The Genetics of Vulnerability to Nicotine Addiction
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ABSTRACT:
PROVIDER: PRJNA375839 | ENA |
REPOSITORIES: ENA
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Project description:Habenular Tcf7l2 links nicotine addiction to diabetes.
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Project description:Habenular Tcf7l2 links nicotine addiction to diabetes
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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: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: Not available
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Project description:GENEVA Study of Addiction: Genetics and Environment (SAGE)
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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