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

项目概要/摘要 尼古丁是一种高度成瘾的物质，存在于香烟和电子尼古丁蒸汽产品中。 最近，通过电子蒸汽系统递送的尼古丁越来越受欢迎，特别是在吸烟者中。 青少年人口。虽然这些产品通常作为更安全的替代品销售， 电子递送的尼古丁蒸汽暴露对大脑和行为的影响仍然研究不足。尼古丁 激活大脑奖赏通路，主要由腹侧被盖的多巴胺能神经元组成 腹侧被盖区（VTA），其发送投射并将多巴胺（DA）释放到脑桥核（NAc）中。VTA是 异源神经元群，包括多巴胺能、多巴胺能和GABA能神经元， 相互作用以差异地调节奖赏信号。尼古丁在调节压力方面也起着重要作用 和焦虑行为，这反过来又会加剧尼古丁成瘾。一个主要的组成部分， 外周应激调节是促肾上腺皮质激素释放因子（CRF）系统。CRF神经肽结合 主要与脑中的促肾上腺皮质激素释放因子1受体（CRFR 1）结合， 神经元然而，腹侧被盖区CRFR 1神经元在奖赏通路中的作用和尼古丁蒸汽的影响 奖励信号的暴露，仍然不清楚。研究VTA CRFR 1人群及其在 尼古丁对奖赏途径的影响，我将使用一个转基因小鼠模型，表达绿色荧光 CRFR 1启动子下的蛋白质（CRFR 1-GFP）。我会描述细胞类型，突起， VTA CRFR 1神经元的电生理特性和对细胞尼古丁应用的敏感性， 在幼稚雄性和雌性动物中建立基础信息（目标1）。使用啮齿类电子尼古丁 蒸汽系统，我将暴露雄性和雌性小鼠急性和慢性尼古丁蒸汽，并检查 VTA CRFR 1神经元的神经元活性和电生理特性的变化（目的2）。而且我 在不同的奖励下，将通过自我管理电子尼古丁蒸汽来检查动机行为 条件（增加努力或减少奖励值，目标3）。我的首要假设是CRFR 1 腹侧被盖区的神经元参与了中脑边缘奖赏回路， 尼古丁蒸汽将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，拟议的实验将揭示急性和慢性电子 尼古丁蒸汽暴露可以改变中脑边缘奖赏回路的应激敏感成分， 到适应不良的行为比如自我给药理解整合压力的机制 尼古丁成瘾背景下的奖励可以更好地为监管尼古丁供应的政策提供信息 蒸汽产品和潜在的识别治疗的细胞靶点。

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.