Relapse from nicotine abstinence increases the pacemaking frequency of cholinergic habenular neurons
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE43164 | GEO | 2013/12/30
SECONDARY ACCESSION(S): PRJNA184809
REPOSITORIES: GEO
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Project description:The discovery of genetic variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster associated with heavy smoking and higher relapse risk has led to the identification of the midbrain habenula- interpeduncular axis as a critical relay circuit in the control of nicotine addiction Here we profile the cholinergic neurons of the medial habenula and identify the unique transcirptional features of this population of neurons. 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.
2013-12-30 | E-GEOD-43164 | biostudies-arrayexpress
Project description:Translational profiling of cholinergic neurons in the MHb allow identification of genes that are responsive to metabolic changes. Here we use bac TRAP to access translating mRNAs. We confirm a role for the transcription factor Tcf7l2 in the MHb in both glucose homeostasis and nicotine intake.
2019-11-09 | GSE140142 | GEO
Project description:Nicotine contained in tobacco smoke increases blood glucose levels in humans, and the risk of developing diabetes is dramatically increased in habitual smokers. Little is currently known about how nicotine increases blood glucose levels or the relevance of this action to either the persistence of the smoking habit or the pathophysiology of diabetes in smokers. Here, we show that the diabetes-associated gene Tcf7l2 is highly expressed in the medial habenula (mHb), where it regulates the function of local nicotinic acetylcholine receptors. We find that Tcf7l2 mutant (Tcf7l2mut) rats consume far greater quantities of nicotine than wild-type rats. Similarly, CRISPR-mediated cleavage of wild-type Tcf7l2 in the mHb increases nicotine intake in mice. Polysynaptic tracing identified a connection from the mHb to the pancreas, and nicotine-induced activation of the mHb elevates blood glucose. This effect is mimicked by chemogenetic stimulation of the mHb and blocked by Tcf7l2 knockdown in mHb. A history of nicotine consumption elevates circulating levels of the pancreas-derived hormones glucagon and insulin and precipitates diabetes-like dysregulation of blood glucose homeostasis in wild-type rats, whereas Tcf7l2mut rats are resistant to these actions of nicotine. Our findings suggest that Tcf7l2 regulates the stimulatory actions of nicotine on the habenula-pancreas axis, linkings the addictive properties of nicotine to its diabetes-promoting actions.
2019-09-10 | GSE137118 | GEO
Project description:The habenula, an ancient small brain area in the epithalamus, densely expresses nicotinic acetylcholine receptors and is critical for nicotine intake and aversion. As such, identification of strategies to manipulate habenular activity may yield new approaches to treat nicotine addiction. Here we show that GPR151, an orphan G protein-coupled receptor (GPCR) highly enriched in the habenula of humans and rodents is expressed at presynaptic membranes and synaptic vesicles, and associates with synaptic components controlling vesicle release and ion transport. Deletion of Gpr151 inhibits evoked neurotransmission but enhances spontaneous miniature synaptic currents and eliminates short-term plasticity induced by nicotine. We find that GPR151 couples to the G-alpha inhibitory protein Gao1 to reduce cAMP levels in mice and in GPR151 expressing cell lines that are amenable to ligand screens. Gpr151-KO mice show diminished behavioral responses to nicotine, and self-administer greater quantities of the drug, phenotypes rescued by viral re-expression of Gpr151 in the habenula. These data identify GPR151 as a critical modulator of habenular function that controls nicotine addiction vulnerability.
2020-01-18 | GSE143854 | GEO
Project description:Cholinergic Receptor Nicotinic Alpha 5 (CHRNA5), an important susceptibility locus for nicotine addiction and lung cancer, is not well studied in breast cancer. In our study, CHRNA5 was transiently depleted in MCF7 cells and transcriptomic changes were compared to siRNA controls. We for the first time showed by microarray analysis that silencing of CHRNA5 in MCF7 breast cancer cells, downregulated genes involved in the cell cycle and proliferation while resulting in reduced cell viability, DNA synthesis and G1 growth arrest. In addition, simultaneous treatment of CHRNA5 siRNA and topoisomerase inhibitors showed an important role of CHRNA5 in increased drug sensitivity. Phalloidin stained CHRNA5 siRNA treated cells on the other hand exhibited a distinct cellular morphotype with increased cellular extensions and a transcriptome characterized by mixed expression of epithelial-mesenchymal genes. Through bioinformatics analysis of the public transcriptome data we demonstrated a strong positive association of expression signature of CHRNA5 RNAi with that of a differentiated cell as well as hormone starvation. Hence, our study implicates CHRNA5 as an antiproliferative differentiation marker in breast cancer.
2018-12-16 | GSE89333 | GEO
Project description:Medial habenular (mHb) cholinergic neurons that project to the interpeduncular nucleus (IPn) regulate aversive behavioral responses to nicotine that protect against tobacco addiction. Little is known about the nicotine-evoked cellular or molecular adaptations in these neurons that influence the development of the smoking habit. Using in vivo calcium imaging and single-cell RNA sequencing, we show that a dose of nicotine that stimulates mHb neural activity evokes robust transcriptional plasticity in neuronal and non-neuronal cells in the mHb, including upregulated expression of Hedgehog-interacting protein (HHIP) in putative cholinergic neurons. Allelic variation in HHIP confers risk for smoking-related diseases including chronic obstructive pulmonary disease and lung cancer, but underlying mechanisms of action are unclear. Using Translating Ribosome Affinity Purification (TRAP) sequencing and RNAscope, we confirmed that Hhip transcripts are highly enriched in mHb cholinergic neurons. HHIP mutant mice exhibit hundreds of differentially expressed transcripts in the mHb and perturbed transcriptional responses to nicotine. Moreover, acute in vivo CRISPR/Cas9-mediated genomic cleavage of mHb Hhip attenuated noxious responses to nicotine and increased intravenous nicotine self-administration behavior in mice. In vitro knockdown of Hhip reduces intracellular calcium release to nicotine and increases Gli activity. These findings suggest that HHIP acts in the mHb to regulate nicotine intake and that HHIP alleles may increase vulnerability to smoking-related diseases by modulating mHb signaling and enhancing the addictive properties of tobacco.
2022-11-06 | GSE217000 | GEO
Project description:Translational profiling of specific populations in the MHb-IPN circuit allow identification of neurons in the relatively uncharacterized circuit. Here we use bac Cre drivers to direct expression of a Cre-iducible EGFP-tagged ribosomal protein to access translating mRNAs. We describe unique and complementary subsets of Chrna5 cells with differential response to nicotine treatment.
2019-09-11 | GSE137175 | GEO
Project description:After intarvenouse catheter surgery, nicotine self-administration using an operant self-administration chamber, was conducted for 44 days with various doses of nicotine solution. Age-matched mice were used for control. After the self-administration, the Lateral Habenual (LHb) and the Medial Habenula (MHb) of the mouse brain were collected. We used microarrays to detail the mRNA expression profile of the Lateral Habenual (LHb) and the Medial Habenula (MHb) after the nicotine self-administration.
2015-03-04 | E-GEOD-66451 | biostudies-arrayexpress
Project description:Many addictive drugs such as nicotine mediate reward and reinforcing mechanisms within the mesolimbic pathway involving midbrain dopaminergic (mDA) neurons via nicotinic acetylcholine receptors (nAChRs). Previously, genome-wide association analyses (GWAs) identified several nucleotide polymorphism (SNP) associated with increased risk of addictive phenotypes including the nonsynonymous rs16969968 SNP encoding D398->N398 variation in the CHRNA5 gene (Bierut et al., 2008; Saccone et al., 2007) . However, the etiology and the pathophysiology associated with the N398 allele is unknown. Previous animal studies using a knock-in of human CHRNA5 N398 revealed increased nicotine consumption. However, given the evolutionary distance between mice and humans, identifying intrinsic factors that affect addiction may correlate poorly, limiting the conclusiveness of these studies. In this study, induced pluripotent stem cell (iPSC) lines were derived from cryopreserved lymphocytes drawn from patients with homozygous minor alleles (N398) of rs16969968 and demonstrated nicotine addiction as well as age- and gender-matched unaffected controls carrying the major allele (D398). Cultures of primarily mDA neurons were prepared from these iPSC lines. Gene expression analysis using RT-PCR and RNAseq revealed similar expression of mRNAs encoding subunits of nAChR in mDA neurons derived from both D398 and N398 iPSC lines, however, gene ontology (GO) analysis revealed an increased enrichment of genes associated with neuroactive ligand-receptor interactions and Ca2+ signaling pathways in N398 neurons. Moreover, the N398 neuronal population responded more actively to application of nicotine in both electrophysiological analysis and Ca2+-imaging analysis. Together, these results suggest that the N398 variation affects Ca2+-signaling in neurons, which may explain the predisposition of subjects carrying this mutation for addictive behavior in subjects carrying the nonsynonymous rs16969968 SNP (Sherva et al., 2008).
2016-10-04 | GSE56398 | GEO