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.