Biology subjects

Schmidt, M. V.

Publications and source records attributed to Schmidt, M. V..

16 recordsLinked to original sources

bioRxiv2026

Deep Phenotyping with Global Brain Activity and Plasticity Mapping Identify the Dorsal Raphe-Basolateral Amygdala Circuit as a Mediator of Adaptive Stress Responses

Exposure to chronic environmental challenges triggers divergent behavioral trajectories across individuals. At the core, these different trajectories can be classified as individuals actively adapting to the challenges ("responders") and those displaying a rigid, non-responsive phenotype ("non-responders"). The brain system-wide network configurations that dictate why individuals diverge along these differential coping strategies, which can also lead to disease vulnerability or resilience, remain poorly understood. Here, we paired machine-learning-based deep behavioral phenotyping with multi-modal whole-brain imaging, integrating longitudinal Manganese-Enhanced MRI (MEMRI) and post-challenge cFOS mapping, to chart the functional landscape of individual stress trajectories in mice subjected to chronic social defeat stress. High-dimensional behavioral phenotyping revealed that active stress adaptation is a complex trajectory marked by latent, pre-stress kinetic signatures in vigilance-like and locomotive behaviors. At the neural level, longitudinal MEMRI captured distinct, consolidated activity reconfigurations across canonical valence and stress-regulatory circuits that segregated responders from non-responders. Complementary whole-brain cellular cFOS network analysis after an additional acute challenge revealed that non-responders exhibited marked hyper-modularity and network fragmentation, whereas responders feature a tightly integrated functional module co-clustering the periaqueductal gray, ventral tegmental area, basolateral amygdala (BLA), and dorsal raphe (DR). Notably, functional network connectivity along the DR-BLA axis was completely lost in non-responsive animals. Finally, pathway-specific chemogenetic inhibition of BLA-projecting DR neurons during a social challenge significantly attenuated social avoidance and reversed anxiety-like behavioral deficits, effectively shifting active behavioral adaptation toward a non-responsive phenotype. Together, these findings demonstrate that individual stress-coping strategies are driven by coordinated, system-wide reconfigurations of activity and plasticity, identifying the DR-BLA circuit as a critical gatekeeper of adaptive stress responses. Graphical AbstractGlobal neural functional alterations defining responding vs non-responding populations following chronic stress are understudied, yet crucial. Deep phenotyping followed by mapping brain-wide activity and plasticity changes identified these underlying divergent functional networks. Acute manipulation of a dorsal raphe - basolateral amygdala pathway ameliorated adaptive stress responses, highlighting the significance of this network-based approach. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/740522v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1850a04org.highwire.dtl.DTLVardef@1549284org.highwire.dtl.DTLVardef@15f3ebforg.highwire.dtl.DTLVardef@107ca9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Pre-anaesthetic anxiety phenotype stratifies cortical excitability, learned navigation, and post-anaesthetic sleep in sevoflurane-exposed mice

Trait anxiety is a common pre-surgical phenotype and has been linked to adverse postoperative cognitive outcome, but whether it modulates the response to general anaesthesia has not been tested in a controlled design that isolates the anaesthetic from surgical injury. We classified 42 male C57BL/6N mice as low-anxiety (LA, n = 24) or high-anxiety (HA, n = 18) by unsupervised k-medoids clustering on cued fear-retrieval freezing, and exposed all animals to sevoflurane under live-EEG titration without surgery. At adequate anaesthetic depth, HA mice carried a flatter aperiodic (1/f) cortical slope than LA mice (AUC = 0.85, [0.70, 0.95]). Conventional water-cross-maze scoring returned null at post-anaesthetic re-test, but unsupervised decomposition of the same trial videos localised the effect to loss of a specific learned transition in HA mice (AUC = 0.72, [0.56, 0.86]). The dark-phase REMS response reversed direction, with HA mice losing REMS against their own baseline while LA mice gained it (AUC = 0.82, [0.65, 0.94]). The three effects are directionally consistent with modulation of cortical excitation-to-inhibition balance under sevoflurane. The aperiodic exponent and emergence-phase EEG trajectory, both recoverable from routine frontal EEG, are candidate pre-anaesthetic biomarkers.

neuroscience↗

bioRxiv2026

Multilevel sex-specific neurobiological signatures of early life adversity

Stress exposure early in life is an established risk factor for adult psychiatric illness, yet these disorders - including anxiety disorders and depression - show significant sex-dependence in prevalence, symptomatology, and treatment response. The biology underlying these differences remains largely unexplored and may contribute to the clinical heterogeneity in anxiety and depression. Here, we characterize the lasting impact of developmental stress on adulthood neurobiology and behavior in mice by combining analyses of multiple levels of brain function, including whole-brain c-Fos mapping, manganese-enhanced MRI and transcriptomics with advanced behavioral phenotyping. Across levels of investigation, we find distinct and often opposite effects of developmental stress depending on sex. These results together showcase the strong influence of sex on how early life adversity affects the onset of stress-related disorders. This work emphasizes the necessity of considering sex when investigating developmental and neurobiological underpinnings of stress-related disorders and displays a vast range of lasting effects of developmental stress on the brain, which provides a valuable resource for future studies aiming to improve psychiatric treatments.

neuroscience↗

bioRxiv2025

Pharmacological Inhibition of FKBP51 Mitigates Early Life Adversity-Induced Social Deficits

Early life adversity (ELA) is a major risk factor for psychiatric disorders, but targeted preventative strategies are lacking due to poor mechanistic insight. The FKBP51 protein, a co-chaperone of the glucocorticoid receptor, is a key mediator of stress vulnerability. We tested if pharmacological inhibition of FKBP51 with the selective inhibitor SAFit2 prevents the long-term consequences of ELA. Mice exposed to ELA exhibited persistent deficits in social behavior, manifesting as social subordination in adolescence and adulthood. Early-life SAFit2 treatment fully rescued these ELA-induced behavioral impairments. Transcriptional profiling across six stress-relevant brain regions revealed that SAFit2 normalized ELA-driven gene expression changes, particularly in the medial prefrontal cortex and nucleus accumbens. Functional analysis showed the rescue converged on immunoregulatory and neuroactive ligand-receptor signaling pathways. Our findings establish FKBP51 as a critical pharmacological target for reversing the lasting impact of early life adversity on brain function, offering a path toward preventative treatment for ELA-related psychopathology.

neuroscience↗

bioRxiv2025

Loss of noradrenergic Fkbp5 disrupts social behavior and norepinephrine dynamics in the basolateral amygdala

Social dysfunction is common in depression and varies with stress exposure and genetic risk. The current study identifies a cell-type specific role for Fkbp5, a glucocorticoid receptor co-chaperone, in noradrenergic neurons engaged during social stress. Acute social stress upregulated Fkbp5 in the locus coeruleus (LC), whereas repeated exposure attenuated this effect. Noradrenergic Fkbp5 deletion (Fkbp5Nat) increased pro-social behavior exclusively in male mice. In the basolateral amygdala (BLA), social interaction reduced norepinephrine (NE) turnover in wild-type but not Fkbp5Nat mice. Consistently, proteomics revealed mitochondrial/energy and synapse-related remodeling in BLA neurons. Miniscope imaging showed that behavior-locked NE transients in BLA were selectively blunted in Fkbp5Nat mice during interaction with outbred CD1 conspecifics, while same-strain C57BL/6N encounters preserved NE dynamics. Together, this study indicates that Fkbp5 tunes LC-BLA output to social salience in a sex- and context-dependent manner, suggesting a circuit-specific route to normalize social salience without broadly suppressing noradrenergic function.

neuroscience↗

bioRxiv2025

Glucocorticoid receptors mediate reprogramming of astrocytes in depression.

Psychiatric disorders are among the most pressing problems of the modern society, with various forms of depression affecting more than 300 millions of people worldwide. Dysfunction of glial cells has consistently been reported in major depressive disorder (MDD); however, no comprehensive resource detailing glial dysfunction is available. To provide insight into neurobiological mechanisms behind severe psychiatric symptoms, we performed transcriptional analysis of post-mortem samples from a subpopulation of suicide completers with previously reported glial abnormalities. We focused on BA25, a subregion of the prefrontal cortex prioritized for targeted medical interventions, due to its metabolic aberrations in disease. We found that a significant portion of genes deregulated in MDD is enriched in glia, with astrocyte-specific genes representing the highest fraction. Then we employed a novel protocol for enriching astrocytic nuclei to provide a detailed molecular signature of astrocytes in MDD. The analysis of the gene set revealed the glucocorticoid receptor (GR) as a key regulatory transcription factor. We found that astrocyte-specific elimination of the GR in mice largely prevented transcriptional, metabolic and behavioral changes elicited by chronic stress. We also demonstrated that regional manipulation of glutamate turnover in astrocytes suffices to elicit discrete traits of depressive-like behavior. Our data points to astrocytes as a key cellular site of convergence of multiple traits of depression and provide a resource for exploring novel targets for glia-focused therapeutic approaches.

neuroscience↗

bioRxiv2024

Spermidine alleviates depression via control of the stress response

Depression is a stress-associated disorder, and it represents a major global health issue. Its pathophysiology is complex and remains insufficiently understood, with current medications often showing limited efficacy and undesirable side effects. Here, we identify imbalanced polyamine levels and dysregulated autophagy as key components of the acute stress response in humans, and as hallmarks of chronic stress and depressive disorders. Moreover, conventional antidepressant pharmacotherapy increases endogenous plasma concentrations of the polyamine spermidine exclusively in patients who respond to the treatment, suggesting a link between spermidine and successful outcomes. In a clinical trial, involving drug-naive depressed individuals, three weeks of spermidine supplementation increased autophagy and alleviated symptoms of depression. Behavioral and mechanistic findings of spermidine supplementation were validated in various mouse stress and depression models. In summary, spermidine supplementation mitigates polyamine dysregulation and stimulates autophagy under pathological stress conditions, offering a novel and well-tolerated treatment approach for stress-related depressive disorders.

neuroscience↗

bioRxiv2024

Sex-specific fear acquisition following early life stress is linked to amygdala glutamate metabolism

Early life stress (ELS) adversely affects physiological and behavioral outcomes, increasing the vulnerability to stress-related disorders, such as post-traumatic stress disorder (PTSD). PTSD prevalence is significantly higher in women and is partially mediated by genetic risk variants. Understanding how sex influences the interaction of PTSD risk genes, such as FKBP5, with trauma-related behaviors is crucial for uncovering PTSDs neurobiological pathways. The development of in-depth behavioral analysis tools using unsupervised behavioral classification is thereby a crucial tool to increase the understanding of the behavioral outcomes related to stress-induced fear memory formation. The current study investigates the sex-specific effects of ELS exposure by using the limited bedding and nesting (LBN) paradigm. The LBN exposure disrupted different facets of the hypothalamic-pituitary-adrenal (HPA) axis in a sex-specific manner directly after stress and at adult age. Moreover, freezing was altered by LBN exposure in both the acquisition and the retrieval of fear in a sex-dependent manner. Unsupervised behavioral analysis revealed a higher active fear response after LBN exposure during fear acquisition in females, but not in males. The regulation of the HPA axis is closely intertwined with cellular metabolism and core regulatory cascades. To investigate the impact of LBN exposure on tissue-specific metabolism, a metabolomic pathway analysis in the basolateral amygdala revealed a specific sex- and stress-dependent effect on purine, pyrimidine, and glutamate metabolism. The present study highlights the intricate interplay between metabolic pathways and the neurobiological substrates implicated in fear memory formation and stress regulation. Overall, these findings highlight the importance of considering sex-specific metabolic alterations in understanding the neurobiological mechanisms underlying stress-related disorders and offer potential avenues for targeted interventions.

animal behavior and cognition↗

bioRxiv2023

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. We demonstrate that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1{beta} release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1{beta} release, initiating an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D (GSDMD)-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of postmortem brains demonstrate that SA is hyperactivated in Alzheimers disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimers disease, providing new mechanistic insight into the biology of neuroinflammation.

neuroscience↗

bioRxiv2022

Automatically annotated motion tracking identifies a distinct social behavioral profile following chronic social defeat stress

Severe stress exposure is a global problem with long-lasting negative behavioral and physiological consequences, increasing the risk of stress-related disorders such as major depressive disorder (MDD). An essential characteristic of MDD is the impairment of social functioning and lack of social motivation. Chronic social defeat stress is an established animal model for MDD research, which induces a cascade of physiological and social behavioral changes. The current developments of markerless pose estimation tools allow for more complex and socially relevant behavioral tests, but the application of these tools to social behavior remains to be explored. Here, we introduce the open-source tool "DeepOF" to investigate the individual and social behavioral profile in mice by providing supervised and unsupervised pipelines using DeepLabCut annotated pose estimation data. The supervised pipeline relies on pre-trained classifiers to detect defined traits for both single and dyadic animal behavior. Subsequently, the unsupervised pipeline explores the behavioral repertoire of the animals without label priming, which has the potential of pointing towards previously unrecognized motion motifs that are systematically different across conditions. We here provide evidence that the DeepOF supervised and unsupervised pipelines detect a distinct stress-induced social behavioral pattern, which was particularly observed at the beginning of a novel social encounter. The stress-induced social behavior shows a state of arousal that fades with time due to habituation. In addition, while the classical social avoidance task does identify the stress-induced social behavioral differences, both DeepOF behavioral pipelines provide a clearer and more detailed profile. DeepOF aims to facilitate reproducibility and unification of behavioral classification of social behavior by providing an open-source tool, which can significantly advance the study of rodent individual and social behavior, thereby enabling novel biological insights as well as drug development for psychiatric disorders.

neuroscience↗

bioRxiv2022

DiffBrainNet: differential analyses add new insights into the response to glucocorticoids at the level of genes, networks and brain regions

Genome-wide gene expression analyses are invaluable tools for increasing our knowledge of biological and disease processes, allowing a hypothesis-free comparison of gene expression profiles across experimental groups, tissues and cell types. Traditionally, transcriptomic data analysis has focused on gene-level effects found by differential expression. In recent years, network analysis has emerged as an important additional level of investigation, providing information on molecular connectivity, especially for diseases associated with a large number of linked effects of smaller magnitude, like neuropsychiatric disorders and their risk factors, including stress. In this manuscript, we describe how combined differential expression and prior-knowledge-based differential network analysis can be used to explore complex datasets. As an example, we analyze the transcriptional responses following administration of the glucocorticoid/stress hormone receptor agonist dexamethasone in C57Bl/6 mice, in 8 brain regions important for stress processing: the prefrontal cortex, the amygdala, the paraventricular nucleus of the hypothalamus, the cerebellar cortex, and sub regions of the hippocampus: the dorsal and ventral Cornu Ammonis 1, the dorsal and ventral dentate gyrus. By applying a combination of differential network- and differential expression-analyses, we find that these explain distinct but complementary aspects and biological mechanisms of the responses to the stimulus. In addition, network analysis identifies new differentially connected partners of important genes and can be used to generate hypotheses on specific molecular pathways affected. With this work, we provide an analysis framework and a publicly available resource for the study of the transcriptional landscape of the mouse brain: DiffBrainNet (http://diffbrainnet.psych.mpg.de), which can identify molecular pathways important for basic functioning and response to glucocorticoids in a brain-region specific manner.

genomics↗

bioRxiv2021

Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism

The mediobasal hypothalamus (MBH) is the central region in the physiological response to metabolic stress. The FK506-binding protein 51 (FKBP51) is a major modulator of the stress response and has recently emerged as a scaffolder regulating metabolic and autophagy pathways. However, the detailed protein-protein interactions linking FKBP51 to autophagy upon metabolic challenges remain elusive. We performed mass spectrometry-based metabolomics of FKBP51 knockout (KO) cells revealing an increased amino acid and polyamine metabolism. We identified FKBP51 as a central nexus for the recruitment of the LKB1/AMPK complex to WIPI4 and TSC2 to WIPI3, thereby regulating the balance between autophagy and mTOR signaling in response to metabolic challenges. Furthermore, we demonstrated that MBH FKBP51 deletion strongly induces obesity, while its overexpression protects against high-fat diet (HFD) induced obesity. Our study provides an important novel regulatory function of MBH FKBP51 within the stress-adapted autophagy response to metabolic challenges.

neuroscience↗

bioRxiv2020

Stress-primed secretory autophagy drives extracellular BDNF maturation

The stress response is an essential mechanism that strives to maintain homeostasis, and its disruption is implicated in several psychiatric disorders. As a cellular response to stressors, autophagy is activated to regulate homeostasis through protein degradation and recycling. Secretory autophagy is a recently described pathway where autophagosomes fuse with the plasma membrane rather than lysosomes. In this study, we demonstrate that glucocorticoid-mediated stress enhances secretory autophagy, via the stress-responsive co-chaperone FK506-binding protein 51. We identified the matrix metalloproteinase 9 (MMP9) as one of the stress-induced secreted proteins. Using cellular assays and in vivo microdialysis, we further found that stress-enhanced MMP9 secretion increases the cleavage of pro-brain derived neurotrophic factor (proBDNF) to its mature form. BDNF is essential for adult synaptic plasticity and its pathway is associated with major depression and posttraumatic stress disorder. These findings unravel a novel mechanistic link between stress, stress adaptation and the development of psychiatric disorders, with possible therapeutic implications.

molecular biology↗

bioRxiv2020

Sexually divergent effects of social dominance on chronic stress outcomes in mice

BackgroundSex and social context are two major factors in the development of depression and other stress-related disorders. However, few studies of the effects of stress on rodent behavior and physiology have investigated social context and fewer still have assessed the possibility of sex-specific effects of social context. MethodsWe assessed social dominance of group-living mice during several days of monitoring using a high-throughput automated behavioral tracking system. We then exposed groups from each sex to a three-week chronic mild stress (CMS) procedure, followed by a behavioral test battery. Finally, we used principle component analysis and post-hoc tests to explore the sources of variance in the behavioral outcome data. ResultsWe found stable hierarchies in both sexes, however social dominance in males exhibited several additional associations with behaviors related to locomotion and exploration that were not seen in females. Crucially, pre-stress social dominance status was associated with opposing outcomes on multiple behavioral readouts between the two sexes following CMS. In particular, subordinate male mice and dominant female mice appeared more responsive to the environmental challenge, as observed in anxiety-like and locomotor behaviors. ConclusionsThis work demonstrates that sex differences interact with preexisting social dominance status to alter the effects of chronic stress. It highlights the importance of understanding the interplay between sex and social context and its contribution to individual differences in stress response.

neuroscience↗

bioRxiv2019

The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus

Disturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), a main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. Using deletion, overexpression, and rescue of Fkbp5 exclusively in the PVN, we establish the fundamental importance of Fkbp5 in the HPA axis stress response. Furthermore, we show that Fkbp5 manipulation alters GR activation and elucidate the cellular complexity in the PVN, in which Fkbp5 operates.

neuroscience↗

bioRxiv2017

The role of m6A-RNA methylation in stress response regulation

N6-Methyladenosine (m6A) is an abundant internal RNA modification that regulates transcript processing and translation. The regulation of brain m6A by stressful stimuli in vivo and its role in the stress response are currently unknown.\n\nHere, we provide a detailed analysis of the stress-epitranscriptome using m6A-Seq, global and gene-specific m6A measurements. We show that stress exposure and glucocorticoids alter m6A and its regulatory network in a region- and time-specific manner. We demonstrate that depletion of the methyltransferase Mettl3 and the demethylase Fto in adult neurons increases fear memory, and alters the transcriptome response to fear as well as synaptic plasticity. Finally, we report that regulation of m6A is impaired in major depressive disorder patients following glucocorticoid receptor activation.\n\nOur findings indicate that brain m6A represents a novel layer of complexity in gene expression regulation after stress and that dysregulation of the m6A-response may contribute to the pathophysiology of stress-related psychiatric disorders.\n\nHighlightsO_LIm6A RNA methylation in adult mouse brain is regulated by stress\nC_LIO_LIBrain m6A levels are temporally and spatially regulated by stress\nC_LIO_LIMettl3 and Fto-KO alter fear memory, transcriptome response and synaptic plasticity\nC_LIO_LIThe m6A-glucocorticoid-response is impaired in major depressive disorder patients\nC_LI\n\neTOC blurbEngel et al. demonstrate a brain-area-specific and time-dependent role for the mRNA modification, m6A, in stress-response regulation. Manipulating m6A-enzymes alters fear-memory, transcriptome-response and synaptic-plasticity. Altered m6A dynamics in depressed patients suggest an involvement of m6A-modifications in stress-related psychiatric disorders.

neuroscience↗