Biology subjects

Liebscher, S.

Publications and source records attributed to Liebscher, S..

9 recordsLinked to original sources

bioRxiv2026

A dedicated brain circuit controls forward walking in Drosophila

Neural circuits in the brain control high-level parameters of movement, including the initiation, speed, and direction of locomotion. How specific cell types are organized into circuits to compute these control signals and enable context-appropriate behavior remains unclear. Here, we identify central brain neurons in Drosophila that can initiate walking and exert graded control over walking speed. Connectome analyses position the neurons on top of a layered brain circuit, which recruits a specific population of descending neurons to control forward walking independently of turning and other parameters. As predicted by the connectome, the circuit enforces straight walking when activated unilaterally, and the activity of the central brain neurons represents a high-level walking drive. This drive is suppressed during flight but flexibly integrated with other control signals to enable complex movement sequences during obstacle negotiation. Together, our findings elucidate a dedicated brain circuit that enables efficient computation, selection, and integration of forward-walking signals for context-appropriate motor control.

neuroscience↗

bioRxiv2025

Marker-independent imaging reveals a correlation of fibrotic and epigenetic alterations in endometriosis

IntroductionEndometriosis describes the presence of endometrial glands outside of the uterus and can cause various symptoms such as chronic pelvic pain, hypermenorrhea and infertility. These complications pose an extreme burden on the patients, especially as up to date, the average time until diagnosis can consume several years and requires invasive laparoscopy. ObjectivesThe aim of this study is to molecularly characterize endometrium and endometriosis using marker-independent Raman microspectroscopy to identify potential biomarkers and validate its diagnostic potential. MethodsAfter histopathological characterization of tissue sections of human endometrium and endometriosis, Raman microspectroscopy was performed on the gland region. Multivariate analysis of the hyperspectral maps was used to localize major subcellular structures and further decipher their molecular composition. Samples from different anatomical regions and throughout all menstrual cycle phases were analyzed. ResultsRaman imaging enabled label-free visualization of tissue morphology and submolecular tissue characterization. Distinct differences between endometrium and endometriosis were found for collagen type I and nuclear signatures. Spectral deconvolution allowed identification of a Raman biomarker indicative of fibrotic changes in endometriosis samples. Additionally, a significant increase in epigenetic 5mC foci and an increased signal intensity relevant for methylations was detected in nuclei of endometriosis. Furthermore, a neural network-based classification of Raman data resulted in high accuracies in discriminating endometrial and peritoneal tissue from endometriosis. ConclusionThe non-destructive approach by hyperspectral Raman imaging enabled for molecular sensitive characterization of endometriotic lesions which could not only be an asset in complementing histopathological tissue evaluation but combined with data-driven classification models support in situ tissue diagnosis.

biophysics↗

bioRxiv2024

Anti-NMDAR encephalitis alters intrinsic spatiotemporal coding by enhancing neuronal coupling and clustering

Autoimmune anti-NMDA-receptor encephalitis is characterized by severe neuropsychiatric symptoms including memory dysfunction and seizures. However, it remains enigmatic what functional changes at the multi-neuronal level mediate network dysfunction. We used two-photon in vivo recording in a passive-transfer mouse model with patients monoclonal anti-GluN1-autoantibodies during slow-wave sleep-like conditions, a critical phase for memory processing. We find enhanced functional coupling and clustering between hippocampal CA1 pyramidal neurons (PNs), which intrinsically expose the network to hypersynchrony. These connectivity changes are associated with a selective preservation of strong excitatory synapses despite overall reduced excitation, thus enhancing hub-like properties of functionally connected PNs. Furthermore, we find abnormal PN firing characteristics, decreased transmission failure, and increased similarity of spontaneous spatiotemporal activity patterns, all affecting CA1 intrinsic neuronal coding. Collectively, the functional rewiring of hippocampal networks and altered intrinsic information processing provide new mechanistic insights into the NMDAR-hypofunction consequences and pathomechanisms of anti-NMDAR encephalitis symptomatology.

neuroscience↗

bioRxiv2021

Three water restriction schedules used in rodent behavioral tasks transiently impair growth and differentially evoke a stress hormone response without causing dehydration

Water restriction is commonly used to motivate rodents to perform behavioral tasks; however, its on hydration and stress hormone levels are unknown. Here, we report daily body weight and bi-weekly packed red blood cell volume and corticosterone in adult male rats across 80 days for three commonly used water restriction schedules. We also assessed renal adaptation to water restriction using post-mortem histological evaluation of renal medulla. A control group received ad libitum water. After one week of water restriction, rats on all restriction schedules resumed similar levels of growth relative to the control group. Nominal hydration was observed, and water restriction did not drive renal adaptation. An intermittent restriction schedule was associated with an increase in corticosterone relative to the control group. Our results suggest that the water restriction schedules used here will maintain welfare in rats. However, intermittent restriction evokes a stress response which could affect behavioral and neurobiological results. Our results also suggest that stable motivation in behavioral tasks may only be achieved after one week of restriction.

neuroscience↗

bioRxiv2020

Striatal seeding of protofibrillar alpha-synuclein causes cortical hyperreactivity in behaving mice

Alpha-synucleinopathies are characterized by self-aggregation of the protein alpha-synuclein (a-syn), causing alterations on the molecular and cellular level. To unravel the impact of transneuronal spreading and templated misfolding of a-syn on the microcircuitry of remotely connected brain areas, we investigated cortical neuron function in awake mice 9 months after a single intrastriatal injection of a-syn preformed fibrils (PFFs), using in vivo two-photon calcium imaging. We found altered function of layer 2/3 cortical neurons in somatosensory cortex (S1) of PFF-inoculated mice, as witnessed by an enhanced response to whisking and increased synchrony, accompanied by a decrease in baseline Ca2+ levels. Stereological analyses revealed a reduction in GAD67-positive inhibitory cells in S1 in PFF-injected brains. These findings point to a disturbed excitation/inhibition balance as an important pathomechanism in alpha-synucleinopathies and demonstrate a clear association between the spread of toxic proteins and the initiation of altered neuronal function in remotely connected areas.

neuroscience↗

bioRxiv2020

Chronic in vivo STED nanoscopy uncovers multiple drivers of shape volatility in stable cortical spines

Excitatory synapses on dendritic spines of pyramidal neurons are considered a central memory locus. To foster both continuous adaption as well as the storage of long-term information, spines need to be plastic and stable at the same time. Here we advanced in vivo STED nanoscopy to superresolve distinct features of dendritic spines (head size, neck length and width) in mouse neocortex for up to one month. While LTP-dependent changes predict highly correlated modifications of spine geometry, we find both, uncorrelated dynamics, as well as correlated changes, indicating multiple independent drivers of spine remodeling. The magnitude of this remodeling suggests substantial fluctuations in synaptic strength, and is exaggerated in a mouse model of neurodegeneration. Despite this high degree of volatility, all spine features also exhibit persistent components that are maintained over long periods of time. Thus, at the nanoscale, stable dendritic spines exhibit a delicate balance of stability and volatility.

neuroscience↗

bioRxiv2020

Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and defects in inhibitory synapses

Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS, lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a profound increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo. Importantly, RNAseq analysis suggested involvement of defects in inhibitory neurons, that was confirmed by ultrastructural and morphological defects of inhibitory synapses and increased synaptosomal levels of mRNAs involved in inhibitory neurotransmission. Thus, cytoplasmic FUS triggers inhibitory synaptic deficits, leading to increased neuronal activity and behavioral phenotypes. FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, but also in other neurodegenerative diseases with FUS mislocalization.

neuroscience↗

bioRxiv2019

Long-term dynamics of aberrant neuronal activity in Alzheimer’s disease

Alzheimers disease (AD) is associated with aberrant neuronal activity levels. How those activity alterations emerge and how stable they are over time in vivo, however, remains elusive to date. To address these questions we chronically recorded the activity from identified neurons in cortex of awake APPPS1 transgenic mice and their non-transgenic littermates over the course of 4 weeks by means of calcium imaging. Surprisingly, aberrant neuronal activity was very stable over time. Moreover, we identified a slow progressive gain of activity of former intermediately active neurons as the main source of new highly active neurons. Interestingly, fluctuations in neuronal activity were independent from amyloid plaque proximity, but aberrant activity levels were more likely to persist close to plaques. These results support the notion that neuronal network pathology observed in AD patients is the consequence of stable single cell aberrant neuronal activity, a finding of potential therapeutic relevance.\n\nO_FIG O_LINKSMALLFIG WIDTH=181 HEIGHT=200 SRC=\"FIGDIR/small/801902v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (43K):\norg.highwire.dtl.DTLVardef@16f8461org.highwire.dtl.DTLVardef@5c0952org.highwire.dtl.DTLVardef@681c04org.highwire.dtl.DTLVardef@107854a_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2018

Cortical circuit alterations precede disease onset in Huntington’s disease mice

AbstractHuntingtons disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in the disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronic in vivo two-photon calcium imaging to monitor the activity of single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in neuronal activity with a clear increase in activity at the age of 8.5 weeks, preceding the onset of motor and neurological symptoms. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and HD patient samples reveal reduced inputs from parvalbumin-positive interneurons onto layer 2/3 pyramidal cells. Thus, our study provides a time-resolved description as well as mechanistic details of cortical circuit dysfunction in HD.\n\nSignificance statementFuntional alterations in the cortex are believed to play an important role in the pathogenesis of Huntingtons disease (HD). However, studies monitoring cortical activity in HD models in vivo at a single-cell resultion are still lacking. We have used chronic two-photon imaging to investigate changes in the activity of single neurons in the primary motor cortex of awake presymptomatic HD mice. We show that neuronal activity increases before the mice develop disease symptoms. Our histological analyses in mice and in human HD autopsy cases furthermore demonstrate a loss inhibitory synaptic terminals from parvalbimun-positive interneurons, revealing a potential mechanism of cortical circuit impairment in HD.

neuroscience↗