Considerations of the estrous cycle and female gonadal hormones in reward learning and memory

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2021-07-27

Authors

Hilz, Emily N.

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Abstract

Reward learning informs adaptive behaviors that allow us to advantageously engage with our environment; however, this learning can become maladaptive in some individuals and result in disordered behaviors like compulsive eating or drug-dependency. While the behavioral and neural substrates of reward learning are well established in males, much less attention has been given to these same systems in females. As females are at increased risk of disordered reward-seeking and female sex steroid hormones are potent modulators of the neural circuitry that underlies reward learning, developing a thorough understanding of how female hormonal states modulate this type of learning will help inform the development of individual-specific therapeutic interventions. In this dissertation, the findings of several studies using rat models of the estrous cycle in both food- and drug-learning are presented. Two aspects of reward learning are explored: renewal of extinguished conditioned food-seeking behavior, and conditioned place preference for amphetamine (AMP). Both paradigms provide novel methodologies for considering endogenous gonadal hormone states as a modulator of female conditioned responding and explore underlying neural mechanisms. Each experiment also considers conditioned orienting behavior as a potential indicator of individual differences in reward learning and memory. The experiments outlined here (1) consider the estrous cycle in the renewal of extinguished food-seeking, (2) examine estrous cycle modulation of immediate early gene Arc mRNA activity following exposure to separate learning contexts in the renewal paradigm, (3) consider conditioned orienting as a predictor of AMP place preference in female rats and, (4) modulate the estrous cycle with hormonal contraceptives to observe subsequent AMP place preference and related response measures. Behaviorally, a consistent result was found wherein the stage of the estrous cycle associated with high endogenous sex steroid hormone levels (i.e., proestrus or P) stimulated female conditioned responding (either increasing the likelihood of renewed food-seeking or contributing to increased drug preference and hedonic drug responsivity). Functionally, P modulated activity in the brain either in dopamine cells or in downstream targets such as the hippocampus and prefrontal cortex. These effects depended on the specific learning windows when cycle-stage was considered. From this research it is apparent that the hormonal state of the female learner contributes to behavioral outcomes.

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