Estrogen in reward prediction and reinforcement learning

Figure 1: Rats’ trial initiation times are modulated by the value of the state and estrous stage (panels a-e)

Complex cognitive tasks, such as value-based decision-making, can be influenced by sex and by sex steroids, but surprisingly little is known about the nature of these influences or how they happen. This is due, at least in part, to the fact that decades of research looked only at male subjects. In addition, however, there are formidable challenges facing experimenters who aim to explore the effects of sex steroids (such as estrogens) in the brain and behavior. In the case of 17β-estradiol (the most abundant estrogen in humans), one challenge is the low level of expression and the fact that synthesis and release of the hormone in the brain is largely unstudied. But it gets worse; consider these hurdles described in the introduction of an excellent new paper in Nature Neuroscience:

To relate physiological fluctuations of 17β-estradiol to behavior and neural dynamics, we measured behavior and dopamine release in the NAcc over the reproductive cycle and suppressed 17β-estradiol’s function in the midbrain by knocking down estrogen receptors. Challenges of this approach include the fact that certain reproductive stages are only expressed briefly (for example, proestrus lasts for 12 h once every 4–5 days), rats enter reproductive senescence unpredictably, and the likelihood of senescence increases with age, which becomes limiting for complex tasks with long training times.

How did the authors overcome these obstacles?

We overcame these challenges using a brute-force high-throughput behavioral training approach to train hundreds of rats on a rich decision-making task.

Brute force! That’s some strong direct scientific writing. The paper is a great read: clear new insight about estrogen’s role(s) in cognitive function, and an inspiring tour de force of experimental work.

Estrogen modulates reward prediction errors and reinforcement learning
In Nature Neuroscience, 11 November 2025
From the group of Christine Constantinople at NYU

Snippet by Stephen Matheson

Image credit: Figure 1a-1e from Golden et al. cited above (CC BY-NC-ND)

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