unilaterally 6-OHDA treated adult mice. At a minimum of 1 month post 6-OHDA treatment, BGMT neurons showed a highly significant increase in intrinsic excitability, which was primarily due to a decrease in M-type potassium current. BGMT neurons after 6-OHDA treatment also showed an increase in T-type calcium rebound spikes following hyperpolarizing current steps. Biophysical computer modeling of a thalamic neuron demonstrated that an increase in rebound spiking can also be accounted for by a decrease in the M-type potassium current. Modeling also showed that an increase in sag with hyperpolarizing steps found after 6-OHDA treatment could in part but not fully be accounted for by the decrease in M-type current. These findings support the hypothesis that homeostatic changes in BGMT neural properties following 6-OHDA treatment likely influence the signal processing taking place in basal ganglia thalamocortical processing in Parkinsons disease. Significance StatementOur investigation of the excitability properties of neurons in the basal ganglia input receiving motor thalamus (BGMT) is significant because they are likely to be different from properties in other thalamic nuclei due to the additional inhibitory input stream these neurons receive. Further, they are important to understand the role of BGMT in the dynamic dysfunction of cortico - basal ganglia circuits in Parkinsons disease. We provide clear evidence that after 6-OHDA treatment of mice important homeostatic changes occur in the intrinsic properties of BGMT neurons. Specifically we identify the M-type potassium current as an important thalamic excitability regulator in the parkinsonian state.

neuroscience↗

bioRxiv2020

Integrative kinomics reveals kinase-driven subtypes of gastric adenocarcinomas with sunitinib as a potential common inhibitor

Molecular subtyping of tumors promises a personalized stratification into different treatment regimens. In gastric adenocarcinoma, the four molecularly defined subtypes chromosomal instable (CIN), microsatellite unstable (MSI), genomically stable (GS) and EBV-positive subtype have been proposed. Following an integrative kinomics approach this computational analysis aimed to predict the best kinase inhibitor for every molecular subtype of gastric adenocarcinomas using publicly available TCGA data (n=404). Intriguingly, using the regulatory network of gastric cancer to estimate protein activity, 43% of all samples could be identified to be kinase-driven. These samples were divided into three clusters with mutually exclusive kinase activities that were independent of the established molecular subtypes. Integrating the pattern of kinase overexpression with an unsupervised target landscape of 37 approved clinical kinase drugs revealed that sunitinib had the best target spectrum across the activated kinases in all three sample clusters. Future work is warranted to validate the kinase-driven subsets of gastric cancer and sunitinib as a potential common inhibitor.

cancer biology↗

bioRxiv2020

Nigro-Thalamic Projection Controls Timing of Action Initiation

The nigro-thalamic pathway is one of the main outputs from the basal ganglia, known to be involved in action selection, learning motor skills, and/or control the vigor of actions. However, the specific function of the nigral input to the motor thalamus remains unclear. Using a combination of in vivo electrophysiological recordings from motor thalamic neurons and optogenetic activation of nigral inputs in behaving head-fixed mice, we determined that this pathway is primarily involved in the proper timing of the release of goal directed actions. At the behavioral level, we were able to reduce the amount of impulsive licking by activating thalamic terminals. We describe changes in thalamic neuronal activity explaining this effect and propose a parsimonious model to account for our observations. These results provide new insight in the circuitry for timing control, a critical part of motor planning, and reveal a potential new target to modulate impulsivity.

neuroscience↗

bioRxiv2019

Pan-cancer image-based detection of clinically actionable genetic alterations

Precision treatment of cancer relies on genetic alterations which are diagnosed by molecular biology assays.1 These tests can be a bottleneck in oncology workflows because of high turnaround time, tissue usage and costs.2 Here, we show that deep learning can predict point mutations, molecular tumor subtypes and immune-related gene expression signatures3,4 directly from routine histological images of tumor tissue. We developed and systematically optimized a one-stop-shop workflow and applied it to more than 4000 patients with breast5, colon and rectal6, head and neck7, lung8,9, pancreatic10, prostate11 cancer, melanoma12 and gastric13 cancer. Together, our findings show that a single deep learning algorithm can predict clinically actionable alterations from routine histology data. Our method can be implemented on mobile hardware14, potentially enabling point-of-care diagnostics for personalized cancer treatment in individual patients.

genetics↗

bioRxiv2019

Deep learning detects virus presence in cancer histology

Oncogenic viruses like human papilloma virus (HPV) or Epstein Barr virus (EBV) are a major cause of human cancer. Viral oncogenesis has a direct impact on treatment decisions because virus-associated tumors can demand a lower intensity of chemotherapy and radiation or can be more susceptible to immune check-point inhibition. However, molecular tests for HPV and EBV are not ubiquitously available.\n\nWe hypothesized that the histopathological features of virus-driven and non-virus driven cancers are sufficiently different to be detectable by artificial intelligence (AI) through deep learning-based analysis of images from routine hematoxylin and eosin (HE) stained slides. We show that deep transfer learning can predict presence of HPV in head and neck cancer with a patient-level 3-fold cross validated area-under-the-curve (AUC) of 0.89 [0.82; 0.94]. The same workflow was used for Epstein-Barr virus (EBV) driven gastric cancer achieving a cross-validated AUC of 0.80 [0.70; 0.92] and a similar performance in external validation sets. Reverse-engineering our deep neural networks, we show that the key morphological features can be made understandable to humans.\n\nThis workflow could enable a fast and low-cost method to identify virus-induced cancer in clinical trials or clinical routine. At the same time, our approach for feature visualization allows pathologists to look into the black box of deep learning, enabling them to check the plausibility of computer-based image classification.

cancer biology↗