A hallmark of addiction is continued drug use despite often profound adverse consequences, and while the neural basis of this compulsive pattern of drug intake has not been fully elucidated, it likely involves alterations in mesocorticolimbic pathways. Recently, our lab demonstrated that the rostromedial tegmental nucleus (RMTg), a newly identified brake to midbrain dopamine (DA), is essential to suppress reward seeking when operant responding for food or cocaine is immediately punished by footshock. Further, the RMTg modulates punished reward seeking via projections to DA neurons, but it is unclear how downstream targets integrate this information. The nucleus accumbens (NAc) is a key relay for mediating the reinforcing and motivational properties of DA, and as such, poses a likely site for the encoding and expression of drug seeking under punishment. Within the NAc, two distinct neural subpopulations play opposing roles in reward and aversion, and they are identified by the presence of either dopamine D1 or D2 receptors, respectively. Given the role of D2 neurons in aversive responses and their ability to integrate DA signals, I have hypothesized that this neural subpopulation is critically involved in the ability to suppress drug use in the context of aversive consequences, and that our previous findings on the RMTg role in punished reward seeking are ultimately the result of changes in NAc microcircuit activity. To test these hypotheses, I propose to execute an innovative and multifaceted approach to track and manipulate the activity of discrete NAc subpopulations while rats are tested for the suppressive effect of footshock on cocaine self-administration. To accomplish this, I will receive additional training in the use of designer receptors exclusively activated by designer drugs (DREADDs) in transgenic D2 cre+ rats to selectively modulate NAc microcircuitry during punished cocaine-seeking (Aim1). Additionally, I will be trained in deep brain in vivo calcium imaging in rats to assess the timing and cell-type specificity of NAc neural responses to natural rewards (food) and aversive stimuli (footshock), or cues that predict these stimuli (Aim2). After securing an independent research position, I will begin the R00 phase of this award by applying the technical and conceptual training gleaned from the K99 phase to assess real-time NAc activity in behaving rats tested for the suppressive effect of footshock on cocaine seeking (Aim3). And finally, I will build upon the findings of Aim 3 to modulate NAc microcircuitry using optogenetics to recapitulate physiological neural firing patters to prevent compulsive drug seeking and restore appropriate suppression of drug use after RMTg inactivation. Together, the training and scientific advances that will be achieved through the completion of this proposal will allow me to secure a tenure track faculty position in a top research university. Further, these studies will provide critical pilot data necessary to prepare my first R01 application in which I plan to investigate the more distributed neural pathways that mediate cost-benefit decision-making and compulsive drug use.
Addiction is marked by persistent drug use despite often severe negative consequences, but the brain circuits underlying drug seeking in the face of aversive outcomes remain poorly defined. Accordingly, the current proposal incorporates a model of cocaine seeking under punishment to clarify the role of distinct neural subpopulations in the nucleus accumbens in learning from aversive consequences of drug use. Results from these studies have the potential to uncover novel mechanisms underlying the compulsive nature of addiction, and will provide a key advance to our understanding of how the nucleus accumbens integrates diverse signals to influence motivation and decision-making.
