Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice
Xuehong Cao, Pingwen Xu, Mario G. Oyola, Yan Xia, Xiaofeng Yan, Kenji Saito, Fang Zou, Chunmei Wang, Yongjie Yang, Antentor Hinton Jr., Chunling Yan, Hongfang Ding, Liangru Zhu, Likai Yu, Bin Yang, Yuxin Feng, Deborah J. Clegg, Sohaib Khan, Richard DiMarchi, Shaila K. Mani, Qingchun Tong, Yong Xu
Xuehong Cao, Pingwen Xu, Mario G. Oyola, Yan Xia, Xiaofeng Yan, Kenji Saito, Fang Zou, Chunmei Wang, Yongjie Yang, Antentor Hinton Jr., Chunling Yan, Hongfang Ding, Liangru Zhu, Likai Yu, Bin Yang, Yuxin Feng, Deborah J. Clegg, Sohaib Khan, Richard DiMarchi, Shaila K. Mani, Qingchun Tong, Yong Xu
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Research Article Neuroscience

Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice

Abstract

Binge eating afflicts approximately 5% of US adults, though effective treatments are limited. Here, we showed that estrogen replacement substantially suppresses binge-like eating behavior in ovariectomized female mice. Estrogen-dependent inhibition of binge-like eating was blocked in female mice specifically lacking estrogen receptor-α (ERα) in serotonin (5-HT) neurons in the dorsal raphe nuclei (DRN). Administration of a recently developed glucagon-like peptide-1–estrogen (GLP-1–estrogen) conjugate designed to deliver estrogen to GLP1 receptor–enhanced regions effectively targeted bioactive estrogens to the DRN and substantially suppressed binge-like eating in ovariectomized female mice. Administration of GLP-1 alone reduced binge-like eating, but not to the same extent as the GLP-1–estrogen conjugate. Administration of ERα-selective agonist propylpyrazole triol (PPT) to murine DRN 5-HT neurons activated these neurons in an ERα-dependent manner. PPT also inhibited a small conductance Ca2+-activated K+ (SK) current; blockade of the SK current prevented PPT-induced activation of DRN 5-HT neurons. Furthermore, local inhibition of the SK current in the DRN markedly suppressed binge-like eating in female mice. Together, our data indicate that estrogens act upon ERα to inhibit the SK current in DRN 5-HT neurons, thereby activating these neurons to suppress binge-like eating behavior and suggest ERα and/or SK current in DRN 5-HT neurons as potential targets for anti-binge therapies.

Authors

Xuehong Cao, Pingwen Xu, Mario G. Oyola, Yan Xia, Xiaofeng Yan, Kenji Saito, Fang Zou, Chunmei Wang, Yongjie Yang, Antentor Hinton Jr., Chunling Yan, Hongfang Ding, Liangru Zhu, Likai Yu, Bin Yang, Yuxin Feng, Deborah J. Clegg, Sohaib Khan, Richard DiMarchi, Shaila K. Mani, Qingchun Tong, Yong Xu

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Figure 5

An ERα agonist activates DRN 5-HT neurons.

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An ERα agonist activates DRN 5-HT neurons. (A–C) Brightfield (A), fluore...
(A–C) Brightfield (A), fluorescent with FRITC filter (B), and with FITC filter (C) illuminations of a targeted DRN 5-HT neuron. Scale bars: 10 μm. (D and E) Post hoc identification of the recorded neuron within the DRN in the fixed brain slice. Scale bars: 100 μm (D); 20 μm (E). (F–H) Representative traces before and after PPT treatment in 5-HT neurons from WT mice (F), in 5-HT neurons from KO mice (G), and in WT 5-HT neurons preincubated with 100 nM apamin for 2 hours (H). Upper panels: repetitive firing traces; values at the start of each trace are RMs. Lower panels: 3 continuous APs zoomed in from the upper-panel repetitive firing traces; values at the bottom of each trace are AHPA. (I) Cell numbers of 5-HT neurons with (responsive) or without (irresponsive) RM depolarization (> 1 mV) by PPT in various groups. ***P < 0.001. (J) Magnitude of depolarization induced by PPT in various groups. n = 9–18/group. Results are shown as mean ± SEM. **P < 0.01; ***P < 0.001. (K) Changes in firing rate induced by PPT in various groups. n = 7–18/group. Results are shown as mean ± SEM. ***P < 0.001. (L) Changes in AHPA induced by PPT in various groups. n = 7–18/group. Results are shown as mean ± SEM. ***P < 0.001.