Biology subjects

Wagner, L.

Publications and source records attributed to Wagner, L..

32 records · Page 2Linked to original sources

bioRxiv2023

Decoding Arbitrary and Informed Decisions from Intracranial Recordings in Humans

Ideally, decisions are made based on prior knowledge, which allows for informed choices. Real life, however, often requires us to make decisions arbitrarily, without sufficient information. Decoding decision making processes from neural activity could allow for cognitive neuroprostheses and Brain-Computer Interfaces (BCIs) to support decision processes in rapid human-machine interactions, weigh decision-making confidence, and further enable neuromodulation protocols for the treatment of reward-related dysfunctions. To understand the differences between the decision-making processes in arbitrary and informed decisions, we recorded intracranial electroencephalography in a large number of cortical and subcortical areas from 5 patients during a categorization task. We demonstrate that individual decisions can be decoded from Local Field Potentials (LFPs) before motor response, in both arbitrary and informed conditions. Our analysis revealed dissimilar spatio-temporal patterns between arbitrary and informed decision-making, with arbitrary decisions being decodable in fewer brain regions and earlier in time compared to informed decisions.

neuroscience↗

bioRxiv2022

Huntingtin expression influences spontaneous seizure disorder susceptibility in FVN/B mice

Huntington disease (HD) is an adult-onset neurodegenerative disorder that is caused by a trinucleotide CAG repeat expansion in the HTT gene that codes for the protein huntingtin (HTT or Htt in mice). HTT is a multi-functional, ubiquitously expressed protein that is essential for embryonic survival, normal neurodevelopment, and adult brain function. The ability of wild-type HTT to protect neurons against various forms of death raises the possibility that loss of normal HTT function may worsen disease progression in HD. Huntingtin-lowering therapeutics are being evaluated in clinical trials for HD, but concerns have been raised that decreasing wild-type HTT levels may have adverse effects. Here we show that Htt levels modulate the occurrence of an idiopathic seizure disorder that spontaneously occurs in FVB/N mice. These abnormal FVB/N mice demonstrate various cardinal features of mouse models of epilepsy including spontaneous seizures, astrocytosis, neuronal hypertrophy, upregulation of brain-derived neurotrophic factor (BDNF), and sudden seizure-related death. Interestingly, decreasing wild-type Htt levels increased the frequency of this disorder, while over-expression of HTT completely prevented it. Examination of the mechanism underlying huntingtins ability to modulate the frequency of this seizure disorder indicated that over-expression of full length HTT can promote neuronal survival following seizures. Overall, our results demonstrate a protective role for huntingtin in this form of epilepsy and provide a plausible explanation for the observation of seizures in the juvenile form of HD, Lopes-Maciel-Rodan syndrome, and Wolf-Hirschhorn syndrome. Adverse effects caused by altering huntingtin levels has ramifications related to Huntingtin-lowering therapies in development to treat HD.

neuroscience↗

bioRxiv2022

A natural language fMRI dataset for voxelwise encoding models

Speech comprehension is a complex process that draws on humans abilities to extract lexical information, parse syntax, and form semantic understanding. These sub-processes have traditionally been studied using separate neuroimaging experiments that attempt to isolate specific effects of interest. More recently it has become possible to study all stages of language comprehension in a single neuroimaging experiment using narrative natural language stimuli. The resulting data are richly varied at every level, enabling analyses that can probe everything from spectral representations to high-level representations of semantic meaning. We provide a dataset containing BOLD fMRI responses recorded while 8 subjects each listened to 27 complete, natural, narrative stories (~6 hours). This dataset includes pre-processed and raw MRIs, as well as hand-constructed 3D cortical surfaces for each participant. To address the challenges of analyzing naturalistic data, this dataset is accompanied by a python library containing basic code for creating voxelwise encoding models. Altogether, this dataset provides a large and novel resource for understanding speech and language processing in the human brain.

neuroscience↗

bioRxiv2022

An autoregulatory feedback loop converging on H2A ubiquitination drives synovial sarcoma

The SS18-SSX fusion drives oncogenic transformation in synovial sarcoma by bridging SS18, a member of mSWI/SNF complex, to Polycomb repressive complex 1 (PRC1) target genes. Here we show that the SSX C-terminus, via its SSXRD domain, directs SS18-SSX chromatin binding independently of SS18. SSXRD specific targeting is mediated by interaction with mono ubiquitinated H2A (H2AK119ub1) and histone MacroH2A with which the fusion overlaps genome wide. Variant Polycomb Repressive Complex 1.1 (PRC1.1) acts as the main depositor of H2AK119ub1 and is therefore required for SS18-SSX occupancy. Importantly, the SSX C-terminus not only depends on H2AK119ub1 for localization but also further increases it by promoting PRC1.1 complex stability. Consequently, high H2AK119ub1 levels are a feature of murine and human synovial sarcomas. These results reveal an SSX/PRC1 autoregulatory feedback loop that reinforces fusion chromatin binding and therefore its oncogenic activity, and could play a role in a wider range of cancers and physiological settings where SSX proteins are overexpressed.

cancer biology↗

bioRxiv2022

Executed and imagined grasping movements can be decoded from lower dimensional representation of distributed non-motor brain areas.

Using brain activity directly as input for assistive tool control can circumvent muscular dysfunction and increase functional independence for physically impaired people. Most invasive motor decoding studies focus on decoding neural signals from the primary motor cortex, which provides a rich but superficial and spatially local signal. Initial non-primary motor cortex decoding endeavors have used distributed recordings to demonstrate decoding of motor activity by grouping electrodes in mesoscale brain regions. While these studies show that there is relevant and decodable movement related information outside the primary motor cortex, these methods are still exclusionary to other mesoscale areas, and do not capture the full informational content of the motor system. In this work, we recorded intracranial EEG of 8 epilepsy patients, including all electrode contacts except those contacts in or adjacent to the central sulcus. We show that executed and imagined movements can be decoded from non-motor areas; combining all non-motor contacts into a lower dimensional representation provides enough information for a Riemannian decoder to reach an area under the curve of 0.83 {+/-} 0.11. Additionally, by training our decoder on executed and testing on imagined movements, we demonstrate that between these two conditions there exists shared distributed information in the beta frequency range. By combining relevant information from all areas into a lower dimensional representation, the decoder was able to achieve high decoding results without information from the primary motor cortex. This representation makes the decoder more robust to perturbations, signal non-stationarities and neural tissue degradation. Our results indicate to look beyond the motor cortex and open up the way towards more robust and more versatile brain-computer interfaces.

neuroscience↗

bioRxiv2022

Speech Production in Intracranial Electroencephalography: iBIDS Dataset

Speech production is an intricate process involving a large number of muscles and cognitive processes. The neural processes underlying speech production are not completely understood. As speech is a uniquely human ability, it can not be investigated in animal models. High-fidelity human data can only be obtained in clinical settings and is therefore not easily available to all researchers. Here, we provide a dataset of 10 participants reading out individual words while we measured intracranial EEG from a total of 1103 electrodes. The data, with its high temporal resolution and coverage of a large variety of cortical and sub-cortical brain regions, can help in understanding the speech production process better. Simultaneously, the data can be used to test speech decoding and synthesis approaches from neural data to develop speech Brain-Computer Interfaces and speech neuroprostheses.

neuroscience↗

bioRxiv2022

Interoperability of RTN1A in dendrite dynamics and immune functions in human Langerhans cells

Skin is an active immune organ where professional antigen-presenting cells such as epidermal Langerhans cells (LCs) link innate and adaptive immune responses. While Reticulon 1A (RTN1A) was recently identified in LCs and dendritic cells in cutaneous and lymphoid tissues of humans and mice, its function is still unclear. Here, we studied the involvement of this protein in cytoskeletal remodeling and immune responses towards pathogens by stimulation of Toll-like receptors (TLRs) in resident LCs (rLCs) and emigrated LCs (eLCs) in human epidermis ex vivo and in a transgenic THP-1 RTN1A+ cell line. Hampering RTN1A functionality through an inhibitory antibody induced significant dendrite retraction of rLCs and inhibited their emigration. Similarly, expression of RTN1A in THP-1 cells significantly altered their morphology, enhanced aggregation potential and inhibited the Ca2+ flux. Differentiated THP-1 RTN1A+ macrophages exhibited long cell protrusions and a larger cell body size in comparison to wild type cells. Further, stimulation of epidermal sheets with bacterial lipoproteins (TLR1/2 and TLR2) and single-stranded RNA (TLR7) resulted in the formation of substantial clusters of rLCs and a significant decrease of RTN1A expression in eLCs. Together, our data indicate involvement of RTN1A in dendrite dynamics and structural plasticity of primary LCs. Moreover, we discovered a relation between activation of TLRs, clustering of LCs and downregulation of RTN1A within the epidermis, thus indicating an important role of RTN1A in LC residency and maintaining tissue homeostasis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/487626v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@8011c8org.highwire.dtl.DTLVardef@f784borg.highwire.dtl.DTLVardef@1a28a1corg.highwire.dtl.DTLVardef@195b0f_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIBlocking of RTN1A induces dendrite retraction of resident LCs (rLCs) in epidermal explants. C_LIO_LIDespite a roundish morphology rLCs exhibit reduced migration capacity. C_LIO_LIRTN1A has an inhibitory effect on the calcium flux. C_LIO_LIToll-like receptor-activated rLCs form vast clusters and significantly diminish RTN1A expression after emigration. C_LIO_LIRTN1A plays a central role in LC residency and maintaining tissue homeostasis. C_LI

cell biology↗

bioRxiv2022

Urinary single-cell sequencing captures intrarenal injury and repair processes in human acute kidney injury

Acute kidney injury (AKI) is a major health issue, the outcome of which depends primarily on damage and reparative processes of tubular epithelial cells (TEC). Mechanisms underlying AKI remain incompletely understood, specific therapies are lacking and monitoring the course of AKI in clinical routine is confined to measuring urine output and plasma levels of filtration markers. Here we demonstrate feasibility and potential of a novel approach to assess the cellular and molecular dynamics of AKI by establishing a robust urine-to-single cell RNA sequencing (scRNAseq) pipeline for excreted kidney cells via flow cytometry sorting. We analyzed 42,608 single cell transcriptomes of 40 urine samples from 32 AKI patients and compared our data with reference material from human AKI post-mortem biopsies and published mouse data. We demonstrate that TEC transcriptomes mirror intrarenal pathology and reflect distinct injury and repair processes, including oxidative stress, inflammation, and tissue rearrangement. We also describe an AKI-specific abundant urinary excretion of progenitor-like cells. In conclusion, single cell transcriptomics of kidney cells excreted in urine provides non-invasive, unprecedented insight into cellular processes underlying AKI, thereby opening novel opportunities for target identification, AKI sub-categorization and monitoring of natural disease course and interventions. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/479234v2_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@e7175corg.highwire.dtl.DTLVardef@1aed1e6org.highwire.dtl.DTLVardef@5655f4org.highwire.dtl.DTLVardef@2512a7_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2022

Preclinical establishment of a divalent vaccine against SARS-CoV-2

First-generation vaccines against SARS-CoV-2 have been administered to more than 60% of the population in developed countries. However, the monovalent vaccines currently available in Europe do not confer adequate and durable immune protection. To satisfy the need for a novel vaccine, we engineered a divalent gene construct consisting of the receptor binding domain (RBD, 300-685 aa) of the spike protein and the immunodominant region of the nucleocapsid (100-300 aa). This fusion protein was cloned into a pET-30a plasmid and expressed either in Escherichia coli or in a recombinant baculovirus in insect cells. Following purification via its His-tag, the fusion protein was mixed with adjuvant, and administered to mice in a prime-booster-mode. Upon testing for IgG antibody response against nucleocapsid and RBD, a titer of 10-4 - 10-5 was demonstrated 14 days after the first booster injection in 72% of the animals, which could be increased to 100% by a second booster. Notably, comparable IgG responses were detected against the delta, gamma and omicron variants of the RBD region. Durability testing revealed the presence of IgG beyond 90 days. In addition, granzyme A and perforin mRNA expression (cytolytic effector cell molecules) was increased in cytotoxic lymphocytes isolated from peripheral blood. Ex vivo stimulation of T-cells by nucleocapsid and RBD peptides showed antigen-specific upregulation of CD44 in vaccinated mice among their CD4+ and CD8+ T-cells. No side-effect was documented in the central nervous system, be it either endothelial inflammation or neuronal damage. Cumulatively, the combined induction of B-cell and T-cell response by a bivalent protein-based vaccine directed against two structural SARS-CoV-2 proteins represents a proof-of-principle approach alternative to existing mRNA vaccination strategies, which could confer long-lasting immunity against all known viral strains.

bioengineering↗

bioRxiv2021

Localizing spontaneous memory reprocessing during human sleep

Reactivation of newly acquired memories during sleep across hippocampal and neocortical systems is proposed to underlie systems memory consolidation. Here, we investigate spontaneous memory reprocessing during sleep by applying machine learning to source space-transformed magnetoencephalographic data in a two-step exploratory and confirmatory study design. We decode memory-related activity from slow oscillations in hippocampus, frontal cortex and precuneus, indicating parallel memory processing during sleep. Moreover, we show complementary roles of hippocampus and neocortex: while gamma activity indicated memory reprocessing in hippocampus, delta and theta frequencies allowed decoding of memory in neocortex. Neocortex and hippocampus were linked through coherent activity and modulation of high-frequency gamma oscillations by theta, a dynamic similar to memory processing during wakefulness. Overall, we noninvasively demonstrate localized, coordinated memory reprocessing in human sleep.

neuroscience↗

bioRxiv2021

Mapping drug-microenvironment-genetic interplay in CLL reveals trisomy 12 as a modulator of microenvironmental signals

The tumour microenvironment and genetic alterations collectively influence drug efficacy in cancer, but current evidence is limited to small scale studies and systematic analyses are lacking. We chose Chronic Lymphocytic Leukaemia (CLL), the most common leukaemia in adults, as a model disease to study this complex interplay systematically. We performed a combinatorial assay using 12 drugs individually co-applied with each of 17 microenvironmental stimuli in 192 primary CLL samples, generating a comprehensive map of drug-microenvironment interactions in CLL. This data was combined with whole-exome sequencing, DNA-methylation, RNA-sequencing and copy number variant annotation. Our assay identified four distinct CLL subgroups that differed in their responses to the panel of microenvironmental stimuli. These subgroups were characterized by distinct clinical outcomes independently of known prognostic markers. We investigated the effect of CLL- specific recurrent genetic alterations on microenvironmental responses and identified trisomy 12 as an amplifier of multiple microenvironmental stimuli. We further quantified the impact of microenvironmental stimuli on drug response, confirmed known interactions such as Interleukin (IL) 4 mediated resistance to B cell receptor (BCR) inhibitors, and identified new interactions such as Interferon-{gamma} induced resistance to BCR inhibitors. Finally, we identified interactions which were limited to genetic subgroups. Resistance to chemotherapeutics, such as Fludarabine, induced by Toll-Like Receptor (TLR) agonists could be observed in IGHV unmutated patient samples and IGHV mutated samples with trisomy 12. In-vivo relevance was investigated in CLL-infiltrated lymph nodes, which showed increased IL4 and TLR signalling activity compared to healthy samples (p<0.001). High IL4 activity in lymph nodes correlated with faster disease progression (p=0.038). We provide a publicly available resource (www.dietrichlab.de/CLL_Microenvironment/) which uncovers tumour cell extrinsic influences on drug response and disease progression in CLL, and how these interactions are modulated by cell intrinsic molecular features.

cancer biology↗

bioRxiv2020

Real-time Synthesis of Imagined Speech Processes from Minimally Invasive Recordings of Neural Activity

Speech neuroprosthetics aim to provide a natural communication channel to individuals who are unable to speak due to physical or neurological impairments. Real-time synthesis of acoustic speech directly from measured neural activity could enable natural conversations and significantly improve quality of life, particularly for individuals who have severely limited means of communication. Recent advances in decoding approaches have led to high quality reconstructions of acoustic speech from invasively measured neural activity. However, most prior research utilizes data collected during open-loop experiments of articulated speech, which neglects the critical human-in-the-loop aspect of a practical speech neuroprosthetic. Here we present an approach that synthesizes audible speech in real-time for both imagined and whispered speech conditions. Using a participant implanted with stereotactic depth electrodes, we were able to reliably generate audible speech in real-time. The decoding models rely predominately on frontal activity suggesting that speech processes have similar representations when vocalized, whispered, or imagined. Our real-time synthesis approach represents an essential step towards investigating how patients will learn to operate a closed-loop speech neuroprosthesis, as well as the development of techniques that incorporate co-adaptation of the user and system for optimized performance.

neuroscience↗

bioRxiv2020

Social signaling via bioluminescent blinks drives schooling behavior in the flashlight fish Anomalops katoptron

The bioluminescent flashlight fish Anomalops katoptron live in schools of several hundred specimens. To understand how flashlight fish, integrate bioluminescent signaling into their schooling behavior, we analyzed movement profiles and blink frequencies. Isolated specimen of A. katoptron show a high motivation to align with fixed or moving artificial light organs. Depending on presented frequencies A. katoptron responds with a reduction in swimming speed and its own blink frequency. Higher presented blink frequencies reduce the nearest neighbor distance. In the natural environment A. katoptron is changing its blink frequencies and nearest neighbor distance in a context specific manner. Blink frequencies are increased from day to night and during avoidance behavior, while nearest neighbor distance is decreased with increasing blink frequencies. A. katoptron changes its blink frequencies by modifying light organ occlusion. Our results suggest that visually transmitted information via specific blink patterns determine intraspecific communication and group cohesion in schooling A. katoptron.Competing Interest StatementThe authors have declared no competing interest.View Full Text

animal behavior and cognition↗

bioRxiv2019

Brain-wide genetic mapping identifies the indusium griseum as a prenatal and shared target of pharmacologically-unrelated psychostimulants

Psychostimulant use is an ever-increasing socioeconomic burden, including a dramatic rise during pregnancy. Nevertheless, brain-wide effects of psychostimulant exposure are incompletely understood. Here, we performed Fos-CreERT2-based activity mapping, correlated for pregnant mouse dams and their fetuses with amphetamine, nicotine and caffeine applied acutely during mid-gestation. While light-sheet microscopy-assisted intact tissue imaging revealed drug- and age-specific neuronal activation, the indusium griseum (IG) appeared indiscriminately affected. By using GAD67gfp/+ mice we subdivided the IG into a dorsolateral domain populated by GABA interneurons and a ventromedial segment containing glutamatergic neurons, many showing drug-induced activation and sequentially expressing Pou3f3/Brn1 and secretagogin (Scgn) during differentiation. We then combined Patch-seq and circuit mapping to show that the ventromedial IG is a quasi-continuum of glutamatergic neurons (IG-Vglut1+) reminiscent to dentate granule cells in both rodents and humans, whose dendrites emanate perpendicularly towards, while their axons course parallel with the superior longitudinal fissure. IG-Vglut1+ neurons receive Vglut1+ and Vglut2+ excitatory afferents that topologically segregate along their somatodendritic axis. In turn, their efferents terminate in the olfactory bulb, thus being integral to a multi-synaptic circuit that could feed information antiparallel to the olfactory-cortical pathway. In IG-Vglut1+ neurons, prenatal psychostimulant exposure delayed the onset of Scgn expression. Genetic ablation of Scgn was then found to sensitize adult mice towards methamphetamine-induced epilepsy, suggesting a role for this Ca2+-binding protein in scaling IG-Vglut1+ neuronal excitability. Overall, our study identifies brain-wide targets of the most common psychostimulants, among which Scgn+/Vglut1+ neurons of the IG link limbic and olfactory circuits.\n\nSignificance statementDrug abuse during pregnancy is a significant socioeconomic problem. The use of psychostimulants is particularly common during pregnancy even though a risk to the developing fetus is significant. Here, we show that short-lived exposure to amphetamine, nicotine and caffeine during pregnancy induces neuronal activation in the fetal brain with the indusium griseum (IG), a brain area situated parallel to the central surface of the cortical hemispheres, becoming indiscriminately activated. By using mouse genetics, we find that psychostimulants preferentially target glutamatergic IG neurons, and delay their differentiation postnatally. Notably, the expressional onset of secretagogin, a Ca2+-sensor amenable for synaptic integration, is deregulated. This is significant because these neurons are integral to a multi-synaptic neuronal pathway that links limbic and olfactory circuits. As such, genetic deletion of secretagogin brings about heightened sensitivity to psychostimulants, manifesting as epileptiform discharges. Cumulatively, we describe a novel psychostimulant-sensitive neuronal subtype and its circuit arrangement whose developmental delay seems critical for behavioral abnormalities in offspring prenatally exposed to the most common psychostimulants.

neuroscience↗