Morphological analysis of the axonal projections of EGFP-labeled Esr1-expressing neurons in transgenic female medaka

Abstract

Some hypothalamic neurons expressing estrogen receptor α (Esr1) are thought to transmit a gonadal estrogen feedback signal to gonadotropin releasing hormone 1 (GnRH1) neurons, which is the final common pathway for feedback regulation of reproductive functions. Moreover, estrogen-sensitive neurons are suggested to control sexual behaviors in coordination with reproduction. In mammals, hypothalamic estrogen-sensitive neurons release the peptide Kisspeptin and regulate GnRH1 neurons. However, a growing body of evidence in non-mammalian species casts doubt on the regulation of GnRH1 neurons by Kisspeptin neurons. As a first step towards understanding how estrogen regulates neuronal circuits for reproduction and sex behavior in vertebrates in general, we generated a transgenic medaka that expresses EGFP specifically in Esr1-expressing neurons (Esr1 neurons) and analyzed their axonal projections. We found that Esr1 neurons in the POA project to the GnRH1 neurons. We also demonstrated, by transcriptome and histological analyses, that these Esr1 neurons are glutamatergic and/or GABAergic, but not Kisspeptinergic. We therefore suggest that glutamatergic/GABAergic Esr1 neurons in the POA regulate GnRH1 neurons. This hypothesis is consistent with previous studies in mice that glutamatergic/GABAergic transmission is critical for estrogen-dependent changes in GnRH1 neuron firing. Thus, we propose that this neuronal circuit may provide an evolutionarily conserved mechanism for regulation of reproduction. In addition, we showed that telencephalic Esr1 neurons project to medulla, which may control sexual behavior. Moreover, we found that some POA-Esr1 neurons co-express progesterone receptors (PRs). These neurons may form the neuronal circuits that regulate reproduction and sex behavior in response to the serum estrogen/progesterone.

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