Cyclic estrogen and progesterone during instrumental acquisition contributes to habit formation in female rats

Habit formation is thought to involve two parallel processes that are mediated by distinct neural substates: one that suppresses goal-directed behavior, and one that facilitates stimulus-response (S-R) learning, which underscores habitual behavior. In previous studies we showed that habitual responding emerges early during instrumental training in gonadally-intact female, compared to male, rats. The present study aimed to determine the role of ovarian hormones during instrumental acquisition in the transition from goal-directed to habitual behavior in female rats. Ovariectomized (OVX) female rats were given subcutaneous silastic capsules that released low levels of 17-β estradiol (E2) to maintain estrogen receptor availability. Rats were assigned to one of three hormone treatment conditions: no additional hormone replacement (Control group), replacement with high E2 (High E2 group), or replacement with high E2 followed by progesterone (High E2 + P4 group). Hormone replacement occurred twice during acquisition to mimic natural hormone fluctuations. At test, the Control and High E2 groups demonstrated responding that was sensitive to devaluation by lithium chloride-induced illness, indicating goal-directed behavior. In contrast, the High E2 + P4 group exhibited a pattern of devaluation-insensitive, habitual responding, that suggested the suppression of goal-directed processes. In a follow-up experiment, similar procedures were conducted, however during acquisition, OVX rats were given cyclic high E2 plus medroxy-progesterone (MPA), a form of progesterone that does not metabolize to neuroactive metabolites. In this group, goal-directed behavior was observed. These data indicate that habit formation is not facilitated in low estrogen states, nor in the presence of cyclic high E2. However, cyclic high E2, together with progesterone during acquisition, appears to facilitate the early emergence of habitual responding. Furthermore, these data suggest that a neuroactive progesterone metabolite, like allopregnanolone, in combination with high cyclic E2, supports this phenomenon.