Estrogenic control of reward prediction errors and reinforcement learning

Golden, C. E. M.; Kaur, D.; Mah, A.; Martin, A. C.; Levy, D. H.; Yamaguchi, T.; Lin, D.; Aoki, C.; Constantinople, C. M.

doi:10.1101/2023.12.09.570945

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bioRxiv · 10.1101/2023.12.09.570945

Estrogenic control of reward prediction errors and reinforcement learning

Golden, C. E. M.·Kaur, D.·Mah, A.·Martin, A. C.·Levy, D. H.·Yamaguchi, T.·Lin, D.·Aoki, C.·Constantinople, C. M.

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Abstract

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.

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Golden, C. E. M., Kaur, D., Mah, A., Martin, A. C., Levy, D. H., Yamaguchi, T., Lin, D., Aoki, C., Constantinople, C. M.. 2023-12-10. Estrogenic control of reward prediction errors and reinforcement learning. https://doi.org/10.1101/2023.12.09.570945

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