Biology subjects

Uhr, M.

Publications and source records attributed to Uhr, M..

5 recordsLinked to original sources

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↗

bioRxiv2023

Sustained polyphasic sleep restriction abolishes human growth hormone release

Voluntary sleep restriction is a common phenomenon in industrialized societies aiming to increase time spent awake and thus productivity. We explored how restricting sleep to a radically polyphasic schedule affects neural, cognitive, and endocrine characteristics. Ten young healthy participants were restricted to one 30-min nap opportunity at the end of every 4 hours (i.e., 6 sleep episodes per 24 hours) without any extended core sleep window, which resulted in a cumulative sleep amount of just 2 hours per day (i.e., [~]20 min per bout). All but one participant terminated this schedule during the first three weeks. The remaining participant (a 25-year-old male) succeeded to adhere to a polyphasic schedule for 5 weeks with no apparent impairments in cognitive and psychiatric measures except for psychomotor vigilance. While in-blood cortisol or melatonin release pattern and amounts were unaltered by the polyphasic as compared to monophasic sleep, growth hormone seemed almost entirely abolished (>95% decrease), with the residual release showing a considerably changed polyphasic secretional pattern. While coarse sleep structure appeared intact during polyphasic sleep, REM sleep showed decreased oscillatory and increased aperiodic EEG activity compared to monophasic sleep. Considering the decreased vigilance, abolished growth hormone release, and neurophysiological changes observed, it is doubtful that radically polyphasic sleep schedules can subserve the different functions of sleep to a sufficient degree.

neuroscience↗

bioRxiv2023

Divergent associations of slow-wave sleep vs. REM sleep with plasma amyloid-beta

BackgroundRecent evidence shows that during slow-wave sleep (SWS), the brain is cleared from potentially toxic metabolites, such as the amyloid-beta protein. Poor sleep or elevated cortisol levels can worsen amyloid-beta clearance, potentially leading to the formation of amyloid plaques, a neuropathological hallmark of Alzheimers disease. Here, we explore how nocturnal neural and endocrine activity affects amyloid-beta fluctuations in the peripheral blood as a reflection of cerebral clearance. MethodsSimultaneous polysomnography and all-night blood sampling were acquired in 60 healthy volunteers aged 20-68 years old. Nocturnal plasma concentrations of two amyloid-beta species (amyloid-beta-40 and amyloid-beta-42), cortisol, and growth hormone were assessed every 20 minutes from 23:00-7:00. Amyloid-beta fluctuations were modeled with sleep stages, (non)-oscillatory power, and hormones as predictors while controlling for age and multiple comparisons. Time lags between the predictors and amyloid-beta ranged from 20 to 120min. FindingsThe amyloid-beta-40 and amyloid-beta-42 levels correlated positively with growth hormone concentrations, SWS proportion, slow-wave (0.3-4Hz) oscillatory and high-band (30-48Hz) non-oscillatory power, but negatively with cortisol concentrations and rapid eye movement sleep (REM) proportion measured 40-100min before (all t-values>|3|, p-values<0.003). Older participants showed higher amyloid-beta-40 levels. InterpretationSlow-wave oscillations are associated with higher plasma amyloid-beta levels, reflecting their contribution to cerebral amyloid-beta clearance across the blood-brain barrier. REM sleep is related to decreased amyloid-beta plasma levels; however, this link may reflect passive aftereffects of SWS and not REMs effects per se. Strong associations between cortisol, growth hormone, and amyloid-beta presumably reflect the sleep-regulating role of the corresponding releasing hormones. A positive association between age and amyloid-beta-40 may indicate that peripheral clearance becomes less efficient with age. Our study provides important insights into the specificity of different sleep features effects on brain clearance and suggests that cortisol nocturnal fluctuations may serve as a new marker of clearance efficiency.

neuroscience↗

bioRxiv2022

Anti-chemokine antibodies after SARS-CoV-2 infection correlate with favorable disease course

Infection by SARS-CoV-2 leads to diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse COVID-19 outcomes. Instead, we discovered that antibodies against specific chemokines are omnipresent after COVID-19, associated with favorable disease, and predictive of lack of long COVID symptoms at one year post infection. Anti-chemokine antibodies are present also in HIV-1 infection and autoimmune disorders, but they target different chemokines than those in COVID-19. Monoclonal antibodies derived from COVID- 19 convalescents that bind to the chemokine N-loop impair cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising anti-chemokine antibodies associated with favorable COVID-19 may be beneficial by modulating the inflammatory response and thus bear therapeutic potential. One-Sentence SummaryNaturally arising anti-chemokine antibodies associate with favorable COVID-19 and predict lack of long COVID.

immunology↗

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↗