Habenular Tcf7l2 links nicotine addiction to diabetes.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE140142 | GEO | 2019/11/09
REPOSITORIES: GEO
Similar Datasets
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:Habenular Tcf7l2 links nicotine addiction to diabetes.
| PRJNA588418 | ENA
Project description:Habenular Tcf7l2 links nicotine addiction to diabetes
| PRJNA564583 | ENA
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:Diabetes is far more prevalent in smokers than non-smokers, but the underlying mechanisms of vulnerability are unknown. Here we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb) region of the rodent brain, where it regulates the function of nicotinic acetylcholine receptors. Inhibition of TCF7L2 signalling in the mHb increases nicotine intake in mice and rats. Nicotine increases levels of blood glucose by TCF7L2-dependent stimulation of the mHb. Virus-tracing experiments identify a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show increased circulating levels of glucagon and insulin, and diabetes-like dysregulation of blood glucose homeostasis. By contrast, mutant Tcf7l2 rats are resistant to these actions of nicotine. Our findings suggest that TCF7L2 regulates the stimulatory actions of nicotine on a habenula-pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions.
| S-EPMC9851388 | biostudies-literature
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 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: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.
2013-12-30 | GSE43164 | 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: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