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

Abstract

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. To characterize decision strategies, we fit a reinforcement learning model to trial-by-trial behavior across both the initial Discrimination and Reversal phases. Sham females showed a significant increase in the inverse temperature parameter ({beta}) during Reversal, consistent with a shift towards a more exploitative choice policy favoring high-value options. By contrast, pOVX females failed to show a phase-dependent increase in {beta}, suggesting they continued to use a more exploratory strategy. To identify a neural correlate of this behavioral phenotype, we performed whole-cell patch clamp recordings within the dorsomedial striatum (DMS), a region implicated in regulating action selection and explore/exploit choice policy. Intrinsic excitability of dopamine receptor type 2-expressing (D2R) indirect pathway spiny projection neurons (iSPNs) was significantly higher in pOVX females compared to both sham-operated and unmanipulated controls. Finally, to test whether increased D2R(+) iSPN excitability could causally contribute to the exploratory reversal phenotype, we chemogenetically activated DMS D2R(+) neurons in intact female mice. This manipulation increased exploratory choice during reversal learning, recapitulating the pattern observed following pOVX. Together, these data suggest that pubertal status may influence how females adapt their decision strategy between Discrimination and Reversal phases, potentially through long-lasting modulation of DMS iSPN intrinsic excitability.