Estradiol promotes habituation learning via an unidentified target, bypassing the suppressive effects of established Estrogen Receptors

Abstract

Habituating to the constant stimuli in the environment is a critical learning process conserved across species. We use a larval zebrafish visual response to sudden darkness as a model for studying habituation learning, where zebrafish reduce their responses to repeated stimulations. In this paradigm, treatment with estradiol strongly increases learning rate, resulting in more strongly suppressed responses. We used mutant lines for the Estrogen Receptors (esr1, esr2a, esr2b, gper1) in an attempt to identify the receptor(s) mediating these effects. These experiments failed to identify a necessary receptor (or combination of receptors). Surprisingly, esr1, esr2a, and gper1 mutants showed weak but consistent increases in habituation, indicating these receptors suppress habituation learning. These experiments demonstrate that estradiol is a complex modulator of learning in our model, where the learning-promoting effects are mediated by an unidentified estradiol target, and the classical Estrogen Receptors act in competition to subtly suppress learning.