TY - JOUR A1 - Ahmad, Ruhel A1 - Wolber, Wanja A1 - Eckardt, Sigrid A1 - Koch, Philipp A1 - Schmitt, Jessica A1 - Semechkin, Ruslan A1 - Geis, Christian A1 - Heckmann, Manfred A1 - Brüstle, Oliver A1 - McLaughlin, John K. A1 - Sirén, Anna-Leena A1 - Müller, Albrecht M. T1 - Functional Neuronal Cells Generated by Human Parthenogenetic Stem Cells JF - PLoS One N2 - Parent of origin imprints on the genome have been implicated in the regulation of neural cell type differentiation. The ability of human parthenogenetic (PG) embryonic stem cells (hpESCs) to undergo neural lineage and cell type-specific differentiation is undefined. We determined the potential of hpESCs to differentiate into various neural subtypes. Concurrently, we examined DNA methylation and expression status of imprinted genes. Under culture conditions promoting neural differentiation, hpESC-derived neural stem cells (hpNSCs) gave rise to glia and neuron-like cells that expressed subtype-specific markers and generated action potentials. Analysis of imprinting in hpESCs and in hpNSCs revealed that maternal-specific gene expression patterns and imprinting marks were generally maintained in PG cells upon differentiation. Our results demonstrate that despite the lack of a paternal genome, hpESCs generate proliferating NSCs that are capable of differentiation into physiologically functional neuron-like cells and maintain allele-specific expression of imprinted genes. Thus, hpESCs can serve as a model to study the role of maternal and paternal genomes in neural development and to better understand imprinting-associated brain diseases. KW - methylation KW - derivation KW - blastocysts KW - pluripotent KW - differentiation KW - lines KW - brain development KW - in-vitro KW - mice KW - specification Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130268 VL - 7 IS - 8 ER - TY - JOUR A1 - Frey, Anna A1 - Popp, Sandy A1 - Post, Antonia A1 - Langer, Simon A1 - Lehmann, Marc A1 - Hofmann, Ulrich A1 - Siren, Anna-Leena A1 - Hommers, Leif A1 - Schmitt, Angelika A1 - Strekalova, Tatyana A1 - Ertl, Georg A1 - Lesch, Klaus-Peter A1 - Frantz, Stefan T1 - Experimental heart failure causes depression-like behavior together with differential regulation of inflammatory and structural genes in the brain JF - Frontiers in Behavioral Neuroscience N2 - Background: Depression and anxiety are common and independent outcome predictors in patients with chronic heart failure (CHF). However, it is unclear whether CHF causes depression. Thus, we investigated whether mice develop anxiety- and depression-like behavior after induction of ischemic CHF by myocardial infarction (MI). Methods and Results: In order to assess depression-like behavior, anhedonia was investigated by repeatedly testing sucrose preference for 8 weeks after coronary artery ligation or sham operation. Mice with large MI and increased left ventricular dimensions on echocardiography (termed CHF mice) showed reduced preference for sucrose, indicating depression-like behavior. 6 weeks after MI, mice were tested for exploratory activity, anxiety-like behavior and cognitive function using the elevated plus maze (EPM), light-dark box (LDB), open field (OF), and object recognition (OR) tests. In the EPM and OF, CHF mice exhibited diminished exploratory behavior and motivation despite similar movement capability. In the OR, CHF mice had reduced preference for novelty and impaired short-term memory. On histology, CHF mice had unaltered overall cerebral morphology. However, analysis of gene expression by RNA-sequencing in prefrontal cortical, hippocampal, and left ventricular tissue revealed changes in genes related to inflammation and cofactors of neuronal signal transduction in CHF mice, with Nr4a1 being dysregulated both in prefrontal cortex and myocardium after MI. Conclusions: After induction of ischemic CHF, mice exhibited anhedonic behavior, decreased exploratory activity and interest in novelty, and cognitive impairment. Thus, ischemic CHF leads to distinct behavioral changes in mice analogous to symptoms observed in humans with CHF and comorbid depression. KW - chronic heart failure KW - myocardial infarction KW - anxiety KW - depression KW - mice Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118234 SN - 1662-5153 VL - 8 ER - TY - JOUR A1 - Hassouna, I. A1 - Ott, C. A1 - Wüstefeld, L. A1 - Offen, N. A1 - Neher, R. A. A1 - Mitkovski, M. A1 - Winkler, D. A1 - Sperling, S. A1 - Fries, L. A1 - Goebbels, S. A1 - Vreja, I. C. A1 - Hagemeyer, N. A1 - Dittrich, M. A1 - Rossetti, M. F. A1 - Kröhnert, K. A1 - Hannke, K. A1 - Boretius, S. A1 - Zeug, A. A1 - Höschen, C. A1 - Dandekar, T. A1 - Dere, E. A1 - Neher, E. A1 - Rizzoli, S. O. A1 - Nave, K.-A. A1 - Sirén, A.-L. A1 - Ehrenreich, H. T1 - Revisiting adult neurogenesis and the role of erythropoietin for neuronal and oligodendroglial differentiation in the hippocampus JF - Molecular Psychiatry N2 - Recombinant human erythropoietin (EPO) improves cognitive performance in neuropsychiatric diseases ranging from schizophrenia and multiple sclerosis to major depression and bipolar disease. This consistent EPO effect on cognition is independent of its role in hematopoiesis. The cellular mechanisms of action in brain, however, have remained unclear. Here we studied healthy young mice and observed that 3-week EPO administration was associated with an increased number of pyramidal neurons and oligodendrocytes in the hippocampus of similar to 20%. Under constant cognitive challenge, neuron numbers remained elevated until >6 months of age. Surprisingly, this increase occurred in absence of altered cell proliferation or apoptosis. After feeding a \(^{15}\)N-leucine diet, we used nanoscopic secondary ion mass spectrometry, and found that in EPO-treated mice, an equivalent number of neurons was defined by elevated \(^{15}\)N-leucine incorporation. In EPO-treated NG2-Cre-ERT2 mice, we confirmed enhanced differentiation of preexisting oligodendrocyte precursors in the absence of elevated DNA synthesis. A corresponding analysis of the neuronal lineage awaits the identification of suitable neuronal markers. In cultured neurospheres, EPO reduced Sox9 and stimulated miR124, associated with advanced neuronal differentiation. We are discussing a resulting working model in which EPO drives the differentiation of non-dividing precursors in both (NG2+) oligodendroglial and neuronal lineages. As endogenous EPO expression is induced by brain injury, such a mechanism of adult neurogenesis may be relevant for central nervous system regeneration. KW - neural stem-cells KW - recombinat-human-erythropoietin KW - cognitive functions KW - pyramidal neurons KW - nervous-sytem KW - brain-injury KW - mouse-brain KW - progenitors KW - mice KW - memory Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186669 VL - 21 IS - 12 ER -