Biology subjects

Ehrenreich, H.

Publications and source records attributed to Ehrenreich, H..

At least 19 recordsLinked to original sources

bioRxiv2026

A single-nucleus regulatory atlas links transposable elements to adult hippocampal neurogenesis

Adult hippocampal neurogenesis can be enhanced or even triggered by extrinsic stimuli, but the lineage-specific regulatory changes that accompany a stimulated neurogenic response remain undefined. We used recombinant human erythropoietin (rhEPO), a defined influencing factor that enriches newly formed pyramidal neurons by ~2 fold in this paradigm, to profile ~35,000 nuclei by single-nucleus ATAC sequencing (snATAC-seq) from rhEPO- and placebo-treated adult mouse hippocampi and to integrate them with matched single-nucleus RNA sequencing (snRNA-seq) of ~120,000 nuclei. Thirty-five accessibility-defined clusters resolved 11 major lineages. Of 39,404 differentially accessible regions (DARs), more than half arose in pyramidal neurons, whereas dentate gyrus granule neurons and interneurons showed predominantly reduced accessibility; within the pyramidal lineage, remodelling was predominant in newly-formed rather than mature neurons. About 20% of hippocampal candidate cis-regulatory elements (cCREs) overlapped transposable elements (TEs) at baseline, rising to about 50% among regions that gained accessibility upon stimulation, and multiple families were significantly bound above the expected threshold by neurogenic transcription factors, whereby the many neighbouring genes have established roles for neuronal differentiation and synapse formation. These data define TE-derived sequences as candidate components of stimulus-responsive neurogenic regulatory networks and provide a cell-type-specific chromatin resource for the adult hippocampus at single-nucleus resolution.

neuroscience↗

bioRxiv2026

HIF1A recruits primate-specific endogenous retroviruses into the human hypoxic and immune responses

Oxygen availability varies profoundly across the human body and changes further during inflammation, infection, tissue injury and disease. Immune cells must therefore continuously adapt their transcriptional and metabolic state based on the oxygen availability to them. Hypoxia-inducible factor 1 (HIF1A) is central to this adaptation and a marker of the cellular response to low oxygen, yet its genomic targets have been assembled from a non-repetitive fraction of the genome, leaving nearly half of the human genome largely unexplored. Here we define the gene and transposable-element (TE) landscape of the human hypoxic response across different human tissues, cell lines, and conditions. This directional TE response was reproduced in transformed cells and in primary immune cells isolated from blood and the physiologically oxygen-restricted tonsil. Single-cell profiling of peripheral blood mononuclear cells (PBMC) under hypoxia, pharmacological HIF stabilization, and interferon stimulation revealed a striking difference between the gene and retrotranscriptome responses. While gene responses were strongly cell-type dependent and in a bidirectional manner, TEs were overwhelmingly activated. This pattern extended to blood and tonsil immune cells, where ~70-90% of tested TE families were induced under hypoxia, with activated tonsil cells showing exclusively induced significant families, including THE1B, alongside increased LTR7 and HERVH. Integrating HIF1A ChIP-seq with transcriptional responses revealed that HIF1A does not engage repetitive DNA indiscriminately. Instead, its binding converged on LTR7, the promoter long terminal repeat of the HERVH endogenous retrovirus. Approximately 80% of HIF1A-bound LTR7 elements contained a canonical hypoxia-response element, and disruption of HIF1A DNA binding dramatically reduced the expression of occupied HERVH loci. CRISPR deletion of individual LTR7/HERVH loci altered the expression of distant and neighboring genes, demonstrating that hypoxia-responsive retroelements can participate directly in host gene regulation and contribute to overall physiology. Our findings reveal the repetitive genome as a previously underappreciated component of oxygen sensing. We propose that HIF1A recruits selected endogenous retroviral elements into the human hypoxic response, extending oxygen-dependent regulation beyond conventional gene promoters and providing an additional regulatory layer through which tissue oxygenation can shape immune-cell state and human physiology.

genomics↗

bioRxiv2025

Transposable Element-Mediated Epigenomic Remodeling Drives Erythropoietin-Induced Neurogenesis in the Adult Hippocampus

Understanding the molecular mechanisms by which erythropoietin (EPO) acts as neurotrophic factor that enhances hippocampal function and learning is essential to harness its therapeutic potential. Here, we employ single-nucleus ATAC-seq and RNA-seq to map the epigenomic and transcriptional landscapes of adult mouse hippocampus under recombinant human EPO (rhEPO) treatment. We discover significant lineage-specific chromatin remodeling predominantly in newly formed and immature excitatory neurons, highlighting a robust EPO-driven neurogenic response as the first direct evidence that an extrinsic factor can induce adult hippocampal neurogenesis. Notably, many EPO-induced accessible regions overlap ancient transposable elements, particularly ancient LINEs and SINEs, that are bound by key neurogenic transcription factors such as NEUROD1/2, NEUROG2, FOXG1, and ASCL1 and are linked to nearby genes governing neuronal differentiation and synaptic plasticity. Our findings uncover a previously unrecognized transposon-mediated mechanism underlying EPO-induced neurogenesis, highlighting an underappreciated role for TE-derived sequences in this process, and establish a publicly available single-nucleus multiomic atlas as a resource for understanding cell-type-specific gene regulation and neuroplasticity in the adult brain.

neuroscience↗

bioRxiv2025

Transcriptional dynamics of the oligodendrocyte lineageand its regulation by the brain erythropoietin system

Oligodendrocytes differentiate from oligodendrocyte progenitor cells (OPC) in early postnatal development, but some oligodendrogenesis is maintained throughout adulthood, where oligodendrocyte lineage dynamics may contribute to neuroplasticity, adaptive myelination, and myelin repair. Here, we studied the effect of erythropoietin (EPO) and its receptor (EPOR) on oligodendrocyte lineage dynamics employing murine hippocampus and its myelinated fibers as model region. Using multiple stage-specific markers and single-nuclei-RNA-seq data, we find that EPO stimulates all oligodendroglial lineage cells directly, driving differentiation/maturation. Differential gene expression analysis reveals multiple EPO-regulated mRNAs, including downregulated transcripts for GABA-A receptors, fitting the known inhibition of oligodendrocyte maturation by GABA. Importantly, analogous oligodendrocyte responses are seen when endogenous EPO expression in brain is stimulated by hypoxia. Mice lacking EPOR from mature oligodendrocytes show subtle deficiencies of adult myelination in hippocampal fimbria and mild working memory deficits. These gain- and loss-of-function experiments may further suggest EPO as clinically safe treatment for remyelination therapies.

neuroscience↗

bioRxiv2025

Erythropoietin alleviates intellectual disability and autism-like behavior of mice caused by Zbtb20 haploinsufficiency, a construct-valid model of Primrose syndrome

Among the known genetic causes of syndromic autism spectrum disorders (ASD) are transcription factor deficiencies. In this regard, haploinsufficiency of the zinc finger and broad complex, tramtrack, bric and brac domain-containing protein 20 (ZBTB20) leads to a prototypical clinical picture, referred to as Primrose syndrome, comprising severe ASD symptoms together with intellectual disability. Here, we present a comprehensive behavioral and phenotypical characterization of Zbtb20+/- mice, a construct valid model of this thus far untreatable human condition. Zbtb20+/- mice exhibit diminished sociability, reduced vocalization, distinct repetitive behaviors, impaired cognitive flexibility, hyperactivity and hypoalgesia. Magnetic resonance imaging reveals increased volumes of hippocampus, cerebellum, brain matter, and whole brain, confirmed by postmortem brain weight measurements. Due to our previous observation of enhanced ZBTB20 expression in CA1 pyramidal neurons upon recombinant human erythropoietin (rhEPO) injections, we anticipated a mitigating effect through rhEPO treatment of Zbtb20 deficiency/Primrose syndrome. Indeed, after three weeks of alternate-day rhEPO injections, a remarkable improvement in the behavioral phenotype was observed. Our results highlight rhEPO as a first promising treatment for Primrose syndrome.

neuroscience↗

bioRxiv2025

Forebrain-specific loss of erythropoietin provokes compensatory upregulation of different EPO receptors

The procognitive growth factor erythropoietin (EPO) and its canonical receptor, EPOR, have long been recognized to be expressed by most cell types in the brain. Cognitive domains, improved by injections of exogenous EPO or by endogenous, hypoxia-stimulated EPO, include important forebrain functions, namely attention, working memory, drive, and executive performance. To gain mechanistic insight into the involvement of forebrain-expressed EPO, we deleted EPO in mice using as specific cre-driver Emx1. Here, we report that these mutant mice act comparably to their wildtype littermates in a comprehensive behavioral test battery. Importantly, we find that the transcripts of both EPOR and a novel, brain-expressed EPO receptor, EphB4, respond to EPO deletion with compensatory upregulation. EphB4 expression in brain and its increase upon forebrain erasure of EPOR are confirmed by in situ hybridization and immunohistochemistry. The augmented expression of both EPOR and EphB4 and their regulatory intercorrelation may explain why EmxEPO mutants show an even superior performance in the most challenging working memory task. Using the previously published single-nuclei-RNA-seq dataset, we further confirm the suggested compensatory mechanism, wherein EPO loss or reduction drives elevated EPOR expression, adding another layer to the intricate regulation of EPO signaling in hippocampal pyramidal neurons. Collectively, these data may explain the lack of behavioral and negative cognitive consequences upon forebrain-wide EPO elimination.

neuroscience↗

bioRxiv2024

IntelliR: A comprehensive and standardized pipeline for automated profiling of higher cognition in mice

In the rapidly evolving field of rodent behavior research, observer-independent methods facilitate data collection within a social, stress-reduced, and thus more natural environment. A prevalent system in this research area is the IntelliCage, which empowers experimenters to design individual tasks and higher cognitive challenges for mice, driven by their motivation to access reward. The extensive amount and diversity of data provided by the IntelliCage system explains the growing demand for automated analysis among users. Here, we introduce IntelliR, a standardized pipeline for analyzing raw data generated by the IntelliCage software, as well as novel parameters including the cognition index, which enables comparison of performance across various challenges. With IntelliR, we provide the tools to implement and automatically analyze 3 challenges that we designed, encompassing spatial, episodic-like, and working memory with their respective reversal tests. Using results from 3 independent control cohorts of adult female wildtype mice, we demonstrate their ability to comprehend and learn the tasks, thereby improving their proficiency over time. To validate the sensitivity of our approach for detecting cognitive impairment, we used adult female NexCreERT2xRosa26-eGFP-DTA mice after tamoxifen induced diphtheria toxin-mediated ablation of pyramidal neurons in cortex and hippocampus. We observed deterioration in learning capabilities and cognition index across several tests. IntelliR can be readily integrated into and adapted for individual research, thereby improving time management and reproducibility of data analysis. HIGHLIGHTSO_LIIntelliR is a standardized pipeline for analyzing raw data of IntelliCage software. C_LIO_LIDomains include spatial, episodic-like, and working memory with reversals. C_LIO_LIWT mice (3 cohorts) comprehend, learn and improve proficiency over time. C_LIO_LICognition index permits comparison of performance across cognitive domains. C_LIO_LIMice with ablation of pyramidal neurons decline mainly in working memory. C_LI

animal behavior and cognition↗

bioRxiv2023

Erythropoietin restrains the inhibitory potential of interneurons in the mouse hippocampus

Erythropoietin (EPO) aids in rectifying hippocampal transcriptional networks and synaptic structures of pyramidal lineages, thereby mitigating mood and cognition-associated disorders. An imminent conundrum is how EPO restores synapses by involving interneurons. By analyzing [~] 12,000 single-nuclei transcriptomic data, we generated a comprehensive molecular atlas of hippocampal interneurons, resolved into 15 interneuron subtypes. Next, we studied molecular alterations upon recombinant human (rh)EPO and saw that gene expression changes relate to synaptic structure, trans-synaptic signaling and intracellular catabolic pathways. Putative ligand-receptor interactions between pyramidal and inhibitory neurons, regulating synaptogenesis, are altered upon rhEPO. An array of in/ex vivo experiments confirms that specific interneuronal populations exhibit reduced dendritic complexity, synaptic connectivity, and changes in plasticity-related molecules. Metabolism and inhibitory potential of interneuron subgroups are compromised, leading to greater excitability of pyramidal neurons. To conclude, improvement by rhEPO of neuropsychiatric phenotypes may partly owe to restrictive control over interneurons, facilitating re-connectivity and synapse development.

neuroscience↗

bioRxiv2023

Transcriptional networks predating cognition-associated pyramidal lineages are restructured by erythropoietin

Recombinant human erythropoietin (rhEPO) has potent procognitive effects, hematopoiesis-independent, but underlying mechanisms and physiological role of brain-expressed EPO have remained obscure. Here, we provide encyclopedic transcriptional hippocampal profiling of mice treated with rhEPO. Based on [~]108,000 single nuclei, we unmask multiple pyramidal lineages with their comprehensive molecular signatures. By temporal profiling and gene regulatory analysis, we build a developmental trajectory of CA1 pyramidal neurons derived from multiple predecessor lineages and elucidate gene regulatory networks underlying their fate determination. With EPO as tool, we discover novel populations of newly differentiating pyramidal neurons, overpopulating to [~]200% upon rhEPO with upregulation of genes crucial for neurodifferentiation, dendrite growth, synaptogenesis, memory formation, and cognition. Using a Cre-based approach to visually distinguish pre-existing from newly formed pyramidal neurons for patch-clamp recordings, we learn that rhEPO treatment differentially affects excitatory and inhibitory inputs. Our findings provide mechanistic insight into how EPO modulates neuronal functions and networks.

neuroscience↗

bioRxiv2022

Regulation of excitatory presynaptic activity by Ambra1 protein determines neuronal networks in sex-dimorphic manner

Heterozygous mutation of Ambra1, known as a positive autophagy regulator, produces autismlike behavior in mice and autistic phenotypes in humans in a female-specific manner. However, the substantial roles of the Ambra1 mutation in neurons are still unknown. We find that Ambra1 heterozygotes display a moderate decrease in excitatory synaptic release in-vitro and ex-vivo exclusively in females without autophagy activity, resulting in significant alterations in {gamma}-oscillation power and seizure susceptibility by excitatory/inhibitory (E/I) imbalance. Specifically, Ambra1 deficiency has no effect on neurogenesis and morphogenesis, but selectively decreases excitatory synaptic activity without changes in synapse number, quantal size, synaptic release probability, and synaptic plasticity. Therefore, the limited excitatory synaptopathy by Ambra1 expression levels ultimately determines E/I imbalance in global neural networks leading to the female-specific ASD.

neuroscience↗

bioRxiv2022

Isolated catatonia-like executive dysfunction in micewith forebrain-specific loss of myelin integrity

A key feature of advanced brain aging includes structural defects of intracortical myelin that are associated with secondary neuroinflammation. A similar pathology is seen in specific myelin mutant mice that model advanced brain aging and exhibit a range of behavioral abnormalities. However, the cognitive assessment of these mutants is problematic because myelin-dependent motor-sensory functions are required for quantitative behavioral readouts. To better understand the role of cortical myelin integrity for higher brain functions, we generated mice lacking Plp1, encoding the major integral myelin membrane protein, selectively in ventricular zone stem cells of the mouse forebrain. In contrast to conventional Plp1 null mutants, subtle myelin defects were restricted to the cortex, hippocampus and underlying callosal tracts. Moreover, forebrain-specific Plp1 mutants exhibited no defect of basic motor-sensory performance at any age tested. Surprisingly, several behavioral alterations reported for conventional Plp1 null mice (Gould et al., 2018) were absent and even social interactions appeared normal. However, with novel behavioral paradigms, we determined catatonia-like symptoms and isolated executive dysfunction in both genders. This suggests that loss of myelin integrity has an impact on cortical connectivity and underlies specific defects of executive function. These observations are likewise relevant for human neuropsychiatric conditions and other myelin-related diseases.

neuroscience↗

bioRxiv2022

Myelin lipids as nervous system energy reserves

Neuronal functions and impulse propagation depend on the continuous supply of glucose1,2. Surprisingly, the mammalian brain has no obvious energy stores, except for astroglial glycogen granules3. Oligodendrocytes make myelin for rapid axonal impulse conduction4 and also support axons metabolically with lactate5-7. Here, we show that myelin itself, a lipid-rich membrane compartment, becomes a local energy reserve when glucose is lacking. In the mouse optic nerve, a model white matter tract, oligodendrocytes survive glucose deprivation far better than astrocytes, by utilizing myelin lipids which requires oxygen and fatty acid beta-oxidation. Importantly, fatty acid oxidation also contributes to axonal ATP and basic conductivity. This metabolic support by fatty acids is an oligodendrocyte function, involving mitochondria and myelin-associated peroxisomes, as shown with mice lacking Mfp2. To study reduced glucose availability in vivo without physically starving mice, we deleted the Slc2a1 gene from mature oligodendrocytes. This caused a significant decline of the glucose transporter GLUT1 from the myelin compartment leading to myelin sheath thinning. We suggest a model in which myelin turnover under low glucose conditions can transiently buffer axonal energy metabolism. This model may explain the gradual loss of myelin in a range of neurodegenerative diseases8 with underlying hypometabolism9.

neuroscience↗

bioRxiv2022

Modelling non-local neural information processing in the brain

The representation of the surrounding world emerges through integration of sensory information and actions. We present a novel neural model which implements non-local, parallel information processing on a neocolumnar architecture with lateral interconnections. Information is integrated into a holographic wave interference pattern. We compare the simulated in silico pattern with observed in vivo invasive and non-invasive electrophysiological data in human and non-human primates. Our model replicates the modulation of neural high-frequency activity during visual perception showing that phase-locked low and high-frequency oscillations self-organize efficiently and carry high information content. The simulation further models how criticality (high content) of information processing emerges given a sufficiently high number of correlated neurons. Non-local information processing, forming one holographic wave pattern, suggests a platform for emergence of conscious perception. One sentence summarySimulated non-local information processing on a neocolumnar architecture models well multiple electrophysiological observations of brain activity, including high-frequency activity during visual perception in primates.

neuroscience↗

bioRxiv2021

Ageing-associated myelin dysfunction drives amyloid deposition in mouse models of Alzheimer's disease

The prevalence of Alzheimers disease (AD), the leading cause of dementia, shows a strict age-dependency, but why ageing constitutes the main risk factor for this disease is still poorly understood. Brain ageing affects oligodendrocytes1 and the structural integrity of myelin sheaths2, the latter associated with secondary neuroinflammation3. Since oligodendrocytes support axonal and neuronal health4-7, we hypothesised that ageing-associated loss of myelin integrity could be an upstream risk factor for neuronal amyloid-{beta} (A{beta}) deposition, the primary neuropathological hallmark of AD. Here, we show that in AD mouse models different genetically induced defects of myelin integrity or demyelinating injuries are indeed potent drivers of amyloid deposition in vivo, quantified by whole brain light sheet microscopy. Conversely, the lack of myelin in the forebrain provides protection against plaque deposition. Mechanistically, we find that myelin dysfunction causes the accumulation of the A{beta} producing machinery within axonal swellings and increases cortical amyloid precursor protein (APP) cleavage. Surprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia but show a disease-associated microglia (DAM)-like signature as revealed by bulk and single cell transcriptomics. These activated microglia, however, are primarily engaged with myelin, preventing the protective reactions of microglia to A{beta} plaques. Our data suggest a working model, in which age-dependent structural defects of myelin promote plaque formation, directly and indirectly, and are thus an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay AD.g

neuroscience↗

bioRxiv2020

White matter integrity requires continuous myelin synthesis at the inner tongue

Myelin, the electrically insulating axonal sheath, is composed of lipids and proteins with exceptionally long lifetime. This raises the question how myelin function is affected by myelin turnover. We have studied the integrity of myelinated tracts after experimentally preventing the formation of new myelin in the CNS of adult mice, using an inducible Mbp null allele. Oligodendrocytes survived recombination, continued expressing myelin genes, but failed to maintain compacted myelin sheaths. Using 3D electron microscopy and mass spectrometry imaging we visualized myelin-like membranes that failed to incorporate adaxonally, most prominently at juxta-paranodes. Myelinoid body formation indicated degradation of existing myelin at the abaxonal side and at the inner tongue of the sheath. Compacted myelin thinning and shortening of internodes, with about 50% myelin lost after 20 weeks (=5 months), ultimately led to axonal pathology and neurological disease. These data reveal that functional axon-myelin units require the continuous incorporation of new myelin membranes.

neuroscience↗

bioRxiv2020

Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

BACKGROUNDSex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODSWe conducted the largest to date genome-wide genotype-by-sex (GxS) interaction of risk for these disorders, using 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH. RESULTSAcross disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815; p=3.2x10-8), that interacts with sodium/potassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence (p<1x10-6) for cross-disorder GxS interaction (rs7302529, p=1.6x10-7; rs73033497, p=8.8x10-7; rs7914279, p=6.4x10-7) implicating various functions. Gene-based analyses identified GxS interaction across disorders (p=8.97x10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282; p=1.5x10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509; p=1.1x10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD (pFDR<0.05). CONCLUSIONSIn the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.

genetics↗

bioRxiv2019

Quantifying and modelling non-local information processing of associative brain regions

Short abstractBrain world representation emerges not by philosophy but from integrating simple followed by more complex actions (due to drives, instincts) with sensory feedback and inputs such as rewards. Our simulation provides this world representation holistically by identical information encoded as holographic wave patterns for all associative cortex regions. Observed circular activation in cell culture experiments provides building blocks from which such an integrative circuit can evolve just by excitation and inhibition transfer to neighbouring neurons. Large-scale grid-computing of the simulation brought no new emergent phenomena but rather linear gains and losses regarding performance. The circuit integrates perceptions and actions. The resulting simulation compares well with data from electrophysiology, visual perception tasks, and oscillations in cortical areas. Non-local, wave-like information processing in the cortex agrees well with EEG observations such as cortical alpha, beta, and gamma oscillations. Non-local information processing has powerful emergent properties, including key features of conscious information processing.

neuroscience↗

bioRxiv2019

The Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc.

Kaufman oculocerebrofacial syndrome (KOS) is a severe autosomal recessive disorder characterized by intellectual disability, developmental delays, microcephaly and characteristic dysmorphisms. Biallelic mutations of UBE3B, encoding for a ubiquitin ligase E3B are causative for KOS. In this report, we characterize neuronal functions of its murine ortholog Ube3b. We show that Ube3b regulates dendritic branching in a cell-autonomous manner. Moreover, Ube3b knockout (KO) neurons exhibit increased density and aberrant morphology of dendritic spines, altered synaptic physiology and changes in hippocampal circuit activity. Dorsal forebrain-specific Ube3b KO animals show impaired spatial learning and alterations in social interactions. We further demonstrate that Ube3b ubiquitinates the catalytic {gamma}-subunit of calcineurin (Ppp3cc), the overexpression of which phenocopies the loss of Ube3b with regard to dendritic spine density. This work provides insights into the molecular pathologies underlying intellectual disability-like phenotypes in a genetic mouse model for KOS.

neuroscience↗