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All animals can learn that a previously neutral sensory stimulus followed by an outcome can predict that outcome. This learning, or classical conditioning, can be appetitive in nature, predicting natural positive outcomes like food, water, and sex or drug outcomes including ethanol. The learning can also be aversive, predicting negative outcomes like predators or pain. Learning the cues that predict each value of outcome is necessary so that an animal can modify its behavior to satisfy its needs, including finding food and avoiding predators which ensures survival. The prefrontal cortex (PFC) in humans, primates, and rodents is important for encoding an internal representation of associations between cues and outcomes. In the rat model, the medial prefrontal cortex (mPFC) is necessary for learning cue-outcome contingencies in both appetitive and aversive conditioning. However, when making claims that the mPFC is encoding the value of a cue, most studies ignore the mPFC’s role in movements and motivation to receive or avoid an outcome. My main goal in the first part of this dissertation was to clarify the role of the mPFC in appetitive and aversive classical conditioning and whether it encodes value, motor, or a combination of task components. Towards this end I developed two complementary paradigms that I tested concurrently. First was a passive task where cued appetitive and aversive outcomes were delivered to the rat using intraoral catheters (IOC). This eliminated the locomotor component of going to get an outcome. I compared neuronal firing during the passive task to an active task where the rat had to approach the well to receive the cued outcome. My data indicate that mPFC incorporates action parameters during appetitive and aversive cue learning together with value signals for the most relevant contextual features. Our findings demonstrate that careful consideration of all task components is essential for interpretation of value in neuronal firing. Classical conditioning is also relevant beyond natural outcomes. Applying what I learned about the fundamental features of positive and negative cues and outcomes in the first part of my dissertation, I explored cue and outcome value encoding features of ethanol in the second part of my dissertation with a focus on individual differences in ethanol preference and exposure. Neural systems implicated in ethanol use and addiction are widespread across the brain and the mPFC and orbitofrontal cortex (OFC) are particularly positioned functionally and anatomically to drive ethanol use and abuse, yet they are understudied in the context of alcohol. Even more understudied are the individual differences in rat aversion towards and appetite for ethanol or the effects of chronic exposure to ethanol on cue learning, both important potential determinants of ethanol abuse and addiction. The second goal of this dissertation was to compare across these factors of susceptibility to determine the neurobiological underpinnings that modulate ethanol cue relationships to better understand the potential for ethanol abuse. I utilized the active and passive classical conditioning paradigms to analyze motivation and reactivity for ethanol after cue. I found that all animals showed responses to ethanol in the passive task similar to appetitive stimuli regardless of duration of homecage exposure to alcohol, preference, or activity in the active task. In addition, mPFC and OFC tracked relative value of ethanol compared to sucrose, and the nature of the OFC response was dependent on chronic exposure and alcohol preference. The second part of my dissertation shows not only the feasibility of using the passive task to study ethanol cue reactivity in rats, but also highlights the important factors underlying valence of ethanol. In conclusion, this dissertation advances the literature by providing evidence of behavioral components in appetitive, aversive, and drug classical conditioning. I propose these findings and paradigms can be used to expand the understanding of valence and action across multiple brain areas towards the end of understanding the neural basis of cue encoding.
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