Biology subjects

Schaller, K.

Publications and source records attributed to Schaller, K..

10 recordsLinked to original sources

bioRxiv2026

Htr3a receptors control attenuation of fear responses by modulating the corticolimbic network activity and synchronization

The fear circuit orchestrates defensive responses to environmental threats and is essential for survival. Dysregulation of this system is thought to contribute to the pathophysiology of several psychiatric disorders. Within this fear circuit, the corticolimbic network, particularly the amygdala and the medial prefrontal cortex (mPFC), is strongly modulated by serotonin. Previous studies have shown that Htr3a knockout (Htr3a-KO) mice exhibit deficits in the extinction of cued fear memory; however, the circuit level mechanisms underlying these impairments remain unknown. Here, we investigated this question by recording local field potentials evoked by auditory conditioned stimuli (CS) in the prelimbic (PrL), infralimbic (IL), and basolateral amygdala (BLA) of head-fixed wild-type (WT) and Htr3a-KO mice prior to fear conditioning and during fear memory retrieval. Behaviorally, Htr3a-KO mice displayed a delayed attenuation of fear-induced freezing during cued fear memory retrieval, whereas WT mice showed a rapid attenuation in freezing. Electrophysiologically, Htr3a-KO mice exhibited reduced fear-evoked theta power in the PrL, IL, and BLA, along with diminished mPFC-BLA theta synchrony. Moreover, theta-phase modulation of gamma oscillations within the BLA, which has been shown to increase during fear states, was perturbed in the absence of Htr3a signaling. Together, these findings indicate that Htr3a is critical for maintaining proper oscillatory dynamics within the mPFC-BLA circuit and for supporting effective attenuation of learned fear. Highlights- Attenuation of fear responses during fear memory retrieval sessions is protracted in Htr3a knock-out mice - The fear-induced theta response in the medial prefrontal cortex and the basolateral amygdala is less powerful in the Htr3a knock-out mice than in wild-type - Htr3a knock-out mice show a deficit in fear-induced synchronization as well as in theta modulation of gamma power in the cortico-limbic network - These results suggest that malfunction of the Htr3a receptor cause alterations in fear network circuit mechanisms that might be linked to deficits in fear responses attenuation

neuroscience↗

bioRxiv2026

Progressive bilateral recruitment and resilient network reorganization during temporal lobe epilepsy

BackgroundTemporal lobe epilepsy (TLE) often originates from focal hippocampal injury but progressively evolves into a bilateral epileptic network engaging both hippocampi and distributed cortical regions. A mechanistic understanding of how this network emerges, and whether early perturbation of specific nodes can alter its trajectory, is essential for developing network-level therapeutic strategies. ObjectiveWe used a kainate-induced rodent model of TLE to (1) characterize the spatiotemporal emergence of epileptic discharges during the latent phase, (2) determine how bilaterally synchronized events develop, and (3) test whether transient chemogenetic silencing of either the ipsilateral epileptogenic focus (EF) or the contralateral hippocampus (CH) modifies large-scale epileptogenesis. MethodsFreely moving mice were implanted with multi-site electrodes spanning bilateral hippocampal subfields (dentate gyrus, CA1, subiculum) and cortical regions (M2, Cg1, PrL, V1, entorhinal cortex). Longitudinal LFP recordings were performed every other day during the latent and early chronic phases following KA or saline injection. DREADD-based chemogenetic inhibition of glutamatergic neurons was applied between days 2-7 post-KA. Epileptiform events were quantified via spike rates, waveform metrics, high-frequency oscillations (HFOs), and short-latency interregional co-spiking ResultsEarly after KA, epileptic spiking emerged locally in the ipsilateral dentate gyrus and progressively organized into HFO-coupled discharges. Contralateral hippocampal recruitment followed a distinctive biphasic time course, characterized by transient early activation, subsequent suppression, and later re-emergence with increasing bilateral coactivation. Cortical regions gradually developed higher spike rates and enhanced DG-related co-spiking, indicating large-scale network integration. Ipsilateral silencing modified local spike composition but did not prevent global network progression, whereas contralateral silencing accelerated ipsilateral epileptogenesis and strengthened pathological HFO expression. ConclusionEpileptogenesis in the KA model reflects a transition from a focal hippocampal insult to a resilient, bilateral cortico-hippocampal network. Targeting a single hippocampal node--even at early latent stages--is insufficient to halt this progression, highlighting the need for network-level therapeutic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/701979v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@171797dorg.highwire.dtl.DTLVardef@df13d3org.highwire.dtl.DTLVardef@18e9594org.highwire.dtl.DTLVardef@1fe68f8_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

iSleep: Continuous, binocular pupil tracking in sleep and reduced consciousness for physiological monitoring, predictions and interventions

Monitoring pupil dynamics is a key tool in understanding arousal. Pupil size can serve as a biomarker for the autonomic nervous system balance as well as for identifying brain states. While internal states can also be self-reported when awake, automated detection and non-invasive monitoring is crucial during sleep and reduced consciousness. Here, we introduce iSleep, an innovative pupil tracking and analysis framework for sleep in humans. It features comfortable, humidified eye-tracking goggles and a platform for integrated analysis and prediction capabilities. We show that iSleep allows safe and continuous access to binocular pupil size and ocular dynamics during sleep and anesthesia. iSleep reveals that pupillary fluctuations correlate tightly with brain activity, heartbeat, and breathing, and can reliably predict brain states. Pupil constrictions reflect parasympathetic drive and likely serve a protective function for deep sleep stability; while dilations indicate arousals. Unexpectedly, we observed a decoupling of binocular movements during periods of sleep, indicating alterations in reflexes which usually govern voluntary eye movements. Finally, iSleep was tested in surgery patients under general anesthesia, revealing dynamic pupil changes to noxious stimuli, suggesting the potential for nociception monitoring during surgeries. In summary, iSleep offers an easy-to-use, robust alternative to read out brain states during sleep and anesthesia, opening new avenues in monitoring, diagnostics, and treatments, previously obscured by closed eyelids.

neuroscience↗

bioRxiv2024

Interrelationship of substrate crystallinity, enzyme binding strength, and cellulase activity

Structural polysaccharides are difficult to degrade due to their crystalline structure. Hence, industrial conversion of biomass has focused on both substrate pretreatment and enzyme engineering to improve the biochemical conversion of biomass into fuels and chemicals. However, few studies have explored the interrelationship between substrate crystallinity and cellulase activity. Here, we systematically investigated the kinetics of structurally diverse cellulases on five cellulosic substrates with varying crystallinity. Regardless of enzyme structure and catalytic mechanism, we observed a linear scaling of the kinetic parameters (KM and kcat) in a log-log plot, indicating a linear free energy relationship (LFER) between binding and activation energy. LFERs were observed for all investigated substrates, but their slopes varied distinctly and appeared linked to the substrate crystallinity. Substrates with low crystallinity exhibited LFERs with a slope near 1, while highly crystalline substrates had a slope of approximately 0.25, providing insights into the transition state (TS) for the rate-limiting step. We propose that maximal turnover was limited by slow dissociation, with the TS structurally close to the enzyme-ligand complex on crystalline substrate, while on amorphous substrate, the TS structure was closer to the dissociated system. We suggest that these observations reflect competing interactions of the ligand with respectively the enzyme binding cleft and the substrate matrix. This study emphasizes the interconnected nature of substrate pretreatment and enzyme engineering, urging a holistic approach to propel the biochemical conversion of lignocellulosic biomass, crucial for advancing sustainable production of fuels and chemicals.

biochemistry↗

bioRxiv2023

PTPRZ1-targeting RNA CAR-T cells exert antigen-specific and bystander antitumor activity in glioblastoma

The great success of chimeric antigen receptor (CAR)-T cell therapy in B-cell malignancies has prompted its translation to solid tumors. In the case of glioblastoma (GBM), clinical trials have shown modest efficacy, but anti-GBM CAR-T cells are being intensely developed. In this study, we selected PTPRZ1 as an attractive new target for GBM treatment. We isolated six anti-human PTPRZ1 scFv from a human phage display library and produced 2nd generation CAR-T cells in an RNA format. Patient-derived GBM PTPRZ1-knock-in cell lines were used to select the CAR construct (471_28z), which showed high cytotoxicity while consistently displaying high CAR expression. CAR-T cells incorporating 471_28z were able to release IFN-{gamma}, IL-2, TNF-, Granzyme B, IL-17A, IL-6, and soluble FasL, and displayed low tonic signaling. Additionally, they maintained an effector memory phenotype after in vitro killing. Importantly, 471_28z CAR-T cells displayed strong bystander killing against PTPRZ1-negative cell lines after pre-activation by PTPRZ1-positive tumor cells, but did not kill antigen-negative non-tumor cells. In an orthotopic xenograft tumor model using NSG mice, a single dose of anti-PTPRZ1 CAR-T cells significantly delayed tumor growth. Taken together, these results validate the use of PTPRZ1 as a new GBM target and prompt the use of anti-PTPRZ1 CAR-T cells for clinical translation.

immunology↗

bioRxiv2023

Involvement of remote regions in sustained, but not transient, epileptic activities in the kainate mouse model of temporal lobe epilepsy

Animal and human studies have shown that the seizure-generating region is vastly dependent on distant neuronal hubs that can decrease duration and propagation of ongoing seizures. However, we still lack a comprehensive understanding of the impact of distant brain areas on specific interictal or ictal epileptic activities (e.g., isolated spikes, spike trains, seizures). Such knowledge is critically needed since all kinds of epileptic activities are not equivalent in terms of clinical expression and impact on the progression of the disease. We used surface, high-density EEG and multisite intracortical recordings, combined with pharmacological silencing of specific brain regions in the well-known kainate mouse model of temporal lobe epilepsy. We tested the impact of selective regional silencing on the generation of epileptic activities within a continuum ranging from very transient to more sustained and long-lasting discharges reminiscent of seizures. Silencing the contralateral hippocampus completely suppresses sustained ictal activities in the focus, as efficiently as silencing the focus itself, but while focus silencing abolishes all focal activities, contralateral silencing fails to control transient spikes. In parallel, we observed that sustained epileptic discharges in the focus are preceded by contralateral firing and more strongly phase locked to bi-hippocampal delta/theta oscillations than transient spiking activities, reinforcing the presumed dominant role of the contralateral hippocampus in promoting long-lasting, but not transient, epileptic activities. Altogether, our work provides suggestive evidence that the contralateral hippocampus is necessary for the interictal-to ictal-state transition and proposes that cross-talk between contralateral neuronal activity and ipsilateral delta/theta oscillation could be a candidate mechanism underlying the progression from short to long-lasting epileptic activities. Key PointsO_LIWe study how regions remote from the focus influence epileptic activities in the kainate mouse model of temporal lobe epilepsy. C_LIO_LIThe contralateral hippocampus plays a decisive role in the initiation of sustained epileptic activities C_LIO_LIIntegration of contralateral activities and bi-hippocampal delta/theta oscillations precedes focal paroxysmal activities C_LIO_LIWe propose that a large-scale epileptic network might be necessary for the transition from interictal to ictal states C_LI

neuroscience↗

bioRxiv2022

Reaction pathways for the enzymatic degradation of poly(ethylene terephthalate): What characterizes an efficient PET-hydrolase?

Bioprocessing of polyester waste has emerged as a promising tool in the quest for a cyclic plastic economy. One key step is the enzymatic breakdown of the polymer, and this entails a complicated pathway with substrates, intermediates, and products of variable size and solubility. We have elucidated this pathway for poly(ethylene terephthalate) (PET) and four enzymes. Specifically, we combined different kinetic measurements and a novel stochastic model, and found that the ability to hydrolyze internal bonds in the polymer (endo-lytic activity) was a key parameter for overall enzyme performance. Endo-lytic activity promoted the release of soluble PET fragments with two or three aromatic rings, which, in turn, were broken down with remarkable efficiency (kcat/KM-values of about 105 M-1s-1) in the aqueous bulk. This meant that about 70% of the final, monoaromatic products was formed via soluble di-or tri-aromatic intermediates.

biochemistry↗

bioRxiv2021

Molecular atlas of the human brain vasculature at the single-cell level

A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains poorly understood. Here, we performed single-cell RNA sequencing of 599,215 freshly isolated endothelial, perivascular and other tissue-derived cells from 47 fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We uncover extensive molecular heterogeneity of healthy fetal and adult human brains and across eight vascular-dependent CNS pathologies including brain tumors and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell-cell interaction analyses predict numerous endothelial-to-perivascular cell ligand-receptor crosstalk including immune-related and angiogenic pathways, thereby unraveling a central role for the endothelium within brain neurovascular unit signaling networks. Our single-cell brain atlas provides insight into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.

neuroscience↗

bioRxiv2020

Physical constrains and functional plasticity of cellulases: Linear scaling relationships for a heterogeneous enzyme reaction

Enzyme reactions, both in Nature and technical applications, commonly occur at the interface of immiscible phases. Nevertheless, stringent descriptions of interfacial enzyme catalysis remain sparse, and this is partly due to a shortage of coherent experimental data to guide and assess such work. We have produced and kinetically characterized 83 cellulases, which revealed a conspicuous linear free energy relationship (LFER) between the strength of substrate binding and the activation barrier. This common scaling occurred despite the investigated enzymes were structurally and mechanistically diverse. We suggest that the scaling reflects basic physical restrictions of the hydrolytic process and that evolutionary selection have condensed cellulase phenotypes near the line. One consequence of the LFER is that the activity of a cellulase can be estimated from substrate binding strength, irrespectively of structural and mechanistic details, and this appears promising for in silico selection and design within this industrially important group of enzymes. On a more general note, the LFER may identify a link to inorganic heterogeneous catalysis, and hence open for the implementation of approaches from this field within interfacial enzymology.

biochemistry↗

bioRxiv2018

Audio-tactile and peripersonal space processing around the trunk in human parietal and temporal cortex: an intracranial EEG study

Interactions with the environment happen by the medium of the body within ones peripersonal space (PPS) - the space surrounding the body. Studies in monkey and humans have highlighted a multisensory distributed cortical network representing the PPS. However, electrophysiological evidence for a multisensory encoding of PPS in humans is lacking. Here, we recorded for the first time intracranial electroencephalography (iEEG) in humans while administering tactile stimulation (T) on the trunk, approaching auditory stimuli (A), and the combination of the two (AT). To map PPS, in AT trials, tactile stimulation was delivered when the sound was far, at an intermediate location, or close to the body. We first identified electrodes showing AT multisensory integration (i.e., AT vs. A+T): 19% of the recording electrodes. Among those electrodes, we identified those showing a PPS effect (30% of the AT electrodes), i.e., a modulation of the evoked response to AT stimulation as a function of the distance between the sound and body. For most sites, AT multisensory integration and PPS effects had similar spatiotemporal characteristics, with an early response (~50ms) in the insular cortex, and later responses (~200ms) in pre- and post-central gyri. Superior temporal cortex showed a different response pattern with AT multisensory integration at ~100ms without PPS effect. These results, representing the first iEEG delineation of PPS processing in humans, show that PPS processing happens at neural sites where also multisensory integration occurs and at similar time periods, suggesting that PPS representation (around the trunk) is based on a spatial modulation of multisensory integration.

neuroscience↗