Dopamine D2L Receptor Deficiency Causes Stress Vulnerability through 5-HT1A Receptor Dysfunction in Serotonergic Neurons
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PROVIDER: PRJNA513844 | ENA |
REPOSITORIES: ENA
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Project description:Mental disorders are caused by genetic and environmental factors. We here show that deficiency of an isoform of dopamine D2 receptor (D2R), D2LR, causes psychosocial stress vulnerability in mouse. This occurs through dysfunction of type 1A serotonin (5-hydroxytryptamine, 5-HT) receptor (5-HT1AR) on serotonergic neurons in the mouse brain. Exposure to forced swim stress significantly increased anxiety- and depressive-like behaviors in D2LR knockout (D2LR-KO) male mice as compared with wild-type mice. Treatment with 8-OH-DPAT, a 5-HT1AR agonist, failed to alleviate the stress-induced behaviors in D2LR-KO mice. In forced swim-stressed D2LR-KO mice, 5-HT release in the medial prefrontal cortex was elevated and the expression of genes related to 5-HT levels was up-regulated by the transcription factor PET1 in the dorsal raphe nucleus. Notably, D2LR formed a heteromer with 5-HT1AR in serotonergic neurons, thereby suppressing 5-HT1AR–activated G-protein–activated inwardly rectifying potassium (GIRK) conductance in D2LR-KO serotonergic neurons. Finally, D2LR overexpression in serotonergic neurons in the dorsal raphe nucleus alleviated stress vulnerability observed in D2LR-KO mice. Taken together, we conclude that disruption of the negative feedback regulation by the D2LR/5-HT1A heteromer causes stress vulnerability.
2019-01-09 | GSE124806 | GEO
Project description:Mental disorders are caused by genetic and environmental factors. We here show that deficiency of an isoform of dopamine D2 receptor (D2R), D2LR, causes stress vulnerability in mouse. This occurs through dysfunction of serotonin [5-hydroxytryptamine (5-HT)] 1A receptor (5-HT1AR) on serotonergic neurons in the mouse brain. Exposure to forced swim stress significantly increased anxiety- and depressive-like behaviors in D2LR knock-out (KO) male mice compared with wild-type mice. Treatment with 8-OH-DPAT, a 5-HT1AR agonist, failed to alleviate the stress-induced behaviors in D2LR-KO mice. In forced swim-stressed D2LR-KO mice, 5-HT efflux in the medial prefrontal cortex was elevated and the expression of genes related to 5-HT levels was upregulated by the transcription factor PET1 in the dorsal raphe nucleus. Notably, D2LR formed a heteromer with 5-HT1AR in serotonergic neurons, thereby suppressing 5-HT1AR-activated G-protein-activated inwardly rectifying potassium conductance in D2LR-KO serotonergic neurons. Finally, D2LR overexpression in serotonergic neurons in the dorsal raphe nucleus alleviated stress vulnerability observed in D2LR-KO mice. Together, we conclude that disruption of the negative feedback regulation by the D2LR/5-HT1A heteromer causes stress vulnerability.SIGNIFICANCE STATEMENT Etiologies of mental disorders are multifactorial, e.g., interactions between genetic and environmental factors. In this study, using a mouse model, we showed that genetic depletion of an isoform of dopamine D2 receptor, D2LR, causes stress vulnerability associated with dysfunction of serotonin 1A receptor, 5-HT1AR in serotonergic neurons. The D2LR/5-HT1AR inhibitory G-protein-coupled heteromer may function as a negative feedback regulator to suppress psychosocial stress.
| S-EPMC6750932 | biostudies-literature
Project description:Dopamine Receptor Antagonists and Radiation Create a Metabolic Vulnerability in Mouse Models of Glioblastoma
| PRJNA695232 | ENA
Project description:The selective vulnerability of dopaminergic neurons to trauma-induced neurodegeneration is a conserved phenomenon across species, extending from nematodes to humans. However, the molecular mechanisms contributing to this hypersensitivity to blunt force injury remain poorly understood. We find that dopamine oxidation, a key driver of Parkinson’s Disease, extends its toxic role to the acute challenges of blunt force trauma. Ectopic synthesis of dopamine in serotonergic neurons alone proves sufficient in determining neuronal subtype sensitivity to trauma-induced death. While dopaminergic neurons maintain this neurotransmitter in a functional and benign state, trauma-induced subcellular redox imbalances elicit dopamine-dependent cytotoxicity. Perturbing dopamine synthesis and its packaging into synaptic vesicles further demonstrate how cytosolic dopamine is both necessary and sufficient to drive cell loss upon mechanical stress and during aging. Additionally, trauma activates the B-Zip transcription factor, fos-1, which exacerbates this toxic cascade by transcriptionally upregulating the rate-limiting enzyme in dopamine synthesis, cat-2. In summary, our study unravels the molecular intricacies that render dopaminergic neurons uniquely prone to physical perturbation, highlighting a shared vulnerability across different evolutionary lines.
2024-06-17 | GSE254141 | GEO
Project description:The selective vulnerability of dopaminergic neurons to trauma-induced neurodegeneration is a conserved phenomenon across species, extending from nematodes to humans. However, the molecular mechanisms contributing to this hypersensitivity to blunt force injury remain poorly understood. We find that dopamine oxidation, a key driver of Parkinson’s Disease, extends its toxic role to the acute challenges of blunt force trauma. Ectopic synthesis of dopamine in serotonergic neurons alone proves sufficient in determining neuronal subtype sensitivity to trauma-induced death. While dopaminergic neurons maintain this neurotransmitter in a functional and benign state, trauma-induced subcellular redox imbalances elicit dopamine-dependent cytotoxicity. Perturbing dopamine synthesis and its packaging into synaptic vesicles further demonstrate how cytosolic dopamine is both necessary and sufficient to drive cell loss upon mechanical stress and during aging. Additionally, trauma activates the B-Zip transcription factor, fos-1, which exacerbates this toxic cascade by transcriptionally upregulating the rate-limiting enzyme in dopamine synthesis, cat-2. In summary, our study unravels the molecular intricacies that render dopaminergic neurons uniquely prone to physical perturbation, highlighting a shared vulnerability across different evolutionary lines.
2024-06-17 | GSE254138 | GEO
Project description:Glioblastoma is the deadliest brain tumor in adults and the standard-of-care consists of surgery followed by radiation and treatment with temozolomide. Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options. Using patient-derived glioblastoma lines and mouse models of glioblastoma we tested the effect of radiation and the dopamine receptor antagonist on glioblastoma self-renewal in vitro and survival in vivo. A possible resistance mechanism was investigated using RNA-Sequencing. Treatment of glioma cells with the dopamine receptor antagonist quetiapine reduced glioma cell self-renewal in vitro and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing animals. The combined treatment induced the expression of genes involved in cholesterol biosynthesis. This rendered the tumors vulnerable to simultaneous treatment with atorvastatin and further significantly prolonged the survival of the animals. Our results indicate promising therapeutic efficacy with the triple combination of quetiapine, atorvastatin and radiation treatment against glioblastoma without increasing the toxicity of radiation. With both drugs readily available for clinical use our study could be rapidly translated into a clinical trial.
2021-01-28 | GSE165624 | GEO
Project description:The interior of the neuronal cell nucleus is a highly organized 3-dimensional (3D) structure in which regions of the genome that are millions of bases apart participate in specialized sub-structures with dedicated functions. To investigate neuronal chromatin organization and dynamics in vivo, we generated bitransgenic mice that express histone GFP-tagged H2B in principal neurons of the forebrain. Surprisingly, the expression of this chimeric histone in mature neurons causes chromocenter declustering and disrupts the association of heterochromatin with the nuclear lamina. The loss of these structures does not affect neuronal viability but is associated with specific transcriptional and behavioral deficits related to serotonergic dysfunction. Overall, our results demonstrate that the 3D-organization of chromatin in the neuronal nucleus supports an additional level of epigenetic regulation of gene expression that critically influences neuronal function and indicate that some loci associated with neuropsychiatric disorders may be particularly sensitive to changes in chromatin architecture. Genome-wide profiling by high throughput sequencing of H3K27me3 in the adult hippocampus of CaMKII-tTA/tetO-H2BGFP (H2BGFP) and their wild-type littermates mice (WT). Chromatin immunoprecipitation (ChIP) was carried out using pooled hippocampal tissue from 3 mice (one hippocampus per mouse). One DNA library was constructed per genotype. Each DNA library was prepared from pooled immunoprecipitated DNA from 4 independent ChIP assays. In total, tissue from 12 different mice was used to prepare each DNA library. 60% of a lane was used to perform single end (1x50bp) multiplex sequencing in HiSeq 2500 apparatus (Illumina). Each library, was sequenced in duplicate (in two independent sequencing runs. Technical replicates).
2014-07-18 | E-GEOD-56809 | biostudies-arrayexpress
Project description:In a study focused on the role dopamine receptor 3, we completed RNA-sequencing of D456 and JX39, glioblastoma xenograft lines after SRI-21979 or dmso treatment
2020-07-01 | GSE148740 | GEO
Project description:The interior of the neuronal cell nucleus is a highly organized 3-dimensional (3D) structure in which regions of the genome that are millions of bases apart participate in specialized sub-structures with dedicated functions. To investigate neuronal chromatin organization and dynamics in vivo, we generated bitransgenic mice that express histone GFP-tagged H2B in principal neurons of the forebrain. Surprisingly, the expression of this chimeric histone in mature neurons causes chromocenter declustering and disrupts the association of heterochromatin with the nuclear lamina. The loss of these structures does not affect neuronal viability but is associated with specific transcriptional and behavioral deficits related to serotonergic dysfunction. Overall, our results demonstrate that the 3D-organization of chromatin in the neuronal nucleus supports an additional level of epigenetic regulation of gene expression that critically influences neuronal function and indicate that some loci associated with neuropsychiatric disorders may be particularly sensitive to changes in chromatin architecture.
2014-07-18 | GSE56809 | GEO
Project description:Midbrain dopamine neurons project to numerous targets throughout the brain to modulate various behaviors and brain states. Within this small population of neurons exists significant heterogeneity based on physiology, circuitry, and disease susceptibility. Recent studies have shown that dopamine neurons can be subdivided based on gene expression; however, the extent to which genetic markers represent functionally relevant dopaminergic subpopulations has not been fully explored. Here we performed single-cell RNA-sequencing of mouse dopamine neurons and validated studies showing that Neurod6 and Grp are selective markers for dopaminergic subpopulations. Using a combination of multiplex fluorescent in situ hybridization, retrograde labeling, and electrophysiology in mice of both sexes, we defined the anatomy, projection targets, physiological properties, and disease vulnerability of dopamine neurons based on Grp and/or Neurod6 expression. We found that the combinatorial expression of Grp and Neurod6 defines dopaminergic subpopulations with unique features. Grp/Neurod6 dopamine neurons reside in the ventromedial VTA, send projections to the medial shell of the nucleus accumbens, and have noncanonical physiological properties. Grp/Neurod6- DA neurons are found in the VTA as well as in the ventromedial portion of the SNc, where they project selectively to the dorsomedial striatum. Grp-/Neurod6 DA neurons represent a smaller VTA subpopulation, which is preferentially spared in a 6-OHDA model of Parkinson’s disease. Together, our work provides detailed characterization of Neurod6 and Grp expression in the midbrain and generates new insights into how these markers define functionally relevant dopaminergic subpopulations with distinct projection patterns, physiology, and disease vulnerability.
2018-05-31 | GSE115070 | GEO