Attentional deficits are defining hallmarks of some of the most prevalent and disruptive neuropsychiatric disorders—including attention deficit hyperactivity disorder (ADHD) and substance abuse disorders. The anterior cingulate cortex (ACC) is a brain region that is highly implicated in shifting attention allocation towards relevant stimuli after unexpected events or outcomes occur. Importantly, increases in attention facilitate flexible learning, as attention allows you to dynamically filter relevant and necessary information during decision-making. My dissertation work seeks to identify the ACC as a novel point of intervention for the treatment of neuropsychiatric and addiction disorders by providing an in-depth perspective on its involvement in cognitive control and attentional processes.My research explores the neural correlates of decision-making by using electrophysiology to record single unit activity while rats perform a complex reward-based decision-making task, and employing chemical, optogenetic, and epigenetic manipulations to modulate attentional correlates in the ACC. I explored the ACC’s role in attention—and how it is impacted by drug use—using electrophysiology to record from ACC neurons as both cocaine-exposed and drug-naïve rats performed a reward-guided decision-making task. Using this task, we found a dose-dependent attenuation of ACC signaling after cocaine self-administration, which was correlated with decreases in task performance and attention to the task. Rats that had self-administered large amounts of cocaine had diminished neural responsiveness to cues, which translated into reductions in behavioral measures of attention, disruptions in cognitive flexibility, and decision-making impairments. These results both supported previous findings establishing the ACC’s role in attentional allocation, and revealed an intake-dependent effect of drugs on decision-making and neural encoding. In aim 2, we wanted to be able to precisely modulate ACC activity in order to better interrogate the role of the ACC in the absence of confounding variables (e.g. cocaine use results in the dysregulation of various neural circuits), and conduct within-subject analyses. Thus, in our next experiment we used optogenetics to inactivate the ACC, and found that ACC inhibition severely impaired task engagement, as evinced by reductions in trial initiations, and trial and session completions—resulting in overall impaired session performance. In order to disambiguate whether these behavioral deficits resulted from ACC impairment dysregulating downstream action-outcome encoding, we performed chemical lesions of the ACC, and recorded neural activity from the dorsomedial striatum (DMS)—a downstream brain region that is importantly involved in goal-directed behavior—as rats performed the previously mentioned decision-making task. Again, we found that ACC lesions resulted in disrupted attention to the task, and similar behavioral deficits to the ones we observed following cocaine use. Interestingly, we found that DMS encoding was minimally impacted, reinforcing that the observed decision-making deficits stem from disruptions in attentional signaling and not dysregulations in downstream action-outcome encoding. In the aforementioned experiments, we employed an array of techniques to dissect how disrupting ACC signaling in a variety of manners impacted task performance and engagement, so for our final experiment we sought to explore a therapeutically relevant way to potentially repair signaling disruptions that lead to the breakdown in attentional signaling. Thus, we turned to epigenetics—specifically, decreasing the expression of HDAC5, an enzyme that is involved in negatively regulating gene expression—to explore whether epigenetic changes might map onto specific alterations of neural activity and behavior. Surprisingly, we found that HDAC5 knockdown in the ACC dysregulates attentional signals that are necessary for flexible and adaptive decision-making. Together, these studies established that signaling in the functional ACC is importantly involved in attention, and that dampening these signals leads to decision-making impairments and decreased task engagement, notably characterized by significant reductions in the proportion of initiated and completed trials, and prolonged periods of inattention.