Biology subjects

Tischer, A.

Publications and source records attributed to Tischer, A..

6 recordsLinked to original sources

bioRxiv2026

D2 autoreceptors gate vulnerability to cocaine use disorder

A defining feature of substance use disorder is that repeated drug use does not always lead to addiction, motivating the search for biomarkers of vulnerability1. Reduced striatal dopamine D2/3 receptor availability is a robust PET correlate of problematic stimulant use2-5, but the signal may reflect high endogenous dopamine level, and it conflates presynaptic D2 autoreceptors on dopamine axons with postsynaptic D2/3 heteroreceptors on striatal projection neurons. We dissociated these contributions using cell type-specific Drd2 haploinsufficiency in dopamine neurons (autoD2KD), D2-expressing medium spiny neurons (MSN-D2KD), or both. Autoreceptor haploinsufficiency (autoD2KD) weakened presynaptic control of dopamine release, enhanced phasic gain, and prolonged cocaine-evoked dopamine elevations. This was accompanied by a hyper-exploratory trait and altered cocaine adaptation. Specifically, autoD2KD mice showed greater cocaine-seeking behavior, despite intact responses to sucrose reward and punishment. Although all genotypes showed graded reductions in striatal D2/3 binding, D1-like compensations diverged, resulting in different D1:D2/3 ratio in the striatum. The clinical implication is that striatal D1 density and D1:D2/3 balance may emerge as critical biomarkers for distinguishing cell-type-specific D2 reductions relevant to addiction vulnerability.

neuroscience↗

bioRxiv2026

Reforestation under climate change - a cross-regional deadwood retention experiment to develop multifunctional forests on disturbed Norway spruce areas

The impact of extreme weather events such as droughts, heatwaves, storms and the associated intensification of bark beetle outbreaks in Norway spruce forests in recent years, has led to a large-scale forest loss in Central Europe. There are various options for post-disturbance management, from complete clearing to no intervention, but their pros and cons - in the context of multifunctional forest management - are not resolved. The "ResEt-Fi" project ("Pioneering reforestation: Regional management for establishing multifunctional forests on post-disturbed Norway spruce areas") consortium implemented a cross-regional field trial to test how specific practices of deadwood retention affect the ecological conditions and subsequent reforestation dynamics of natural regeneration and planted trees. It aims at generating climate-stable mixed forests within an ecological valuable transition, balancing ecosystem functioning and socio-economic benefits. As an outcome for stakeholders and forest practitioners, guidelines and showcase scenarios for facilitating the selection of management procedures will be created. In this article, we provide insight into (i) the applied post-disturbance deadwood management practices and the rationale for their selection, (ii) the experimental setup of our cross-regional field trial, (iii) the initial post-disturbance status and perspective with respect to regional site conditions and deadwood treatment. While the setup and site conditions will primarily serve as a reference for subsequent studies in our joint project, this is the first systematic, cross-regional study on the effects of the management options standing deadwood, high stumps and clearing on microclimate, biodiversity, and tree regeneration in the critical early stages of forest regeneration after disturbance.

ecology↗

bioRxiv2025

Early life adversity increases striatal dopamine D1 receptor density and promotes social alcohol drinking in mice, especially males

The brains reward circuitry remains sensitive to experience throughout early life and into adulthood, allowing individuals to adapt to their unique environments. Adverse experiences early in life can increase vulnerability to substance use disorders, likely through alterations to this circuitry. Yet, the precise neurobiological mechanisms by which early life adversity acts are incompletely characterized. In this study, we used a limited bedding and nesting (LBN) paradigm as a translationally relevant model of early life adversity in genetically-identical C57BL/6J mice. After LBN-rearing, we assess the lasting behavioral and neurobiological impacts of this experience in adulthood. In robust sample sizes, our results validated previous findings of increased risk avoidance, enhanced acute response to alcohol, and greater voluntary alcohol drinking in socially-housed LBN-reared mice, especially males. Further, using autoradiography, we found LBN-reared mice had increased striatal D1-like receptor binding, skewing D1-to D2-like receptor balance relative to cross-fostered controls. However, after voluntary alcohol drinking, we found a strong downregulation in D1-like, and some D2-like, receptor binding, negating pre-existing differences in striatal dopamine receptor binding. We posit that via both transcriptional and post-transcriptional mechanisms, LBN-rearing upregulates striatal D1-receptor density and alters risk avoidance and acute alcohol stimulation to promote alcohol drinking among adversity-exposed mice. Together, these findings reveal specific neurobiological mechanisms that promote alcohol consumption following early life adversity and suggest complex interactions between early life adversity, sex-related factors, and dopamine receptor regulation in contributing to alcohol use disorder (AUD) vulnerability.

neuroscience↗

bioRxiv2025

Rainwater-driven transport of matter and microbes from phyllosphere to soil in a temperate beech forest

In forest ecosystems, the transport of organic matter including microbial cells by throughfall and stemflow represents a central linkage between the phyllosphere and soil. However, the extent and taxon-specificity of rainwater-mediated vertical transfer of microorganisms, and its relevance for matter fluxes is sparsely understood. We investigated the rainwater-driven transport of bacteria and its contribution to matter transport in bulk rainfall, throughfall, stemflow and seepage in a temperate deciduous forest and compared the transported communities to those in phyllosphere and soil. Throughfall-mediated cell fluxes equaled those in seepage below the litter layer, pointing to a substantial above-ground translocation of bacteria. Bacterial cells contributed up to 11 % and 33 % to the exported total organic carbon and total nitrogen, respectively. Bacteria affiliated with Pseudomonadaceae, Oxalobacteraceae, Hymenobacteraceae, and Sphingomonadaceae were differentially transmitted from the canopy with increased abundances in throughfall and stemflow compared to bulk rain. A small fraction of shared taxa pointed to the import, proliferation and mobilization of selected bacterial taxa between neighboring ecohydrological compartments. The genetic potential of the transported bacterial communities was strongly linked to organic matter degradation particularly of carbohydrates and proteins. Our findings extend our understanding of rainwater-mediated vertical matter transport in forest ecosystems and highlight the contribution of microbial cells to this transport especially in above-ground compartments. Strong shifts in community composition and abundance of the transported taxa between throughfall, stemflow and soil seepage are linked to differences in source communities but may also point to different mechanisms of cell detachment across compartments. HighlightsO_LIRainwater flow paths are important carriers for organic matter and microorganisms. C_LIO_LIThroughfall and stemflow contained high abundances of microbial cells. C_LIO_LIBacteria contributed up to 11 % and 33 % to exported carbon and nitrogen. C_LIO_LIBacterial taxa were selectively mobilized by throughfall, stemflow and seepage. C_LI

microbiology↗

bioRxiv2020

Drought and rewetting events enhance nitrate leaching and seepage-mediated translocation of microbes from beech forest soils

Nitrification in forest soils is often associated with increased leaching of nitrate to deeper soil layers with potential impacts on groundwater resources, further enhanced under scenarios of anthropogenic atmospheric nitrogen deposition and predicted weather extremes. We aimed to disentangle the relationships between soil nitrification potential, seepage-mediated nitrate leaching and the vertical translocation of nitrifiers in soils of a temperate mixed beech forest in central Germany before, during and after the severe summer drought 2018. Leaching of nitrate assessed below the litter layer and in 4, 16 and 30 cm soil depth showed high temporal and vertical variation with maxima at 16 and 30 cm during and after the drought period. Maximum of soil potential nitrification activity of 4.4 mg N kg-1 d-1 only partially coincided with maximum nitrate leaching of 10.5 kg N ha-2. Both ammonia oxidizing bacteria (AOB) and ammonia oxidizing archaea (AOA) were subject to translocation by seepage, and AOB decreased at least by half and AOA increased by one to three orders of magnitude in their abundance in seepage with increasing soil depth. On the level of the total bacterial population, an increasing trend with depth was also observed for Cand. Patescibacteria while Bacteroidetes were strongly mobilized from the litter layer but poorly transported further down. Despite stable population densities in soil over time, abundances of AOA, AOB and total bacteria in seepage increased by one order of magnitude after the onset of autumn rewetting. Predicted future higher frequency of drought periods in temperate regions may result in more frequent seepage-mediated seasonal flushes of nitrate and bacteria from forest soils. Moreover, the observed translocation patterns point to taxon-specific differences in the susceptibility to mobilization, suggesting that only selected topsoil derived microbial groups are likely to affect subsoil or groundwater microbial communities and their functional potential.

microbiology↗

bioRxiv2020

Functional succinate dehydrogenase deficiency is a pathognomonic adverse feature of clear cell renal cancer

BackgroundReduced succinate dehydrogenase (SDH) activity resulting in adverse succinate accumulation was previously thought to be relevant only in 0.05-0.5% of kidney cancers associated with germline SDH mutations (categorized SDH-deficient Renal Cell Carcinoma in the 2016 WHO classification) ResultsWe show that under-expression of SDH subunits resulting in accumulation of oncogenic succinate is a common feature in clear cell renal cell carcinoma (ccRCC) tumors during pathogenesis and progression, with a marked adverse impact on survival in a large cohort (n=516) of ccRCC patients. From a mechanistic standpoint, we show that von Hippel-Lindau (VHL) loss induced hypoxia-inducible factor (HIF) dependent upregulation of mir-210 in ccRCC causes direct inhibition of the SDHD transcript. We demonstrate that reduced expression of SDH subunits is associated with genome-wide increase in methylation and enhancement of epithelial mesenchymal transition (EMT) in ccRCC tumors, consistent with succinate-induced inhibition of TET activity and increase in invasiveness/ migratory ability of ccRCC cells. TET-2 inhibition-induced global regulatory DNA hypermethylation drives SDH loss-induced enrichment of EMT. SDH subunits under-expression had a striking association with CDHI (E-cadherin) loss in ccRCC tumors, in keeping with succinate-induced CDH1 hypermethylation and under-expression in ccRCC cells. Next, in conformity with recombinant TET-2 fluorescence quenching dynamics with succinate and ascorbic acid (AA, a TET enzyme co-factor), AA treatment led to reversal of succinate-induced inhibition of TET activity, CDH1 hypermethylation and under-expression, as well as enhanced invasiveness in ccRCC cells. Furthermore, using immunohistochemical analysis and artificial intelligence quantitation, we report that ccRCC is characterized by a marked loss of ascorbic acid transporter SLC23A1 [median percent positive cells in ccRCC primary tumors (n=104) and normal kidney cortex (n=7) was 0.7 and 32.4 respectively; p=0.0012]. Lower SLC23A1 was associated with worse survival in ccRCC (TCGA). Lastly, intravenous AA significantly prolonged survival in a metastatic ccRCC xenograft model with increased succinate and reduced SLC23A1 expression. ConclusionsTaken together, these findings strongly indicate that functional SDH deficiency is a pathognomonic adverse feature of ccRCC (which accounts for [~]80% of all kidney cancers), and that the WHO category SDH-deficient RCC should be re-named SDH germline mutation-associated RCC. Furthermore, oncogenic accumulation of succinate can be abrogated by TET modulation with AA. STATEMENT OF SIGNIFICANCEIn this study, we show that under-expression of succinate dehydrogenase (SDH) subunits resulting in the accumulation of oncogenic succinate is a common, adverse, epigenetic modulating feature occurring in a vast majority of clear cell renal cell carcinoma (ccRCC), during pathogenesis and progression. Functional SDH deficiency is therefore a pathognomonic feature of ccRCC (which accounts for [~]80% of all kidney cancers), and not just limited to the 0.05-0.5% of kidney cancer patients with germline SDH mutations. Based on the findings reported, we propose that the SDH-deficient RCC category in the 2016 WHO classification of kidney tumors be renamed SDH germline mutation-associated RCC. Furthermore, we demonstrate that oncogenic accumulation of succinate in ccRCC can be countered by TET modulation with ascorbic acid, and that ccRCC is characterized by a marked loss of ascorbic acid transporter SLC23A1. O_FIG O_LINKSMALLFIG WIDTH=172 HEIGHT=200 SRC="FIGDIR/small/188433v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@728d5eorg.highwire.dtl.DTLVardef@9f2e24org.highwire.dtl.DTLVardef@8e7011org.highwire.dtl.DTLVardef@15f8d33_HPS_FORMAT_FIGEXP M_FIG Graphical abstract depicting the consequential adverse downregulation of Succinate Dehydrogenase in ccRCC and its central role in oxidative phosphorylation C_FIG

cancer biology↗