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

• 批准号: 10618784
• 负责人: ManHua Zhu
• 金额: $ 2.05万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10618784
• 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; Electronics; Electrophysiology (science); Exposure to; Female; Glutamates; Green Fluorescent Proteins; Immunohistochemistry; In Situ Hybridization; Intravenous; Marketing; Measures; Membrane; Mus; Neuronal Plasticity; Neurons; Neuropeptides; Nicotine; Nicotine Dependence; Nose; 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; cell type; cellular targeting; combustible cigarette; dopaminergic neuron; experimental study; maladaptive behavior; male; motivated behavior; mouse model; neuromechanism; nicotine self-administration; nicotine use; nicotine vapor; promoter; reward circuitry; targeted treatment; transmission process; vaping; vapor

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.

项目摘要/摘要 尼古丁是一种高度上瘾的物质，存在于香烟和电子尼古丁蒸气产品中。 最近，通过电子蒸气系统输送的尼古丁越来越受欢迎，特别是在 青少年人口。尽管这些产品经常被宣传为更安全的替代品，但 电子传递的尼古丁蒸气暴露对大脑和行为的影响仍未得到充分研究。尼古丁 激活大脑奖赏通路，该通路主要由腹侧被盖的多巴胺能神经元组成 向伏隔核(NAC)发送投射和释放多巴胺(DA)的区域(VTA)。VTA是 异质神经元群体，包括多巴胺能、谷氨酸能和GABA能神经元 相互作用，以不同的方式调制奖励信号。尼古丁在调节压力方面也起着重要作用。 以及焦虑行为，这反过来又会加剧尼古丁成瘾。中央和中央的一个主成分 外周应激调节是促肾上腺皮质激素释放因子(CRF)系统。促肾上腺皮质激素释放因子神经肽结合 主要与VTA中表达的脑内促肾上腺皮质激素释放因子1受体(CRFR1)有关 神经元。然而，VTA CRFR1神经元在奖赏通路中的作用和尼古丁蒸气的影响 关于奖励信号的暴露，目前仍不清楚。目的：研究VTA CRFR1人群及其在发病中的作用 尼古丁对奖赏途径的影响，我将使用表达绿色荧光的转基因小鼠模型 CRFR1启动子下的蛋白(CRFR1-GFP)。我会描述细胞的类型，投射， VTA CRFR1神经元的电生理特性及其对细胞尼古丁应用的敏感性 在幼稚的雄性和雌性动物中建立基础信息(目标1)。使用啮齿动物电子尼古丁 蒸汽系统，我将使雄性和雌性小鼠急性和长期暴露于尼古丁蒸汽中，并检查 VTA CRFR1神经元的神经元活动和电生理特性的变化(目标2)。此外，我 将在不同的奖励中使用电子尼古丁蒸气的自我管理来检查动机行为 条件(增加努力或减少奖励价值，Aim3)。我的主要假设是CRFR1 VTA中的神经元参与了中脑边缘奖赏回路和慢性电子暴露 尼古丁蒸气会改变基本的电生理特性和对细胞尼古丁的敏感性，导致 适应不良的行为。总之，拟议中的实验将揭示急性和慢性电子 尼古丁蒸气暴露可以改变中脑边缘奖赏回路的应激敏感成分，并有助于 不适应的行为，如药物自我给药。了解整合压力的机制 而尼古丁成瘾背景下的奖励可以更好地为管理尼古丁可获得性的政策提供信息 蒸气产物，并有可能识别治疗的细胞靶点。