Prepubertal ovariectomy alters dorsomedial striatum indirect pathway neuron excitability and explore/exploit balance in female mice

Decision-making circuits are modulated across life stages (e.g. juvenile, adolescent, or adult)—as well as on the shorter timescale of reproductive cycles in females—to meet changing environmental and physiological demands. Ovarian hormone signaling may contribute to this flexibility by regulating neural circuits involved in adaptive decision making. Here, we examined how prepubertal ovariectomy (pOVX) influences adult performance in an odor-guided multiple-choice reversal task. During reversal learning, pOVX females exhibited a distinct pattern of errors compared to sham-operated controls. Reinforcement learning models fit to trial-by-trial behavior showed that the inverse temperature parameter (β) increased during Reversal in sham females, consistent with a shift toward a more exploitative choice policy favoring high-value options. In contrast, pOVX females did not show this phase-dependent increase, suggesting continued use of a more exploratory strategy. To identify a neural correlate, we performed whole-cell patch clamp recordings within the dorsomedial striatum (DMS), a region implicated in regulating action selection and explore/exploit choice policy. Dopamine receptor type 2-expressing (D2R) indirect pathway spiny projection neurons (iSPNs) were significantly more intrinsically excitable in pOVX females compared to sham-operated and unmanipulated controls. Finally, we tested whether increasing D2R(+) iSPN excitability was sufficient to produce a similar choice-policy phenotype. In intact female mice, chemogenetic activation increased exploratory choice during reversal learning, resembling the pattern observed following pOVX. Together, these data show that pOVX is associated with long-lasting changes in DMS iSPN intrinsic excitability and reversal-phase choice policy, while experimentally increasing DMS iSPN activity is sufficient to produce a similar behavioral pattern.