Similar Datasets
Project description:Purpose: Investigation of effects of early adversity in mice deficient for brain serotonin on the methylome Methods: Following materal separation in early childhood and behavioural screening in adulthood, 4 moth old males, either wildtype or carrying a hetero- or homozygous knockout of the thryptophan hyroxylase 2 gene, were sacrificed, brains extracted, the amygdalae of both hemispheres dissected, blended and separated in two protions. From one of these portions DNA was processed by an external company, i.e. Nxt-Dx (Ghent, Belgium). DNA was sheared by sonication, followed by methyl binding domain (MBD) based capture, leading to an enrichment of methylated fragments. Subsequently, library preparation was performed followed by multiplexed paired-end sequencing with a read-length of 50 bp and an approximate output of 20 million reads/sample on the Illumina HiSeq4000 platform. Reads were mapped to the Mus musculus GRCm38.p5 genome using Bowtie2 (v2.1.0) software in end-to-end & sensitive-mode. After mapping, coverage peaks were generated using MACS 14 peak caller (Zhang et al. 2008). Results: Either Tph2 genotype, early adversity as well as their interaction resulted in unique profiles of differentially enriched methylated peaks as well as expressed RNA. As expected, the effect sizes and significances were rather subtle and the overlap between top hits of methylome and transcriptome were marginal. Conclusion: Tph2, MS and their interaction induced changes in gene expression and DNA methylation, within a physiological range. The observed changes by MS seemed furthermore strongly influenced by the Tph2 genotype, ergo brain 5-HT availability.
2019-05-06 | GSE110329 | GEO
Project description:Purpose: Investigation of effects of early adversity in mice deficient for brain serotonin on the transcriptome Methods: Following materal separation in early childhood and behavioural screening in adulthood, 4 moth old males, either wildtype or carrying a hetero- or homozygous knockout of the thryptophan hyroxylase 2 gene, were sacrificed, brains extracted, the amygdalae of both hemispheres dissected, blended and separated in two protions. From one of these portions RNA was extracted. Extracted RNA was further processed by an external company, i.e. IGA Technologies (Udine, Italy). , library preparation was performed using TruSeq Stranded Total RNA Library Prep Kit (Illumina, San Diego, CA, US) that captures coding RNA and multiple forms of non-coding RNA, with a total input of 300 ng of RNA, as measured with Qubit 2.0 Fluorometer (Invitrogen, Carlsbad, CA) following manufacturer’s recommendations. The sequencing was performed using the Illumina HiSeq 2500 platform at a read-length of 125 bp with paired end reads yielding 60 million reads/sample. Reads were mapped to the Mus musculus GRCm38.p5 genome using STAR (Dobin et al. 2013). Following mapping, the reads per position were determined using HTSeq (Anders et al. 2015). Results: Either Tph2 genotype, early adversity as well as their interaction resulted in unique profiles of differentially expressed RNA. As expected, the effect sizes and significances were rather subtle. Conclusion: Tph2, MS and their interaction induced changes in gene expression and DNA methylation, within a physiological range. The observed changes by MS seemed furthermore strongly influenced by the Tph2 genotype, ergo brain 5-HT availability.
2019-05-06 | GSE110328 | GEO
Project description:Effects of gene-by-environment interaction on the transcriptome and methylome of mice deficient for tryptophan hydroxylase 2
| PRJNA433806 | ENA
Project description:Effects of gene-by-environment interaction on the methylome of mice deficient for tryptophan hydroxylase 2 [MBD-seq]
| PRJNA433809 | ENA
Project description:Effects of gene-by-environment interaction on the transcriptome of mice deficient for tryptophan hydroxylase 2 [RNA-seq]
| PRJNA433807 | ENA
Project description:The role of peripheral serotonin in nervous system development is poorly understood. Tryptophan hydroxylase-1 (TPH1) is expressed by non-neuronal cells including enterochromaffin cells of the gut, mast cells and the pineal gland and is the rate-limiting enzyme involved in the biosynthesis of peripheral serotonin. Serotonin released into circulation is taken up by platelets via the serotonin transporter and stored in dense granules. It has been previously reported that mouse embryos removed from Tph1-deficient mothers present abnormal nervous system morphology. The goal of this study was to assess whether Tph1-deficiency results in behavioral abnormalities. We did not find any differences between Tph1-deficient and wild-type mice in general motor behavior as tested by rotarod, grip-strength test, open field and beam walk. However, here we report that Tph1 (-/-) mice display altered gait dynamics and deficits in rearing behavior compared to wild-type (WT) suggesting that tryptophan hydroxylase-1 expression has an impact on the nervous system.
| S-EPMC3597584 | biostudies-literature
Project description:BALB/c is an inbred stress-sensitive mouse strain exhibiting low brain serotonin (5-HT) content and a 5-HT biosynthetic enzyme tryptophan hydroxylase (Tph2) variant reported to have lower catalytic activity compared with other inbred base strains. To evaluate other mechanisms that may explain low 5-HT, we compared BALB/cJ mice and a control inbred strain C57Bl/6J mice, for expression of Tph2 mRNA, TPH2 protein and regional levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid. Tph2 mRNA and TPH2 protein in brainstem dorsal raphe nuclei was assayed by in situ hybridization and immunocytochemistry respectively. 5-HT and 5-hydroxyindoleacetic acid were determined by HPLC. BALB/cJ mice had 20% less Tph2 mRNA and 28% fewer TPH2 immunolabeled neurons than C57Bl/6J mice (t = -2.59, p = 0.02). The largest difference in Tph2 transcript expression was in rostral dorsal raphe nuclei (t = 2.731, p = 0.008). 5-HT was 15% lower in the midbrain and 18% lower in the cerebral cortex of BALB/cJ compared with C57Bl/6J mice (p < 0.05). The behavioral differences in BALB/cJ mice relative to the C57Bl/6J strain may be due in part, to fewer 5-HT neurons and lower Tph2 gene expression resulting in less 5-HT neurotransmission. Future studies quantifying expression per neuron are needed to determine whether less expression is explained by fewer neurons or also less expression per neuron, or both.
| S-EPMC4222035 | biostudies-literature
Project description:Probably the foremost hypothesis of depression is the 5-hydroxytryptamine (5-HT, serotonin) deficiency hypothesis. Accordingly, anomalies in putative 5-HT biomarkers have repeatedly been reported in depression patients. However, whether such anomalies in fact reflect deficient central 5-HT neurotransmission remains unresolved. We employed a naturalistic model of 5-HT deficiency, the tryptophan hydroxylase 2 (Tph2) R439H knockin mouse, to address this question. We report that Tph2 knockin mice have reduced basal and stimulated levels of extracellular 5-HT (5-HT(Ext)). Interestingly, cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and fenfluramine-induced plasma prolactin levels are markedly diminished in the Tph2 knockin mice. These data seemingly confirm that low CSF 5-HIAA and fenfluramine-induced plasma prolactin reflects chronic, endogenous central nervous system (CNS) 5-HT deficiency. Moreover, 5-HT(1A) receptor agonist-induced hypothermia is blunted and frontal cortex 5-HT(2A) receptors are increased in the Tph2 knockin mice. These data likewise parallel core findings in depression, but are usually attributed to anomalies in the respective receptors rather than resulting from CNS 5-HT deficiency. Further, 5-HT(2A) receptor function is enhanced in the Tph2 knockin mice. In contrast, 5-HT(1A) receptor levels and G-protein coupling is normal in Tph2 knockin mice, indicating that the blunted hypothermic response relates directly to the low 5-HT(Ext). Thus, we show that not only low CSF 5-HIAA and a blunted fenfluramine-induced prolactin response, but also blunted 5-HT(1A) agonist-induced hypothermia and increased 5-HT(2A) receptor levels are bona fide biomarkers of chronic, endogenous 5-HT deficiency. Potentially, some of these biomarkers could identify patients likely to have 5-HT deficiency. This could have clinical research utility or even guide pharmacotherapy.
| S-EPMC3536482 | biostudies-other
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-01-27 | GSE109930 | GEO
Project description:Transmembrane prolyl 4-hydroxylase (P4H-TM) is an enigmatic enzyme whose cellular function and primary substrate remain to be identified. Its loss-of-function mutations cause a severe neurological HIDEA syndrome with hypotonia, intellectual disability, dysautonomia and hypoventilation. Previously, P4H-TM deficiency in mice was associated with reduced atherogenesis and lower serum triglyceride levels. Here, we characterized the glucose and lipid metabolism of P4h-tm-/- mice in physiological and tissue analyses. P4h-tm-/- mice showed variations in 24-h oscillations of energy expenditure, VO2 and VCO2 and locomotor activity compared to wild-type (WT) mice. Their rearing activity was reduced, and they showed significant muscle weakness and compromised coordination. Sedated P4h-tm-/- mice had better glucose tolerance, lower fasting insulin levels, higher fasting lactate levels and lower fasting free fatty acid levels compared to WT. These alterations were not present in conscious P4h-tm-/- mice. Fasted P4h-tm-/- mice presented with faster hepatic glycogenolysis. The respiratory rate of conscious P4h-tm-/- mice was significantly lower compared to the WT, the decrease being further exacerbated by sedation and associated with acidosis and a reduced ventilatory response to both hypoxia and hypercapnia. P4H-TM deficiency in mice is associated with alterations in whole-body energy metabolism, day-night rhythm of activity, glucose homeostasis and neuromuscular and respiratory functions. Although the underlying mechanism(s) are not yet fully understood, the phenotype appears to have neurological origins, controlled by brain and central nervous system circuits. The phenotype of P4h-tm-/- mice recapitulates some of the symptoms of HIDEA patients, making this mouse model a valuable tool to study and develop tailored therapies.
| S-EPMC11310233 | biostudies-literature