Estrogenic control of reward prediction errors and reinforcement learning

Gonadal hormones act throughout the brain1, and neuropsychiatric disorders vary in symptom severity over the reproductive cycle, pregnancy, and perimenopause2-4. Yet how hormones influence cognitive processes is unclear. Exogenous 17{beta}-estradiol modulates dopamine signaling in the nucleus accumbens core (NAcc)5,6, which instantiates reward prediction errors (RPEs) for reinforcement learning7-16. Here we show that endogenous 17{beta}-estradiol enhances RPEs and sensitivity to previous rewards by reducing dopamine reuptake proteins in the NAcc. Rats performed a task with different reward states; they adjusted how quickly they initiated trials across states, balancing effort against expected rewards. NAcc dopamine reflected RPEs that predicted and causally influenced initiation times. Elevated endogenous 17{beta}-estradiol increased sensitivity to reward states by enhancing dopaminergic RPEs in the NAcc. Proteomics revealed reduced dopamine transporter expression. Finally, knockdown of midbrain estrogen receptors suppressed reinforcement learning. 17{beta}-estradiol therefore controls RPEs via dopamine reuptake, mechanistically revealing how hormones influence neural dynamics for motivation and learning.