ABSTRACT A key feature of cocaine use disorder (CUD) is deficits in dopamine release in the nucleus accumbens core (NAc). These deficits in dopamine release are concomitant with disruptions in the ability to process non-drug stimuli and the severity of these deficits correlates with negative treatment outcomes in patients. Understanding how drug use leads to impaired stimulus processing is critical for both understanding and ultimately treating individuals suffering from CUD. To understand how cocaine dysregulates non-drug stimulus processing, we first need to understand how stimuli evoke dopamine release in healthy animals (Aim 1). Dopamine is often discussed as a reward or valence signal; however, recent work has clearly demonstrated that in the NAc both appetitive and aversive stimuli increase dopamine release. These dopamine increases causally control learning in response to non-drug stimuli. Thus, it is likely that dopamine in the NAc core transmits a saliency signal that notes what is important to an animal, regardless of whether the stimulus is rewarding or aversive. In the saliency framework, both appetitive and aversive stimuli would evoke dopamine release from the same axon terminals. However, while both aversive and appetitive stimuli induce dopamine release in the same brain region as measured with techniques like voltammetry, microdialysis, and fiber photometry with optical dopamine sensors, these techniques suffer from poor spatial resolution. It is thus possible that different stimuli cause dopamine release from different pools that are in the same region, but spatially distinct. In this framework, appetitive and aversive stimuli would evoke dopamine release in spatially distinct patterns. Aim 1 will utilize in vivo microendoscopic imaging of dopamine sensors to visualize spatial dopamine release in awake and behaving animals to test the hypothesis that patterns of dopamine release are spatially distinct in response to appetitive (sucrose) and aversive (quinine) stimuli. Are cocaine-induced deficits in dopamine release in the NAc core stimulus specific (Aim 2)? Regardless of whether dopamine elicits distinct spatial patterns depending on the stimulus, it is well established that cocaine exposure causes deficits in dopamine release in the NAc. It is unclear if these deficits are specific to distinct stimuli (for example, only for rewards or only for non-drug stimuli) or occur in response to all stimuli. Using in vivo dopamine sensor imaging with spatial resolution, Aim 2 will test the hypothesis that cocaine self- administration reduces dopamine release in response to appetitive and aversive stimuli to a greater extent than cocaine associated stimuli. This proposal will complement my current in vivo dopamine neuron electrophysiology expertise while providing exceptional training in in vivo imaging of dopamine biosensors and the computational toolkit necessary to analyze complex signaling patterns.