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An Elongin-Cullin-SOCS-box Complex Regulates Stress-induced Serotonergic Neuromodulation Stress-induced Serotonergic Neuromodulation

ABSTRACT: Neuromodulatory cells transduce environmental information into long lasting behavioral responses. However, the mechanisms governing how defined neuronal cell types influence behavioral plasticity are difficult to characterize. Here we adapted the Translating Ribosome Affinity Purification (TRAP) approach in C. elegans to profile ribosome-associated mRNAs from three major tissues and the neuromodulatory dopaminergic and serotonergic cells. We identified elc-2, an Elongin C ortholog, specifically expressed in stress-sensing ADF serotonergic sensory neurons, and found that it plays a role in mediating long-lasting change in serotonin-dependent feeding behavior induced by heat stress. We demonstrate that ELC-2 and the von Hippel-Lindau protein VHL-1, components of an Elongin-Cullin-SOCS-box (ECS) E3 ubiquitin ligase, modulate this behavior after experiencing stress. Also, heat stress induces a transient redistribution of ELC-2, becoming more nuclearly enriched. Together, our results demonstrate dynamic regulation of an E3 ligase, and a role for an ECS complex in neuromodulation and control of lasting behavioral states.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE106374 | GEO | 2017/11/01

SECONDARY ACCESSION(S): PRJNA416495

REPOSITORIES: GEO

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An Elongin-Cullin-SOCS-box Complex Regulates Stress-induced Serotonergic Neuromodulation Stress-induced Serotonergic Neuromodulation

Project description:An Elongin-Cullin-SOCS-box Complex Regulates Stress-induced Serotonergic Neuromodulation Stress-induced Serotonergic Neuromodulation

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Project description:Performed RNA-seq analysis of animals with xbp-1s overexpression (ER stress response transcription factor) in specific neuron types: pan-neuronal, serotonergic neuron, dopaminergic neuron, and both serotonergic and dopaminergic neurons, all compared to a wild-type control. RNA-seq was performed on purified RNA extracted from ~1000 whole worms using a proprietary Genewiz protocol described briefly in the manuscript. 3 biological replicates are provided for each sample.

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Dopamine D2L Receptor Deficiency Causes Stress Vulnerability through 5-HT1A Receptor Dysfunction in Serotonergic Neurons

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.

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Transcriptional profiling of human serotonergic neurons in vitro

Project description:Human serotonergic neurons are derived using published transdifferentiation protocols. Human Fibroblasts correspond to human fibroblasts (from Line#1, Coriell bought (AG08498)). Samples labeled human neurons or induced neurons (iN) correspond to neurons transdifferentiated from fibroblasts using two transcription factors, as previously described (#1-AG08498 or #2:ERF-1, Erlangen Germany, a line given to us by collaborators) into primarily glutamatergic neruons. Samples labled 5-HT neurons or serotonergic neurons or iSN correspond to serotonergic neurons derived from the stated fibroblast lines, using an additional four transcription factors. For transdifferentiation of iN and iSN, fibroblasts were made to overexpress the stated transcription factors in a doxycycline inducible manner for up to 3 weeks, and then neurons are sorted out and collected directly into Trizol for RNA preparation and sequencing. The non-transdifferentiated fibroblast lines were collected in bulk withtout differentiation into neurons. The line number corresponds to the same fibroblast line either being transdifferentiated into iN or iSN, as labeled - for direct and groupwise comparison.

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Project description:The goals of this study are to generate and study serotonergic neurons from MDD patients that are selective serotonin reuptake inhibitor (SSRI) remitters and SSRI-nonremitters (NR).

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The Disruption of Celf6, a Gene Identified by Translational Profiling of Serotonergic Neurons, Results in Autism-Related Behaviors

Project description:The immense molecular diversity of neurons challenges our ability to deconvolve the relationship between the genetic and the cellular underpinnings of neuropsychiatric disorders. We suspected that comprehensive approaches to parsing this complexity may inform human genetics studies. The serotonergic system has long been suspected in disorders that involve repetitive behaviors and resistance to change, including autism. We generated a bacTRAP mouse line to permit the in vivo profiling of all ongoing translation in serotonergic neurons. From this, we identified 174 serotonergic-cell enriched and specific genes, including all known markers of these cells. Analysis of common variants in these genes in human families with autism implicated two genes, C1QTNF2 and the RNA-binding protein CELF6. This work provides a reproducible and accurate method to assess the translational profiles of serotonergic neurons under a variety of conditions in vivo, and suggests cell-specific information may provide some insight into the genetic etiology of complex psychiatric disorders For each cell population, three independent TRAP replicates were collected, and total RNA from both the immunoprecipitate and unbound fractions were seperately amplified and hybridized. For each tissue, several representative unnbound fractions are provided to serve as controls. Biological replicates are GCRMA normalized within groups. Following averaging of replicates, we recommend further global normalization between groups, using affymetrix biotinylated controls, to correct for any broad biases in scanning and hybridization. Finally for many analyses, we also recommend filtering to remove those probesets with low IP/UB fold change values from each cell type(see PMID:20962086). Researchers can contact us for spreadsheets where these additional steps have been completed.

2012-12-31 | E-GEOD-36068 | biostudies-arrayexpress

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