Effort is a cost that must be overcome to procure rewards, and organisms frequently make cost benefit decisions based on effort in choosing which options to pursue. The majority of previous work probing the neural mechanisms of effort-based choice has focused on the striatum and dopaminergic signaling therein, and less work has investigated behavioral or environmental factors that contribute. In all of the following experiments, an effort-based choice task was adopted from previous findings where rats could freely choose between a high effort, preferred option and a low effort, less preferred option. The high effort option was lever progressing on a progressive ratio schedule for sucrose pellets in which each successive reward became more difficult to earn. The low effort option was freely available lab chow concurrently available that had no work requirement, but was less palatable. Thus, rats could freely choose between these options and self- titrate the amount of effort they were willing to exert. A number of control tasks were used to control for changes in motoric ability, appetite, or food preference. By omitting the freely available lab chow and testing subjects for progressive ratio performance, any impairment in motoric ability, memory, and general willingness to exert effort, rather than cost-benefit valuation per se, could be ruled out. To test whether manipulations had effects on appetite or food preference, rats were tested with both food options freely concurrently available where they did not have to work for either. In the case of manipulations that took place prior to behavioral testing, we recorded the number of sessions it took to reach stable performance to rule out impairments in learning.

In the second chapter of this dissertation, the basolateral amygdala (BLA) was tested for its effects in effort-based choice. In a series of experiments, we found that BLA pharmacological inactivations reduced high effort lever pressing specifically in the context of choice, without impairing progressive ration responding when it was the only option. These effects were also not due to changes in appetite or food preference. Chapter three details effects of anterior cingulate cortex (ACC) lesions. Much like BLA inactivations, lesions of ACC decreased choice lever pressing without affecting lever pressing ability, appetite, or food preference. In chapter four, we tested whether a behavioral manipulation, withdrawal from methamphetamine self-administration, had effects on effort based choice. Methamphetamine withdrawn animals exhibited decreased choice lever pressing, which was not due to general work aversion, learning impairments, changes in appetite, or changes in food preference. This decreased effort was accompanied by decreased activation of anterior cingulate, ventral striatum, and amygdala. In the last set of experiments, we replicated results from the ACC lesion experiments using a modern chemogenetic approach. Finally, all of the above findings are discussed with their relevance to future studies and broader implications of the basic science of effort.

We are surrounded by salient cues and actions in our everyday lives that predict reward in a constantly changing environment. A critical feature of goal-directed behavior is the ability to discriminate stimuli or actions that predict reward from those that do not, and further, to flexibly update our responses if predictions become inaccurate. This is referred to as behavioral flexibility, which measures our ability to re-evaluate previously learned associations that predicted reward and adjust our current responses following changes in the environment. Impairments in behavioral flexibility can lead to maladaptive behavior and impairments in decision-making, and is often associated with many neuropsychiatric disorders. The research presented here investigated the behavioral and neural basis of flexible learning under uncertainty by manipulating the associations and probability of reward outcomes in the environment, following alcohol experience and chemogenetic inhibition. Altogether, this approach establishes a causal link between brain and behavior and increases our understanding of both adaptive and maladaptive decision-making. We first tested the effect of prior alcohol exposure on flexible learning using a probabilistic, stimulus-based reversal learning task. Sex differences in alcohol consumption emerged, with females exhibiting heavier alcohol consumptions patterns than males. Furthermore, all alcohol-exposed animals, regardless of sex, were slower to learn, exhibited attentional deficits, and were less sensitive to negative feedback, compared to water-matched controls. Next, we compared the performance of rats on stimulus-based reversal learning in a rich (90/30) and poor (70/30) reward environment. All rats exhibited increased preservation during early reversal learning, resulting in slower learning. Additionally, a sex-dependent effect emerged on latencies to choose the better option, with females exhibiting longer latencies than males during reversal learning, an indication of slower processing speed. And finally, chemogenetic techniques were used to inhibit pyramidal neurons in the ventrolateral orbitofrontal cortex (vlOFC) and basolateral amygdala (BLA), on both a stimulus- and action-based reversal paradigm. Overall, the BLA seemed to be more necessary for learning action-based probabilistic reversals, as inhibition of this region resulted in poorer learning; whereas, the OFC was more necessary for detection of stimulus-based reversals. There was also evidence of sex-modulated learning flexibility, such that females with vlOFC inhibition were slower to learn during both deterministic and probabilistic action-based reversals compared to non-inhibited females; whereas, females with BLA inhibition were more impaired on probabilistic action-based reversals than non-inhibited females, this pattern was not observed in males. Altogether, these findings highlight the importance of including sex as a biological variable, as all of these studies found sex-dependent effects.