TY  - JOUR
AB  - Schizophrenia is a complex psychiatric disorder with genetic and phenotypic heterogeneity. Accumulating rare and genome-wide association study (GWAS) common risk variant information has yet to yield robust mechanistic insight. Leveraging large-scale gene deletion mouse phenomic data thus has potential to functionally interrogate and prioritize human disease genes. To this end, we applied a cross-species network-based approach to parse an extensive mouse gene set (188 genes) associated with disrupted prepulse inhibition (PPI), a Schizophrenia endophenotype. Integrating PPI genes with high-resolution mouse and human brain transcriptomic data, we identified functional and disease coherent co-expression modules through hierarchical clustering and weighted gene co-expression network analysis (WGCNA). In two modules, Schizophrenia risk and mouse PPI genes converged based on telencephalic patterning. The associated neuronal genes were highly expressed in cingulate cortex and hippocampus; implicated in synaptic function and neurotransmission and overlapped with the greatest proportion of rare variants. Concordant neuroanatomical patterning revealed novel core Schizophrenia-relevant genes consistent with the Omnigenic hypothesis of complex traits. Among other genes discussed, the developmental and post-synaptic scaffold TANC2 (Tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2) emerged from both networks as a novel core genetic driver of Schizophrenia altering PPI. As-pects of psychiatric disease comorbidity and phenotypic heterogeneity are also explored. Overall, this study provides a framework and galvanizes the value of mouse preclinical genetics and PPI to prioritize both existing and novel human Schizophrenia candidate genes as druggable targets.
AU  - Garrett, L.
AU  - Trümbach, D.
AU  - Lee, D.*
AU  - Mandillo, S.*
AU  - Samaco, R.C.*
AU  - Flenniken, A.M.*
AU  - Stewart, M.*
AU  - White, J.K.*
AU  - McKerlie, C.*
AU  - Nutter, L.M.J.*
AU  - Vukobradovic, I.*
AU  - Veeraragavan, S.*
AU  - Yuva, L.*
AU  - Heaney, J.D.*
AU  - Dickinson, M.E.*
AU  - Meziane, H.*
AU  - Hérault, Y.*
AU  - Wells, S.*
AU  - Lloyd, K.C.K.*
AU  - Bower, L.*
AU  - Lanoue, L.*
AU  - Clary, D.*
AU  - Zimprich, A.
AU  - Gailus-Durner, V.
AU  - Fuchs, H.
AU  - Brown, S.D.M.*
AU  - Chesler, E.J.*
AU  - Wurst, W.
AU  - Hrabě de Angelis, M.
AU  - Hölter, S.M.
C1  - 72358
C2  - 56559
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Co-expression of prepulse inhibition and Schizophrenia genes in the mouse and human brain.
JO  - Neurosci. App.
VL  - 3
PB  - Elsevier
PY  - 2024
SN  - 2772-4085
ER  - 

TY  - JOUR
AU  - Hölter, S.M.
C1  - 72355
C2  - 56575
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Addressing pitfalls in translation.
JO  - Neurosci. App.
VL  - 3
PB  - Elsevier
PY  - 2024
SN  - 2772-4085
ER  - 

TY  - JOUR
AB  - Mouse preclinical research is of great scientific interest to understand the mechanisms of human diseases and test potential therapeutic interventions. Researchers characterize biological and physiological traits, behaviors and disease symptoms using standardized phenotypic protocols in the context of in vivo mouse studies. However, the procedures applied do not always fully translate to reported outcomes in clinical trials. Quality of life (QoL) and wellbeing (WB) are particularly relevant outcomes in human medicine in general, and in neurology in particular, that are routinely measured by patient self-reports but rarely monitored in mouse research. In this novel scoping review, we have identified and described the instruments/tests and outcomes used to assess QoL and WB in recent mouse research (spanning 13 years). We found that WB was stated to be measured more frequently in murine studies (77 publications fulfilled our selection criteria) than QoL (only 13 articles). Instruments measuring WB were commonly used in neurology but less frequently in behavior and psychiatric research articles. Interestingly, we found a high variability of QoL and WB instruments/tests used as well as outcomes measured in the reviewed mouse studies. In addition, among similar parameters tested, we observed variable methodological procedures and mouse sample sizes. Thus, there is a lack of consensus on how to measure QoL and WB in the mouse research field. For ensuring a better translation from mouse to human, outcomes that are important in clinical trials (e.g., QoL and WB) should be measured in mouse studies. Finally, we would like to point out that a proper standardization of QoL and WB assessment protocols, for instance through a modified Delphi consultation survey, should be pursued by the mouse research community. Review registration: The study was registered on the PROSPERO Database (registration number CRD42018103507)
AU  - Sanz-Moreno, A.
AU  - da Silva Buttkus, P.
AU  - Terwee, C.B.*
AU  - Raess, M.*
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
C1  - 72354
C2  - 56558
TI  - Assessment of quality of life and wellbeing in mouse preclinical research – A scoping review.
JO  - Neurosci. App.
VL  - 3
PY  - 2024
SN  - 2772-4085
ER  - 

TY  - JOUR
AU  - Schmidt, S.
AU  - Luecken, M.
AU  - Theis, F.J.
AU  - Weisenhorn, D.M.
AU  - Wurst, W.
C1  - 73363
C2  - 56830
TI  - Molecular mechanisms underlying the onset of metabolic deficits in sporadic Parkinson’s disease.
JO  - Neurosci. App.
VL  - 3
PY  - 2024
SN  - 2772-4085
ER  - 

TY  - JOUR
AB  - G-protein-coupled receptors (GPCRs) represent targets for improved low-side-effect therapies to tackle the evolving Western obesity epidemic. The orphan (o) GPCR GPR101 emerged as an attractive candidate in this regard. Expressed on cells in brain areas regulating energy homeostasis, including the hunger-suppressing proopiomelanocortin (POMC) þ neurons, it is minimally expressed outside the brain. To understand the func-
      tion of this receptor in vivo, we herein generated and comprehensively characterized a Gpr101 knockout mouse line, either under standard feeding conditions or with chronic high-fat diet (HFD) access (16 weeks). GPR101 loss accelerated the risk for diet-induced obesity (DIO), hyperinsulinemia and disrupted glucose homeostasis. Hypo-
      thalamic transcriptomic analysis revealed also decreased Pomc activation with HFD suggesting impaired hunger suppression. Moreover, on a standard diet, there was a molecular signature of downregulated tristetraprolin (TTP) interactome gene activation suggesting impaired inflammation resolution. On HFD, there was differential
      expression of genes involved in microglial phagocytosis and lipid metabolism. Morphometry revealed altered hypothalamic arcuate nucleus microglial morphology consistent with the transcriptomic profile. We discuss how the GPR101 specialized pro-resolving mediator (SPM) receptor capacity likely underlies the aberrant microglial
      function and contributes to DIO risk. Thus, this evidence shows that GPR101 is a potential therapeutic target for DIO through, among other factors, effects on hypothalamic inflammation resolution.
AU  - Garrett, L.
AU  - Irmler, M.
AU  - Baljuls, A.*
AU  - Rathkolb, B.
AU  - Dragano, N.R.V.
AU  - Gerlini, R.
AU  - Sanz-Moreno, A.
AU  - Aguilar-Pimentel, J.A.
AU  - Becker, L.
AU  - Kraiger, M.
AU  - Reithmeir, R.
AU  - Beckers, J.
AU  - Calzada-Wack, J.
AU  - Wurst, W.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Zimmermann, T.*
AU  - Hölter, S.M.
AU  - Hrabě de Angelis, M.
C1  - 70161
C2  - 55042
TI  - GPR101 loss promotes insulin resistance and diet-induced obesity risk.
JO  - Neurosci. App.
VL  - 2
PY  - 2023
SN  - 2772-4085
ER  - 

TY  - JOUR
AB  - Glucocorticoid hormones and glucocorticoid receptor activation are essential for in utero organ maturation and fetal development [1]. Increased exposure to glucocorticoids during pregnancy, either caused by elevated stress levels or administration of synthetic hormones such as dexamethasone, have been associated with lasting negative effects on the offspring, including on neurodevelopment and psychiatric disease risk [2,3]. The molecular mechanisms mediating these adverse outcomes, however, remain unclear, especially given the challenges of studying human fetal brain development.
      
      Using human cerebral organoids, we have previously shown 4 that a 12 hour exposure to dexamethasone leads to activation of the glucocorticoid receptor, and to targeted regulation of differentiation- and maturation- related transcripts.
      
      In this study we were interested in further analysing the effects of glucocorticoids on neurogenic processes and cell fate specification. We exposed cerebral organoids to dexamethasone for a prolonged period of time (from day 60 to day 70 of organoid development) and used single cell RNA sequencing (scRNA-seq) to study transcriptional responses to glucocorticoids and neurodevelopmental trajectories. We used MAST to analyze differential gene expression after dexamethasone, and identified robust transcriptional changes in all eight fine-mapped cell clusters (q≤0.05). To identify genes that are reliably regulated by dexamethasone, we aggregated data from organoids generated from two different cell lines and filtered for genes that were significantly up- or down-regulated in both cell lines, maintaining the same directionality. We identified between 55 significantly differentially expressed genes (DEGs) in radial glia cells and 224 significant DEGs in telencephalic neurons (q < 0.05), confirming that a prolonged exposure to glucocorticoids induces a robust and reproducible transcriptional response.
      
      Next, by leveraging our whole dataset we identified genes that were most significantly up- or down-regulated between the progenitor cell classes (radial glia and cycling progenitors) and each of the identified neuronal cell classes (dorsal and ventral telencephalic neurons and non-telencephalic neurons) and thus are most likely drivers of cell fate specification during development. Interestingly, when comparing the top 3% of most strongly associated driver genes with dexamethasone-DEGs, we found a significant overlap between the two gene sets, showing that genes that are crucial for neuronal fate specification, are, in part, also regulated by glucocorticoids (approximately 30%, adjusted p ≤ 0.05 ). This indicates that glucocorticoids impact cell fate specification and possibly neuronal composition in the developing brain.
      
      Risk for psychiatric disorders is largely conferred by common variants located in non-coding regulatory regions. Given the role of glucocorticoids on cell fate specification we are working on elucidating the specific regulatory elements mediating glucocorticoid-effects on driver genes and thus on cell fate specification, using CAGE-sequencing. By identifying specific glucocorticoids-responsive regulatory elements that affect developmental driver genes expression we can further study the role of psychiatric disorders-associated risk variants located in those and analyse their effects using STARR-sequencing in a cell-type specific way across development. With this work we aim on identifying developmental processes affected by glucocorticoids and associated with risk for psychiatric disorders.
AU  - Kaspar, L.*
AU  - Dony, L.*
AU  - Cruceanu, C.*
AU  - Binder, E.B.*
AU  - Theis, F.J.
C1  - 70205
C2  - 55069
TI  - Effects of glucocorticoid exposure on gene expression and cell fate specification in cerebral organoids.
JO  - Neurosci. App.
VL  - 2
PY  - 2023
SN  - 2772-4085
ER  -