Estradiol receptors inhibit long-term potentiation in the dorsomedial striatum.

Estradiol, a female sex hormone and the predominant form of estrogen, has diverse effects throughout the brain including in learning and memory. Estradiol modulates several types of learning that depend on the dorsomedial striatum (DMS), a subregion of the basal ganglia involved in goal-directed learning, cued action-selection, and motor skills. A cellular basis of learning is synaptic plasticity, and the presence of extranuclear estradiol receptors ERα, ERβ, and G protein-coupled estrogen receptor (GPER) throughout the DMS suggests that estradiol may influence rapid cellular actions including those involved in plasticity. To test whether estradiol affects synaptic plasticity in the DMS, corticostriatal long-term potentiation (LTP) was induced using theta-burst stimulation in ex vivo brain slices from intact male and female C57BL/6 mice. Extracellular field recordings showed that female mice in the diestrus stage of the estrous cycle exhibited LTP similar to male mice, while female mice in estrus did not exhibit LTP. Furthermore, antagonists of ERα or GPER rescued LTP in estrus females and agonists of ERα or GPER reduced LTP in diestrus females. In males, activating ERα but not GPER reduced LTP. These results uncover an inhibitory action of estradiol receptors on cellular learning in the DMS and suggest a cellular mechanism underlying the impairment in certain types of DMS-based learning observed in the presence of high estradiol. Due to the dorsal striatum's role in drug addiction, these findings may provide a mechanism underlying an estradiol-mediated progression from goal-directed to habitual drug use. Significance Statement This study examined the role of the female reproductive cycle and female sex hormones in synaptic plasticity, a cellular process that underlies learning behavior, in a brain region involved in goal-directed learning. Synaptic plasticity was similar between male mice and female mice in the low estradiol phase of the cycle. In contrast, female mice in a high estradiol phase of the cycle did not exhibit synaptic plasticity. The effect of estradiol was mediated by two of the three estradiol receptors found in the brain. The results have implications for the role of the female reproductive cycle in the development of drug addiction, which involves a progression from goal-directed learning to habit-based learning as drug use switches from recreational to compulsive.