Integrative studies of the influence of reward on sequential control in human and nonhuman primates

项目摘要/摘要

PROJECT SUMMARY / ABSTRACT Goal-directed and habitual behaviors form the repertoire of daily actions, e.g. making a cup of coffee; however, when combined into more complex rituals or sequences of tasks, such behaviors may underlie reward-driven drug seeking and taking in addiction.! While such task sequences appear simple because they are easily performed, the necessary skills may be complex and require high-level executive function and oversight from the frontal cortex. For example, multiple subtasks to obtain drugs (e.g. obtain money and setup meeting place for exchange) must be planned and then executed (e.g. crush or inject drug) to achieve an overarching goal, which may further depend on the rewarding properties and/or context of the sequence (e.g., amount of drug or preferred drug availability). Although addiction is characterized by dysfunction within frontostriatal circuits that underlie reward-driven behavior, it is unknown whether there is relationship between reward and sequential task control, and whether deficits in reward-driven sequential control may drive addiction. We will establish a cross-species model of the influence of reward on sequential task control, creating a foundation for future studies to develop novel therapies for addictive behaviors. The overarching goal of the proposed training is to utilize integrative human and awake-behaving macaque monkey fMRI in parallel. This research plan will characterize the neural underpinnings of reward and sequential task control across species. The proposed studies will establish a macaque model of complex sequential control that uniquely capitalizes on potential functional homologies between macaques and humans. Importantly, these studies will provide training in fMRI methodology and animal research experience in a model suited to study of higher order behaviors dependent upon the frontal cortex. Aim 1 will test whether reward magnitude (1a) and temporal proximity to sequence completion (1b) in human fMRI studies modulate neural correlates of sequential control. In parallel experiments, awake-behaving monkey fMRI (Aim 2) will directly apply the same sequential task used in humans from Aim 1a. Thus, Aim 2 will test functional network homology across species to determine the influence of reward on sequential behavior (2a). Further, we will test whether brain regions underlying sequential control in macaques show dynamics similar to those found in humans (2b). These studies will not only be the first to examine reward- driven sequential control, but will directly compare complex sequential task performance across both species. Together, the proposed studies will establish an animal model that will enable future studies to invasively manipulate neural circuit function in both humans and monkeys during sequential task behavior; this work will uniquely contribute to cross-species work on addiction in clinical and preclinical models. These findings will have broad applications to understanding how functioning may go awry within these circuits that subserve complex sequential behavior in disorders such as addiction and Parkinson’s disease.