Nicotine & Nodose: A Neural Basis for Peripheral Control over Nicotine Intake
Nicotine & Nodose: A Neural Basis for Peripheral Control over Nicotine Intake
批准号:
10671471
负责人:
Kevin Braunscheidel
金额:
$6.95万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-07-06 至 2025-07-05
关键词:
4-Hydroxy-TamoxifenAblationAfferent NeuronsAgonistApplications GrantsBehaviorBioinformaticsBiological ProcessBrainBrain regionBreedingC57BL/6 MouseCRISPR/Cas technologyCardiovascular DiseasesCathetersCessation of lifeCholecystokininCholecystokinin ReceptorCigarette SmokerClustered Regularly Interspaced Short Palindromic RepeatsCommunicationConsummatory BehaviorDataDevelopmentDisabled PersonsDissectionDoseElectric StimulationEmerging TechnologiesEsthesiaFiberFoodGangliaGastrointestinal DiseasesGenesGeneticGenetic TranscriptionGenomicsHabenulaHabitsHealthcareHeartHumanImmune System DiseasesImplantInfusion proceduresInhalationInjectionsIntakeIntravenousInvestigationLaboratoriesLearningLesionLife StyleLiteratureLungMaintenanceMasticationMedialMediatingMentorsMorbidity - disease rateMotivationMusNeuronsNicotineNicotine DependenceNicotinic AgonistsNicotinic ReceptorsNodose GanglionNucleus solitariusOperative Surgical ProceduresOrganPatternPeptidesPeripheralPharmaceutical PreparationsPharmacologic ActionsPlasmaPlayPopulationPositioning AttributePropertyPublic HealthRecording of previous eventsRelapseResearchResearch PersonnelRespiration DisordersRewardsRiskRodentRoleSatiationSelf AdministrationSelf AssessmentSensorySignal PathwaySignal TransductionSincalideSiteSmokerSystemTechnical ExpertiseTechnologyTestingTobaccoTobacco DependenceTobacco smokeTobacco useTrainingUnited StatesUp-RegulationVagus nerve structureVirusaddictionblood-brain barrier crossingbody systemcareercigarette smokingcomputer programcostdiet and exercisedifferential expressionexperienceganglion cellgenetic approachgenome editinghindbrainin vivoinnovationinterpeduncular nucleusintravenous administrationknock-downmind body interactionmortalitymouse geneticsmouse modelmultidisciplinarynervous system disorderneuralneural circuitneuropsychiatric disordernicotine self-administrationnicotine usenovelprematurerapid growthreceptorresponsesensory inputsensory systemsingle cell sequencingsingle-cell RNA sequencingtobacco controltobacco smokerstooltransmission process
中文摘要
摘要
英文摘要
ABSTRACT
Nicotine addiction in the form of habitual tobacco use is the leading cause of premature death in the United
States and costs at least $170 billion in healthcare-related expenses each year. In addition to its addictive
qualities, nicotine triggers a plethora of respiratory, cardiovascular, gastrointestinal, and immune disorders,
reflecting its actions in not only the brain, but also in the body of smokers. While it is well established that the
addictive properties of nicotine are related to its direct pharmacological actions on nicotinic acetylcholine
receptors located in reward and motivation brain circuits, evidence from our lab suggests that noxious effects of
nicotine related to its actions on hindbrain aversion circuits (e.g. nucleus of the solitary tract (NTS),
interpeduncular nucleus, and medial habenula) play a significant role in regulating nicotine intake as well.
However, it is unclear if nicotine acts solely on these circuits by direct action on centrally expressed nicotinic
receptors or if nicotine also acts indirectly via vagally (nodose ganglia, NG) derived sensory inputs that terminate
primarily at the NTS. Preliminary data presented in this grant application strongly suggest a role for peripheral
actions of nicotine in controlling nicotine intake. For instance, the peripherally-restricted, full nicotine agonist,
methylnicotinium causes a conditioned place aversion beyond that generated by an equimolar dose of nicotine.
Further, the peripherally-restricted cholecystokinin receptor (CCKR) agonist, CCK-8 (10 µ*kg-1) decreased
volitional nicotine intake, especially at anxiogenic nicotine doses. Given these preliminary data and the
observation that plasma CCK levels are dysregulated by nicotine in rodents and humans, I hypothesize that
CCKRs in gut-innervating NG neurons potentiate aversive nicotine signals from the periphery to the NTS thereby
regulating nicotine intake. I will test this hypothesis using a nicotine intravenous self-administration mouse model
in combination with CCKR-specific lesions of the NG, FosTRAP mice, and chemogenetics. I will then define the
transcriptional responsiveness of the NG to an aversive dose of nicotine using single cell RNA sequencing.
Finally, I will employ an in vivo CRISPR-Cas9-mediated genomic cleavage strategy to knockdown prioritized
nicotine-response genes in the NG and assess the consequences on nicotine intake. Completion of this highly
innovative proposal will substantially advance my technical skills in mouse genetics, surgery, and computer
programing, and provide me with entirely new training in single cell sequencing, bioinformatics, and advanced
genome editing technologies. It will also contribute to the currently sparse literature about how sensory
information related to nicotine actions in the periphery are transmitted via the vagus to the hindbrain. Defining
such a mechanism will position me for a successful independent career in the exciting and rapidly growing field
of brain-body interactions. In summation, this training plan will provide me with the conceptual, technical, and
learning experiences that will serve as a springboard for my transition to an independent research investigator.
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批准号:9899236
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项目类别:
-
资助金额:$1.59万
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财政年份:2018
-
负责人:Kevin Braunscheidel
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依托单位:
海外基金