TY - JOUR A1 - Waider, Jonas A1 - Popp, Sandy A1 - Mlinar, Boris A1 - Montalbano, Alberto A1 - Bonfiglio, Francesco A1 - Aboagye, Benjamin A1 - Thuy, Elisabeth A1 - Kern, Raphael A1 - Thiel, Christopher A1 - Araragi, Naozumi A1 - Svirin, Evgeniy A1 - Schmitt-Böhrer, Angelika G. A1 - Corradetti, Renato A1 - Lowry, Christopher A. A1 - Lesch, Klaus-Peter T1 - Serotonin deficiency increases context-dependent fear learning through modulation of hippocampal activity JF - Frontiers in Neuroscience N2 - Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses. KW - tryptophan hydroxylase 2 KW - knockout KW - fear learning KW - extinction KW - long-term potentiation KW - hippocampus KW - immediate-early gene KW - serotonin deficiency Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196077 SN - 1662-453X VL - 13 IS - 245 ER - TY - JOUR A1 - Dischinger, Ulrich A1 - Heckel, Tobias A1 - Bischler, Thorsten A1 - Hasinger, Julia A1 - Königsrainer, Malina A1 - Schmitt-Böhrer, Angelika A1 - Otto, Christoph A1 - Fassnacht, Martin A1 - Seyfried, Florian A1 - Hankir, Mohammed Khair T1 - Roux-en-Y gastric bypass and caloric restriction but not gut hormone-based treatments profoundly impact the hypothalamic transcriptome in obese rats JF - Nutrients N2 - Background: The hypothalamus is an important brain region for the regulation of energy balance. Roux-en-Y gastric bypass (RYGB) surgery and gut hormone-based treatments are known to reduce body weight, but their effects on hypothalamic gene expression and signaling pathways are poorly studied. Methods: Diet-induced obese male Wistar rats were randomized into the following groups: RYGB, sham operation, sham + body weight-matched (BWM) to the RYGB group, osmotic minipump delivering PYY3-36 (0.1 mg/kg/day), liraglutide s.c. (0.4 mg/kg/day), PYY3-36 + liraglutide, and saline. All groups (except BWM) were kept on a free choice of high- and low-fat diets. Four weeks after interventions, hypothalami were collected for RNA sequencing. Results: While rats in the RYGB, BWM, and PYY3-36 + liraglutide groups had comparable reductions in body weight, only RYGB and BWM treatment had a major impact on hypothalamic gene expression. In these groups, hypothalamic leptin receptor expression as well as the JAK–STAT, PI3K-Akt, and AMPK signaling pathways were upregulated. No significant changes could be detected in PYY3-36 + liraglutide-, liraglutide-, and PYY-treated groups. Conclusions: Despite causing similar body weight changes compared to RYGB and BWM, PYY3-36 + liraglutide treatment does not impact hypothalamic gene expression. Whether this striking difference is favorable or unfavorable to metabolic health in the long term requires further investigation. KW - obesity KW - Roux-en-Y gastric bypass surgery KW - liraglutide KW - PYY3-36 KW - hypothalamic gene expression Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252392 SN - 2072-6643 VL - 14 IS - 1 ER - TY - JOUR A1 - Popp, Sandy A1 - Schmitt-Böhrer, Angelika A1 - Langer, Simon A1 - Hofmann, Ulrich A1 - Hommers, Leif A1 - Schuh, Kai A1 - Frantz, Stefan A1 - Lesch, Klaus-Peter A1 - Frey, Anna T1 - 5-HTT Deficiency in Male Mice Affects Healing and Behavior after Myocardial Infarction JF - Journal of Clinical Medicine N2 - Anxiety disorders and depression are common comorbidities in cardiac patients. Mice lacking the serotonin transporter (5-HTT) exhibit increased anxiety-like behavior. However, the role of 5-HTT deficiency on cardiac aging, and on healing and remodeling processes after myocardial infarction (MI), remains unclear. Cardiological evaluation of experimentally naïve male mice revealed a mild cardiac dysfunction in ≥4-month-old 5-HTT knockout (−/−) animals. Following induction of chronic cardiac dysfunction (CCD) by MI vs. sham operation 5-HTT−/− mice with infarct sizes >30% experienced 100% mortality, while 50% of 5-HTT+/− and 37% of 5-HTT+/+ animals with large MI survived the 8-week observation period. Surviving (sham and MI < 30%) 5-HTT−/− mutants displayed reduced exploratory activity and increased anxiety-like behavior in different approach-avoidance tasks. However, CCD failed to provoke a depressive-like behavioral response in either 5-Htt genotype. Mechanistic analyses were performed on mice 3 days post-MI. Electrocardiography, histology and FACS of inflammatory cells revealed no abnormalities. However, gene expression of inflammation-related cytokines (TGF-β, TNF-α, IL-6) and MMP-2, a protein involved in the breakdown of extracellular matrix, was significantly increased in 5-HTT−/− mice after MI. This study shows that 5-HTT deficiency leads to age-dependent cardiac dysfunction and disrupted early healing after MI probably due to alterations of inflammatory processes in mice. KW - chronic heart failure KW - myocardial infarction KW - serotonin transporter deficient mice KW - anxiety KW - depression KW - behavior KW - inflammation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242739 SN - 2077-0383 VL - 10 IS - 14 ER - TY - JOUR A1 - Weidner, Magdalena T. A1 - Lardenoije, Roy A1 - Eijssen, Lars A1 - Mogavero, Floriana A1 - De Groodt, Lilian P. M. T. A1 - Popp, Sandy A1 - Palme, Rupert A1 - Förstner, Konrad U. A1 - Strekalova, Tatyana A1 - Steinbusch, Harry W. M. A1 - Schmitt-Böhrer, Angelika G. A1 - Glennon, Jeffrey C. A1 - Waider, Jonas A1 - van den Hove, Daniel L. A. A1 - Lesch, Klaus-Peter T1 - Identification of cholecystokinin by genome-wide profiling as potential mediator of serotonin-dependent behavioral effects of maternal separation in the amygdala JF - Frontiers in Neuroscience N2 - Converging evidence suggests a role of serotonin (5-hydroxytryptamine, 5-HT) and tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of 5-HT synthesis in the brain, in modulating long-term, neurobiological effects of early-life adversity. Here, we aimed at further elucidating the molecular mechanisms underlying this interaction, and its consequences for socio-emotional behaviors, with a focus on anxiety and social interaction. In this study, adult, male Tph2 null mutant (Tph2\(^{-/-}\)) and heterozygous (Tph2\(^{+/-}\)) mice, and their wildtype littermates (Tph2\(^{+/+}\)) were exposed to neonatal, maternal separation (MS) and screened for behavioral changes, followed by genome-wide RNA expression and DNA methylation profiling. In Tph2\(^{-/-}\) mice, brain 5-HT deficiency profoundly affected socio-emotional behaviors, i.e., decreased avoidance of the aversive open arms in the elevated plus-maze (EPM) as well as decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Tph2\(^{+/-}\) mice showed an ambiguous profile with context-dependent, behavioral responses. In the EPM they showed similar avoidance of the open arm but decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Notably, MS effects on behavior were subtle and depended on the Tph2 genotype, in particular increasing the observed avoidance of EPM open arms in wildtype and Tph2\(^{+/-}\) mice when compared to their Tph2\(^{-/-}\) littermates. On the genomic level, the interaction of Tph2 genotype with MS differentially affected the expression of numerous genes, of which a subset showed an overlap with DNA methylation profiles at corresponding loci. Remarkably, changes in methylation nearby and expression of the gene encoding cholecystokinin, which were inversely correlated to each other, were associated with variations in anxiety-related phenotypes. In conclusion, next to various behavioral alterations, we identified gene expression and DNA methylation profiles to be associated with TPH2 inactivation and its interaction with MS, suggesting a gene-by-environment interaction-dependent, modulatory function of brain 5-HT availability. KW - serotonin KW - maternal separation KW - mouse KW - emotional behavior KW - DNA methylation KW - RNA expression Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201340 VL - 13 ER - TY - JOUR A1 - Hamann, Catharina S. A1 - Bankmann, Julian A1 - Mora Maza, Hanna A1 - Kornhuber, Johannes A1 - Zoicas, Iulia A1 - Schmitt-Böhrer, Angelika T1 - Social fear affects limbic system neuronal activity and gene expression JF - International Journal of Molecular Sciences N2 - Social anxiety disorder (SAD) is a highly prevalent and comorbid anxiety disorder with rather unclear underlying mechanisms. Here, we aimed to characterize neurobiological changes occurring in mice expressing symptoms of social fear and to identify possible therapeutic targets for SAD. Social fear was induced via social fear conditioning (SFC), a validated animal model of SAD. We assessed the expression levels of the immediate early genes (IEGs) cFos, Fosl2 and Arc as markers of neuronal activity and the expression levels of several genes of the GABAergic, serotoninergic, oxytocinergic, vasopressinergic and neuropeptide Y (NPY)-ergic systems in brain regions involved in social behavior or fear-related behavior in SFC+ and SFC− mice 2 h after exposure to a conspecific. SFC+ mice showed a decreased number and density of cFos-positive cells and decreased expression levels of IEGs in the dorsal hippocampus. SFC+ mice also showed alterations in the expression of NPY and serotonin system-related genes in the paraventricular nucleus of the hypothalamus, basolateral amygdala, septum and dorsal raphe nucleus, but not in the dorsal hippocampus. Our results describe neuronal alterations occurring during the expression of social fear and identify the NPY and serotonergic systems as possible targets in the treatment of SAD. KW - social anxiety KW - fear expression KW - social avoidance KW - gene expression KW - Npy KW - Npyr1 KW - Npyr2 KW - Htr1a KW - Htr2a KW - Htr2c Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284274 SN - 1422-0067 VL - 23 IS - 15 ER - TY - JOUR A1 - Sun, Ping A1 - Ortega, Gabriela A1 - Tan, Yan A1 - Hua, Qian A1 - Riederer, Peter F. A1 - Deckert, Jürgen A1 - Schmitt-Böhrer, Angelika G. T1 - Streptozotocin impairs proliferation and differentiation of adult hippocampal neural stem cells in vitro-correlation with alterations in the expression of proteins associated with the insulin system JF - Frontiers in Aging Neuroscience N2 - Rats intracerebroventricularily (icv) treated with streptozotocin (STZ), shown to generate an insulin resistant brain state, were used as an animal model for the sporadic form of Alzheimer's disease (sAD). Previously, we showed in an in vivo study that 3 months after STZ icv treatment hippocampal adult neurogenesis (AN) is impaired. In the present study, we examined the effects of STZ on isolated adult hippocampal neural stem cells (NSCs) using an in vitro approach. We revealed that 2.5 mM STZ inhibits the proliferation of NSCs as indicated by reduced number and size of neurospheres as well as by less BrdU-immunoreactive NSCs. Double immunofluorescence stainings of NSCs already being triggered to start with their differentiation showed that STZ primarily impairs the generation of new neurons, but not of astrocytes. For revealing mechanisms possibly involved in mediating STZ effects we analyzed expression levels of insulin/glucose system-related molecules such as the glucose transporter (GLUT) 1 and 3, the insulin receptor (IR) and the insulin-like growth factor (IGF) 1 receptor. Applying quantitative Real time-PCR (qRT-PCR) and immunofluorescence stainings we showed that STZ exerts its strongest effects on GLUT3 expression, as GLUT3 mRNA levels were found to be reduced in NSCs, and less GLUT3-immunoreactive NSCs as well as differentiating cells were detected after STZ treatment. These findings suggest that cultured NSCs are a good model for developing new strategies to treat nerve cell loss in AD and other degenerative disorders. KW - Alzheimer’s disease KW - streptozotocin KW - proliferation KW - neural stem cells KW - insulin-like growth factor 1 receptor KW - insulin receptor KW - glucose transporter KW - differentiation Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176741 VL - 10 IS - 145 ER -