PROJECT SUMMARY While drug use is an extremely common phenomenon, the vast majority of consumption is voluntary and well controlled by the user. That is, most individuals are able to initiate and end intoxication periods with some amount of behavioral control over those drug taking episodes without a compulsion to seek out and escalate further drug use. However, for a small portion of the population, this loss of behavioral control over drug seek can result in substance use disorder (SUD) and addiction. Animal models of drug abuse overwhelmingly use adult onset drug taking as a starting point in their investigations, which fails to account for the great majority of developmental changes that occur in the brain during early life and adolescence. As such, we propose here that a translational model of human SUD should incorporate important elements of development to understand how individuals may become particularly susceptible to dysregulated drug use that is no longer under of behavioral control. We have recently shown that early life stress (limited access to quality bedding in the first post-natal week of life; “ELS”) in rat pups precipitates persistent changes in prefrontal (PFC) functions that are related to extinction of fear. Based on these observations, the current proposal extends the aims of the parent R01 by investigating whether similar ELS experience affects the ability for rats to acquire behavioral control in a stressor controllability task. Our lab has now demonstrated that neurons in the PFC show greater activation when rats are escaping shock from a controllable stressor (ES) compared to yoked animals receiving an identical (but uncontrollable) shock. Notably, animals in the IS group show significantly less phasic activity to previously-rewarding food-associated cues than ES rats after this experience, suggesting that PFC activation during ES can protect against IS-mediated decrements in motivation. Based on this and our prior work, we here propose that ELS disrupts the proper maturation of the PFC during development, and that these dysfunctions persist into adulthood. As such, we further hypothesize that animals with ELS experience will be unable to appropriately benefit from ES-related resilience, which would have critical consequences on the ability for individuals to regulate stress, drug use, and other forms of behavioral control. To accomplish this, we will assign rats to be raised either in normal conditions, or under limited bedding ELS for PND1-7, and then switched to normal housing until weaning. Rats will then learn a (pre- stress) Pavlovian Conditioned Approach (PCA) task, followed by a stressor controllability session with either ES, IS or unstressed homecage (HC) control, and then finally post-stress PCA sessions. We will record single unit neural activity and local field potentials during in prelimbic (PL) and infralimbic (IL) portions of the PFC during all three phases of the task. This will grant us unprecedented ...