Biology subjects

Ueland, T.

Publications and source records attributed to Ueland, T..

7 recordsLinked to original sources

bioRxiv2026

The non-classic psychedelic muscimol suppresses inflammatory signaling and promotes neuroplasticity in schizophrenia-derived human cortical spheroids and astroglia

Schizophrenia (SCZ) is increasingly linked to neuroimmune dysregulation and impaired synaptic plasticity, yet the cellular mechanisms connecting inflammatory signaling to neural dysfunction remain poorly understood. Using human induced pluripotent stem cell (iPSC)-derived cortical spheroids (hCS) and astrocytes from patients with SCZ and matched controls, we investigated the effects of GABAA receptor modulation on immune signaling and neuroplasticity. Inflammatory stimulation induced robust interferon-responsive transcriptional programs, prominently involving the antiviral effector MX1 and related interferon-stimulated genes. Computational deconvolution and cell type-specific analyses identified astrocytes as key mediators of these responses. Muscimol, a non-classic psychedelic and GABAA receptor agonist, suppressed inflammatory gene expression, reduced secretion of proinflammatory cytokines, and attenuated interferon-associated signaling. In addition, muscimol induced neuroplasticity-associated transcriptional programs, including upregulation of NTRK2 and ELK1 in hCSs, and restored impaired glutamate uptake in iPSC-derived SCZ astrocytes. These effects were blocked by GABAA receptor inhibition, confirming receptor-dependent mechanisms. Proteomic analyses of hCS cultures, and independent human dorsolateral prefrontal cortex datasets revealed baseline dysregulation of GABAergic and neurotrophin signaling in SCZ, supporting translational relevance. Together, these findings demonstrate that GABAA receptor activation by muscimol suppresses inflammatory signaling while promoting neuroplasticity in hCSs, and identify astrocytes as central regulators of interferon-dependent neuroimmune dysfunction in SCZ. These results establish non-classic psychedelic compounds as potential modulators of neuroimmune-plasticity coupling and suggest that targeting astrocyte GABAergic signaling may represent a therapeutic strategy for restoring neural homeostasis in SCZ.

neuroscience↗

bioRxiv2025

The Art of Not Knowing: Accommodating Structured Missingness in Biomedical Research

Missing data remain a ubiquitous and critical challenge in large-scale clinical studies. Despite advances in imputation, most existing methods fail to address structured missingness, where data are missing according a deterministic pattern and which arise due to systematic patterns introduced by experimental design, site protocols, or cohort differences. These patterns violate key assumptions of most imputation algorithms, yet their impact is rarely evaluated. We demonstrate that structured missingness is a fundamental challenge to drawing valid inferences from standard imputation techniques. First, we present a comprehensive framework for understanding and accommodating the effects of structured missingness. Next, we show through simulations and real-world psychometric data with structured missingness, that widely used algorithms optimised for numerical precision (e.g., Extra Trees, AutoComplete) underperform due to site effects, while donor-based methods (e.g., MICE, hierarchical MICE) better preserve multivariate structure. We propose a novel hierarchical approach that provides optimal performance in simulated and experimental data. Finally, we show that commonly used accuracy metrics, such as mean squared error can obscure these failures, and are therefore inadequate for the evaluation of structured missingness. In contrast, other divergence-based metrics offer a more sensitive and interpretable alternative. We apply this approach to harmonising psychometric data across cohorts, which provides excellent item-level alignment across different instruments. Our study highlights the need for a paradigm shift in handling missing data within biomedical research, moving beyond conventional imputation frameworks to develop tools that can account for structured missingness. This shift is essential for ensuring reliable inference in multi-site clinical studies, precision medicine, and large-scale population analyses.

neuroscience↗

bioRxiv2024

Dysregulated Proteins in Plasma Distinguishing Syndromic from Non-syndromic Heritable Thoracic Aortic Disease

BACKGROUNDThoracic aortic aneurysms (TAA) are often found in younger individuals and approximately 20% may be associated with heritable thoracic aortic disease (HTAD). There are some data on genomic biomarkers reflecting inflammation and extracellular matrix remodeling in HTAD. However, data that accurately reflect the corresponding protein changes are scarce. Our aim was to quantify proteins by using targeted proteomics in HTAD patients versus healthy controls (HC). METHODSPatients with Loeys-Dietz syndrome (LDS, n = 8), Marfan syndrome (MFS, n = 11), and Aortic aneurysm, familial thoracic 6 syndrome (AAT6, n = 7) were recruited. For comparison, blood samples were drawn from 16 healthy controls (HC). Plasma samples were analyzed by targeted proteome analysis of 276 proteins using immunoaffinity proteomics. RESULTSSeven proteins were elevated when comparing HTAD to HC, displaying two patterns: i) Oncostatin M (OSM) and Pentraxin-3 (PTX3) were significantly higher in both LDS and MFS, with comparable levels in AAT6, reflecting a generalized increase in HTAD. ii) increased levels of TNF Receptor Superfamily Member 9 (TNFRSF9), Granulysin (GNLY), Glycoprotein 1b-alpha (GP1BA), Vasorin (VASN) and CD5 were restricted to the LDS subgroup and correlated positively with Th17 and platelet counts. CONCLUSIONSThe general increase in OSM and PTX3 in HTAD may reflect early but common mechanisms related to vascular inflammation while the distinct increase in TNFRSF9, GNLY, VASN, GP1BA and CD5 in LDS patients, may reflect involvement of Th17 inflammatory response mechanisms in the progression of TAA. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/624213v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@1234b26org.highwire.dtl.DTLVardef@1ad982org.highwire.dtl.DTLVardef@bdf438org.highwire.dtl.DTLVardef@ec9c67_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Mapping Cerebellar Anatomical Heterogeneity in Mental and Neurological Illnesses

The cerebellum has been linked to motor coordination, cognitive and affective processing, in addition to a wide range of clinical illnesses. To enable robust quantification of individual cerebellar anatomy relative to population norms, we mapped the normative development and aging of the cerebellum across the lifespan using brain scans of > 54k participants. We estimated normative models at voxel-wise spatial precision, enabling integration with cerebellar atlases. Applying the normative models in independent samples revealed substantial heterogeneity within five clinical illnesses: autism spectrum disorder, mild cognitive impairment, Alzheimers disease, bipolar disorder, and schizophrenia. Notably, individuals with autism spectrum disorder and mild cognitive impairment exhibited increased numbers of both positive and negative extreme deviations in cerebellar anatomy, while schizophrenia and Alzheimers disease predominantly showed negative deviations. Finally, extreme deviations were associated with cognitive scores. Our results provide a voxel-wise mapping of cerebellar anatomy across the human lifespan and clinical illnesses, demonstrating cerebellums nuanced role in shaping human neurodiversity across the lifespan and in different clinical illnesses.

neuroscience↗

bioRxiv2020

Evidence for reduced long-term potentiation-like visual cortical plasticity in schizophrenia and bipolar disorder

BackgroundSeveral lines of research suggest that impairments in long-term potentiation (LTP)-like synaptic plasticity might be a key pathophysiological mechanism in schizophrenia (SZ) and bipolar disorder type I (BDI) and II (BDII). Using modulations of visually evoked potentials (VEP) of the electroencephalogram, impaired LTP-like visual cortical plasticity has been implicated in patients with BDII, while there has been conflicting evidence in SZ, a lack of research in BDI, and mixed results regarding associations with symptom severity, mood states, and medication. MethodsWe measured the VEP of patients with SZ spectrum disorders (n=31), BDI (n=34), BDII (n=33), and other BD spectrum disorders (n=2), and age-matched healthy control participants (n=200) before and after prolonged visual stimulation. ResultsCompared to healthy controls, modulation of VEP component N1b, but not C1 or P1, was impaired both in patients within the SZ spectrum ({chi}2=35.1, p=3.1x10-9) and BD spectrum ({chi}2=7.0, p=8.2x10-3), including BDI ({chi}2=6.4, p=0.012), but not BDII ({chi}2=2.2, p=0.14). N1b modulation was also more severely impaired in SZ spectrum than BD spectrum patients ({chi}2=14.2, p=1.7x10-4). The reduction in N1b modulation was related to PANSS total scores ({chi}2=10.8, p=1.0x10-3), and nominally to number of psychotic episodes ({chi}2=4.9, p=0.027). Conclusions. These results suggest that LTP-like plasticity is impaired in SZ and BDI, but not BDII, and related to psychotic symptom severity. Adding to previous genetic, pharmacological, and anatomical evidence, these results implicate aberrant synaptic plasticity as a mechanism underlying SZ and BD.

neuroscience↗

bioRxiv2019

Cannabis use is associated with increased levels of soluble gp130 in schizophrenia but not in bipolar disorder

The complex effects of plant cannabinoids on human physiology is not yet fully understood, but include a wide spectrum of effects on immune modulation. The immune system and its inflammatory effector pathways are recently emerging as possible causative factors in psychotic disorders. The present study aimed to investigate whether self-administered cannabis use was associated with changes in circulating immune and neuroendocrine markers in schizophrenia (SCZ, n=401) and bipolar disorder patients (BD, n=242). A screening of 13 plasma markers reflecting different inflammatory pathways was performed in SCZ and BD patients after subdividing each group into cannabis user and non-user subgroups. We found that i) soluble gp130 (sgp130) concentrations were significantly elevated among cannabis users in the SCZ group (p=0.002) after multiple testing correction, but not in BD. ii) Nominally significant differences were observed in the levels of IL-1RA (p=0.0059), YKL40 (p=0.0069), CatS (p=0.013), sTNFR1 (p=0.031), and BDNF (p=0.020), where these factors exhibited higher plasma levels in cannabis user SCZ patients than in non-users. iii) These differences in systemic levels were not reflected by altered mRNA expression of genes encoding sgp130, IL-1RA, YKL40, CatS, sTNFR1, and BDNF in whole blood. In sum, our results show that cannabis self-administration is associated with markedly higher sgp130 levels in SCZ, but not in BD, and that this phenomenon is independent of the modulation of peripheral immune cells. These findings warrant further investigation into the potential neuroimmune, anti-inflammatory, and biobehavioral-cognitive effects of cannabis use in SCZ.

pharmacology and toxicology↗

bioRxiv2018

White matter aberrations and age-related trajectories in patients with schizophrenia and bipolar disorder revealed by diffusion tensor imaging

Supported by histological and genetic evidence implicating myelin, neuroinflammation and oligodendrocyte dysfunction in schizophrenia spectrum disorders (SZ), diffusion tensor imaging (DTI) studies have consistently shown white matter (WM) abnormalities when compared to healthy controls (HC). The diagnostic specificity remains unclear, with bipolar disorders (BD) frequently conceptualized as a less severe clinical manifestation along a psychotic spectrum. Further, the age-related dynamics and possible sex differences of WM abnormalities in SZ and BD are currently understudied.\n\nUsing tract-based spatial statistics (TBSS) we compared DTI-based microstructural indices between SZ (n=128), BD (n=61), and HC (n=293). We tested for age-by-group and sex-by-group interactions, computed effect sizes within different age-bins and within genders.\n\nTBSS revealed global reductions in fractional anisotropy (FA) and increases in radial (RD) diffusivity in SZ compared to HC, with strongest effects in the body and splenium of the corpus callosum, and lower FA in SZ compared to BD in right inferior longitudinal fasciculus and right inferior fronto-occipital fasciculus, and no significant differences between BD and HC. The results were not strongly dependent on age or sex. Despite lack of significant group-by-age interactions, a sliding-window approach supported widespread WM involvement in SZ with most profound differences in FA from the late 20s.

neuroscience↗