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Impact of electronic nicotine vapor on mouse mesolimbic CRFR1 circuitry and motivated behavior

电子尼古丁蒸气对小鼠中脑边缘 CRFR1 电路和动机行为的影响

基本信息

批准号：
10151988
负责人：
ManHua Zhu
金额：
$ 3.93万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10151988
关键词：
Acute Adolescent Affect Animals Anxiety Behavior Binding Brain CRF receptor type 1 Chronic Cigarette Corticotropin-Releasing Hormone Data Development Dopamine Electronic cigarette Electrophysiology (science)Exposure to Female Foundations Glutamates Green Fluorescent Proteins Immunohistochemistry In Situ Hybridization Lead Measures Membrane Mus Neuronal Plasticity Neurons Neuropeptides Nicotine Nicotine Dependence Nucleus Accumbens Oral Pathway interactions Peripheral Pharmaceutical Preparations Play Policies Population Property Regulation Reinforcement Schedule Rewards Rodent Role Self Administration Serum Signal Transduction Slice Stress System Testing Transgenic Mice Ventral Tegmental Area Viral addiction brain behavior cell type cellular targeting combustible cigarette dopaminergic neuron experimental study male motivated behavior mouse model neuromechanism nicotine use nicotine vapor promoter reward circuitry targeted treatment transmission process vaping vapor

项目摘要

PROJECT SUMMARY/ABSTRACT Nicotine is a highly addictive substance found in cigarettes as well as in electronic nicotine vapor products. More recently, nicotine delivered through electronic vapor systems have grown in popularity, especially in the adolescent population. Although these products are often marketed as safer alternatives, the effects of electronically delivered nicotine vapor exposure on the brain and behavior, remain understudied. Nicotine activates the brain reward pathway which mainly consists of dopaminergic neurons in the ventral tegmental area (VTA) that sends projections and release dopamine (DA) into the nucleus accumbens (NAc). The VTA is a heterogenous neuron population, including dopaminergic, glutamatergic, and GABAergic neurons that can interact to differentially modulate reward signaling. Nicotine also plays an important role in modulating stress and anxiety behaviors which in turn can exacerbate nicotine addiction. A principal component of central and peripheral stress regulation is the corticotropin-releasing factor (CRF) system. The CRF neuropeptide binds primarily to corticotropin-releasing factor 1 receptors (CRFR1) in the brain which are expressed in VTA neurons. However, the role of VTA CRFR1 neurons in the reward pathway and the impact of nicotine vapor exposure on reward signaling, remain unclear. To investigate the VTA CRFR1 population and its role in nicotine effects on the reward pathway, I will use a transgenic mouse model expressing green fluorescent protein under the CRFR1 promoter (CRFR1-GFP). I will characterize the cell types, projections, electrophysiological properties, and sensitivity to cellular nicotine application of VTA CRFR1 neurons to establish foundational information in naïve male and female animals (Aim 1). Using a rodent electronic nicotine vapor system, I will expose male and female mice acutely and chronically to nicotine vapor and examine the changes in neuronal activity and electrophysiological properties of VTA CRFR1 neurons (Aim 2). Additionally, I will examine motivated behavior using self-administration of electronic nicotine vapor in different reward conditions (increasing effort or decreasing reward value, Aim3). My overarching hypothesis is that CRFR1 neurons in the VTA are involved in the mesolimbic reward circuitry and that exposure to chronic electronic nicotine vapor will alter basal electrophysiological properties and sensitivity to cellular nicotine, leading to maladaptive behaviors. Together, the proposed experiments will reveal how acute and chronic electronic nicotine vapor exposure can alter a stress-sensitive component of the mesolimbic reward circuit and contribute to maladaptive behaviors like drug self-administration. Understanding the mechanisms that integrate stress and reward in the context of nicotine addiction can better inform policies that regulate the availability of nicotine vapor products and potentially identify cellular targets for therapeutics.

项目总结/文摘