Biology subjects

Reuss, A. M.

Publications and source records attributed to Reuss, A. M..

8 recordsLinked to original sources

bioRxiv2026

Altered Crosstalk of Bacterial Lipopolysaccharide with Immune Cells in Colorectal Cancer Compared to Paired Adjacent Intestinal Tissue

Commensal bacteria play a crucial role in modulating human immune responses in the intestine. Under homeostatic conditions, gut microbiota are tightly regulated by interactions with the mucosal immune system. However, colorectal cancer (CRC) is characterized by an imbalance in bacterial composition and bacterial translocation across the intestinal barrier. The spatial distribution of bacteria and their interactions with immune cells in CRC tumors are poorly understood. By applying 3D light-sheet imaging, spatial transcriptomics, and imaging mass cytometry to patient-derived CRC and adjacent tissue, bacterial lipopolysaccharide (LPS) is visualized alongside immune cells and vessels. The results show regional bacterial LPS accumulation and colocalization with distinct immune cell subsets. In CRC-adjacent tissue, bacterial LPS is mainly associated with CD11c+ dendritic cells, CD15+ neutrophils, and CD163+ macrophages. In matched CRC tissue, the number and LPS colocalization of CD163+ macrophages and CD11c+ dendritic cells decreased, while CD15+ neutrophils and their colocalization with LPS increased. Notably, immune cell composition and immune cell-bacteria interactions differ between tumor and adjacent tissue, offering insights into host-microbiota dynamics and mechanistic interactions.

cancer biology↗

bioRxiv2025

aDISCO: A Broadly Applicable Method for 3D Microscopy of Archival Paraffin-Embedded Human Tissues

Human surgery and autopsy specimens are routinely stored as formalin-fixed paraffin-embedded (FFPE) tissue blocks. Diagnoses are based on microscopic examination of two-dimensional sections. Good clinical practice requires that samples be retained for decades, thus giving rise to vast archives of healthy and diseased tissues. While tissue clearing and whole-mount microscopy enable 3D analysis, FFPE human tissue blocks are often unsuitable for clearing and immunolabeling due to their large size, extensive cross-linking, and wax embedding. Here, we introduce archival DISCO (aDISCO), a versatile and robust clearing method designed to overcome these challenges. aDISCO achieves complete clearing and immunolabeling of large samples stored for 15 years or more. We applied aDISCO to human brain, spinal cord, peripheral nerve, skin, muscle, heart, kidney, liver, spleen, colon, and lung, using a broad range of antibodies. To investigate the clinical usefulness of quantitative 3D histology by aDISCO, we performed a case study of focal cortical dysplasia, a neurodevelopmental disease causing epilepsy. Using deep-learning-based analysis, we found disrupted cortical layering and both focal and global neuronal density variations in FCD, features that are likely to be overlooked by conventional histology. In summary, aDISCO delivers large datasets suitable for deep-learning-based processing, enabling the detection of subtle and sparse pathologies in large archival human tissue specimens.

bioengineering↗

bioRxiv2024

Quantitative 3D histochemistry reveals region-specific amyloid-β reduction by the antidiabetic drug netoglitazone

A hallmark of Alzheimers disease (AD) is the extracellular aggregation of toxic amyloid-beta (A{beta}) peptides in form of plaques. Here, we identify netoglitazone, an antidiabetic compound previously tested in humans, as an A{beta} aggregation antagonist. Netoglitazone improved cognition and reduced microglia activity in a mouse model of AD. Using quantitative whole-brain three-dimensional histology (Q3D), we precisely identified brain regions where netoglitazone reduced the number and size of A{beta} plaques. We demonstrate the utility of Q3D in preclinical drug evaluation for AD by providing a high-resolution brain-wide view of drug efficacy. Applying Q3D has the potential to improve pre-clinical drug evaluation by providing information that can help identify mechanisms leading to brain region-specific drug efficacy. Significance statementAlzheimers disease (AD) is the most prevalent neurodegenerative disease. Its primary symptom is progressive cognitive decline, which impairs executive brain functions and deprives patients of their autonomy in life. Experimental and clinical evidence points to the critical pathophysiological role of the amyloid-beta (A{beta}) peptide. Despite some limited successes in AD immunotherapy targeting A{beta}, AD is still incurable. Here, we use an innovative pipeline for accurate whole-brain measurements of A{beta} load to test the efficacy of the antidiabetic compound, netoglitazone. We found that netoglitazone decreases A{beta} burden in certain brain areas but not in others. Region-specific assessment of anti-A{beta} efficacy may be useful in the development of effective drugs against Alzheimers disease.

neuroscience↗

bioRxiv2023

The Benchtop mesoSPIM: a next-generation open-source light-sheet microscope for large cleared samples

In 2015, we launched the mesoSPIM initiative (www.mesospim.org), an open-source project for making light-sheet microscopy of large cleared tissues more accessible. Meanwhile, the demand for imaging larger samples at higher speed and resolution has increased, requiring major improvements in the capabilities of light-sheet microscopy. Here, we introduce the next-generation mesoSPIM ("Benchtop") with significantly increased field of view, improved resolution, higher throughput, more affordable cost and simpler assembly compared to the original version. We developed a new method for testing objectives, enabling us to select detection objectives optimal for light-sheet imaging with large-sensor sCMOS cameras. The new mesoSPIM achieves high spatial resolution (1.5 {micro}m laterally, 3.3 {micro}m axially) across the entire field of view, a magnification up to 20x, and supports sample sizes ranging from sub-mm up to several centimetres, while being compatible with multiple clearing techniques. The new microscope serves a broad range of applications in neuroscience, developmental biology, and even physics.

neuroscience↗

bioRxiv2023

Leptomeningeal collaterals regulate reperfusion in ischemic stroke

Recanalization is the mainstay of ischemic stroke treatment. However, even with timely clot removal, many stroke patients recover poorly. Leptomeningeal collaterals (LMCs) are pial anastomotic vessels with yet unknown functions. Utilizing a thrombin-based mouse model of stroke and the gold standard fibrinolytic treatment rt-PA, we here show that LMCs play a critical role in preserving vascular function in ischemic territories. We applied laser speckle contrast imaging, ultrafast ultrasound, and two-photon microscopy, to show that after thrombolysis, LMCs allow for gradual reperfusion resulting in small infarcts. On the contrary, in mice with poor LMCs, distal segments of recanalized arteries collapse and deleterious hyperemia causes hemorrhage and mortality. Accordingly, in stroke patients with poor collaterals undergoing thrombectomy, rapid reperfusion resulted in hemorrhagic transformation and unfavorable recovery. Thus, we identify LMCs as key components regulating reperfusion after stroke. Future therapeutic interventions should aim to enhance collateral function, allowing for gradual reperfusion of ischemic tissues after stroke.

neuroscience↗

bioRxiv2023

Distinct hypothalamus-habenula circuits govern risk preference

Appropriate risk evaluation is essential for survival in complex, uncertain environments. Confronted with choosing between certain (safe) and uncertain (risky) options, animals show strong preference for either option consistently across extended time periods. How such risk preference is encoded in the brain remains elusive. A candidate region is the lateral habenula (LHb), which is prominently involved in value-guided behavior. Here, using a balanced two-alternative choice task and longitudinal two-photon calcium imaging, we identify LHb neurons with risk-preference-selective activity reflecting individual risk preference prior to action selection. By employing whole-brain anatomical tracing, multi-fiber photometry, and projection- and cell-type-specific optogenetics, we find that glutamatergic LHb projections from the medial (MH) but not lateral (LH) hypothalamus provide behavior-relevant synaptic input before action selection. Optogenetic stimulation of MH{lozenge}LHb axons evoked excitatory and inhibitory postsynaptic responses, whereas LH{lozenge}LHb projections were excitatory. We thus reveal functionally distinct hypothalamus-habenula circuits for risk preference in habitual economic decision-making.

neuroscience↗

bioRxiv2022

Reflective multi-immersion microscope objectives inspired by the Schmidt telescope

Rapid advances in tissue clearing protocols have begun to outpace the capabilities of existing microscope objectives: High-resolution imaging inside cm-sized cleared samples is often not possible as it requires multi-immersion objectives with high numerical aperture (NA > 0.7), long working distance (WD > 10 mm) and a large field-of-view (FOV > 1 mm). Here, we introduce a novel mirror-based optical design, the "Schmidt objective", which meets all these criteria despite containing only two optical elements. It consists of a spherical mirror in contact with the immersion medium and an aspherical correction plate. We showcase a multi-photon variant of a Schmidt objective that reaches NA 1.08 at an refractive index of 1.56 and demonstrate its versatility by imaging fixed samples in a wide range of immersion media ranging from air and water to BABB, DBE, and ECI. In addition, we demonstrate in vivo imaging by recording neuronal activity in larval zebrafish.

neuroscience↗

bioRxiv2021

Dendritic integration of sensory and reward information facilitates learning

Learning goal-directed behavior requires association of pertinent sensory stimuli with behaviorally relevant outcomes. In the mammalian neocortex, dendrites of pyramidal neurons are suitable association sites1-3 but how their activities adapt during learning remains elusive. Here, we track calcium signals in apical dendrites of layer 5 (L5) pyramidal neurons in mouse barrel cortex during texture discrimination learning4. We observe diverse task-related responses, either localized to branches or widespread throughout the apical tuft. However, even in expert mice, the tufts capability to discriminate go/no-go stimuli remains poor. Yet, we identify two prevailing response types in dendritic branches: 1) responses to unexpected outcome (reward) in naive mice that decrease with growing task proficiency, and 2) responses associated with salient sensory stimuli, especially the outcome-predicting texture touch, that strengthen upon learning. We demonstrate that these response types match distinct unsigned components of the temporal difference error5 by replicating our results with a reinforcement learning model. Moreover, optogenetic apical inhibition of L5 neurons during the outcome time window prevents naive animals from learning the task, consistent with the effect of equivalent model perturbation. Our findings suggest that salience signals in L5 apical dendrites facilitate the recruitment of task-relevant neurons via dendritic gain modulation.

neuroscience↗