Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion

Hiroyuki Kawai; Youcef Bouchekioua; Naoya Nishitani; Kazuhei Niitani; Shoma Izumi; Hinako Morishita; Chihiro Andoh; Yuma Nagai; Masashi Koda; Masako Hagiwara; Koji Toda; Hisashi Shirakawa; Kazuki Nagayasu; Yu Ohmura; Makoto Kondo; Katsuyuki Kaneda; Mitsuhiro Yoshioka; Shuji Kaneko

doi:10.1038/s41467-022-35346-7

Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion

Hiroyuki Kawai, Youcef Bouchekioua, Naoya Nishitani, Kazuhei Niitani, Shoma Izumi, Hinako Morishita, Chihiro Andoh, Yuma Nagai, Masashi Koda, Masako Hagiwara, Koji Toda, Hisashi Shirakawa, Kazuki Nagayasu, Yu Ohmura, Makoto Kondo, Katsuyuki Kaneda, Mitsuhiro Yoshioka, Shuji Kaneko

Department of Sociology, Psychology, Education and Human Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

Appropriate processing of reward and aversive information is essential for survival. Although a critical role of serotonergic neurons in the dorsal raphe nucleus (DRN) in reward processing has been shown, the lack of rewarding effects with selective serotonin reuptake inhibitors (SSRIs) implies the presence of a discrete serotonergic system playing an opposite role to the DRN in the processing of reward and aversive stimuli. Here, we demonstrated that serotonergic neurons in the median raphe nucleus (MRN) of mice process reward and aversive information in opposite directions to DRN serotonergic neurons. We further identified MRN serotonergic neurons, including those projecting to the interpeduncular nucleus (5-HT^MRN→IPN), as a key mediator of reward and aversive stimuli. Moreover, 5-HT receptors, including 5-HT_2A receptors in the interpeduncular nucleus, are involved in the aversive properties of MRN serotonergic neural activity. Our findings revealed an essential function of MRN serotonergic neurons, including 5-HT^MRN→IPN, in the processing of reward and aversive stimuli.

Original language	English
Article number	7708
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-35346-7
Publication status	Published - 2022 Dec

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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10.1038/s41467-022-35346-7

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Kawai, H., Bouchekioua, Y., Nishitani, N., Niitani, K., Izumi, S., Morishita, H., Andoh, C., Nagai, Y., Koda, M., Hagiwara, M., Toda, K., Shirakawa, H., Nagayasu, K., Ohmura, Y., Kondo, M., Kaneda, K., Yoshioka, M., & Kaneko, S. (2022). Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion. Nature communications, 13(1), [7708]. https://doi.org/10.1038/s41467-022-35346-7

Kawai, H, Bouchekioua, Y, Nishitani, N, Niitani, K, Izumi, S, Morishita, H, Andoh, C, Nagai, Y, Koda, M, Hagiwara, M, Toda, K, Shirakawa, H, Nagayasu, K, Ohmura, Y, Kondo, M, Kaneda, K, Yoshioka, M & Kaneko, S 2022, 'Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion', Nature communications, vol. 13, no. 1, 7708. https://doi.org/10.1038/s41467-022-35346-7

@article{53eea6f1b60a4acfa5d1809438818001,

title = "Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion",

abstract = "Appropriate processing of reward and aversive information is essential for survival. Although a critical role of serotonergic neurons in the dorsal raphe nucleus (DRN) in reward processing has been shown, the lack of rewarding effects with selective serotonin reuptake inhibitors (SSRIs) implies the presence of a discrete serotonergic system playing an opposite role to the DRN in the processing of reward and aversive stimuli. Here, we demonstrated that serotonergic neurons in the median raphe nucleus (MRN) of mice process reward and aversive information in opposite directions to DRN serotonergic neurons. We further identified MRN serotonergic neurons, including those projecting to the interpeduncular nucleus (5-HTMRN→IPN), as a key mediator of reward and aversive stimuli. Moreover, 5-HT receptors, including 5-HT2A receptors in the interpeduncular nucleus, are involved in the aversive properties of MRN serotonergic neural activity. Our findings revealed an essential function of MRN serotonergic neurons, including 5-HTMRN→IPN, in the processing of reward and aversive stimuli.",

author = "Hiroyuki Kawai and Youcef Bouchekioua and Naoya Nishitani and Kazuhei Niitani and Shoma Izumi and Hinako Morishita and Chihiro Andoh and Yuma Nagai and Masashi Koda and Masako Hagiwara and Koji Toda and Hisashi Shirakawa and Kazuki Nagayasu and Yu Ohmura and Makoto Kondo and Katsuyuki Kaneda and Mitsuhiro Yoshioka and Shuji Kaneko",

note = "Funding Information: We would like to thank Dr. Hiroyuki Hasegawa for kindly gifting us anti-tryptophan hydroxylase 2 antibodies. We would like to thank Drs. Akihiro Yamanaka and Kenji F. Tanaka for kindly providing us with Tph2-tTA and TetO-ChR2(C128S) mice. We would like to thank Dr. Hitomi Sasamori for her help in the breeding of transgenic mice. We would like to thank Drs. Mike Robinson and Kent Berridge for telling us how to conduct the surgery of oral infusion. We would like to thank Hitoshi Saito for his help in programming. We would like to thank Dr. Masaaki Sato for kindly lending us an infusion pump. We would like to thank Drs. Katsuyuki Kaneda and Satoshi Deyama for help on the CPP/CPA tests. We would like to thank Drs. Atsushi Miyawaki (pCSII-EF-Venus), Adam Cohen (CheRiff; addgene #51694), Karl Deisseroth (eArchT; addgene #35513), Douglas Kim and GENIE Project (GCaMP6s; addgene #40753), and Lin Tian (axon-GCaMP6s; addgene #112008) for providing us the constructs. This work was supported by Grants-in-Aid for Scientific Research from JSPS (to K.Nagayasu (JP20H04774, JP20K07064), to S.K. (JP18H04616, JP20H00491), to Y.O. (21K07473), to M.Y. (21H02668), to M.Kondo (JP22K11498), Grant-in-Aid for Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan (to H.K. (N-184403)), Grants-in-Aid for JSPS Fellows (to H.K. (JP20J12341), Y.N. (JP21J14215), and C.A. (JP21J21091)), AMED (to S.K. (JP20ak0101088h0003, JP21ak0101153h0001), to M.Kondo (JP21wm0525026, JP20lm0203007)), Smoking Research Foundation (to Y.O.), The Shimizu Foundation for Immunology and Neuroscience Grant (to K.Nagayasu), The Uehara Memorial Foundation (to K.Nagayasu), The Lotte Foundation (to K.Nagayasu), Takeda Science Foundation (to M.Kondo), SENSHIN Medical Research Foundation (M.Kondo). Funding Information: We would like to thank Dr. Hiroyuki Hasegawa for kindly gifting us anti-tryptophan hydroxylase 2 antibodies. We would like to thank Drs. Akihiro Yamanaka and Kenji F. Tanaka for kindly providing us with Tph2-tTA and TetO-ChR2(C128S) mice. We would like to thank Dr. Hitomi Sasamori for her help in the breeding of transgenic mice. We would like to thank Drs. Mike Robinson and Kent Berridge for telling us how to conduct the surgery of oral infusion. We would like to thank Hitoshi Saito for his help in programming. We would like to thank Dr. Masaaki Sato for kindly lending us an infusion pump. We would like to thank Drs. Katsuyuki Kaneda and Satoshi Deyama for help on the CPP/CPA tests. We would like to thank Drs. Atsushi Miyawaki (pCSII-EF-Venus), Adam Cohen (CheRiff; addgene #51694), Karl Deisseroth (eArchT; addgene #35513), Douglas Kim and GENIE Project (GCaMP6s; addgene #40753), and Lin Tian (axon-GCaMP6s; addgene #112008) for providing us the constructs. This work was supported by Grants-in-Aid for Scientific Research from JSPS (to K.Nagayasu (JP20H04774, JP20K07064), to S.K. (JP18H04616, JP20H00491), to Y.O. (21K07473), to M.Y. (21H02668), to M.Kondo (JP22K11498), Grant-in-Aid for Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan (to H.K. (N-184403)), Grants-in-Aid for JSPS Fellows (to H.K. (JP20J12341), Y.N. (JP21J14215), and C.A. (JP21J21091)), AMED (to S.K. (JP20ak0101088h0003, JP21ak0101153h0001), to M.Kondo (JP21wm0525026, JP20lm0203007)), Smoking Research Foundation (to Y.O.), The Shimizu Foundation for Immunology and Neuroscience Grant (to K.Nagayasu), The Uehara Memorial Foundation (to K.Nagayasu), The Lotte Foundation (to K.Nagayasu), Takeda Science Foundation (to M.Kondo), SENSHIN Medical Research Foundation (M.Kondo). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-35346-7",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion

AU - Kawai, Hiroyuki

AU - Bouchekioua, Youcef

AU - Nishitani, Naoya

AU - Niitani, Kazuhei

AU - Izumi, Shoma

AU - Morishita, Hinako

AU - Andoh, Chihiro

AU - Nagai, Yuma

AU - Koda, Masashi

AU - Hagiwara, Masako

AU - Toda, Koji

AU - Shirakawa, Hisashi

AU - Nagayasu, Kazuki

AU - Ohmura, Yu

AU - Kondo, Makoto

AU - Kaneda, Katsuyuki

AU - Yoshioka, Mitsuhiro

AU - Kaneko, Shuji

N1 - Funding Information: We would like to thank Dr. Hiroyuki Hasegawa for kindly gifting us anti-tryptophan hydroxylase 2 antibodies. We would like to thank Drs. Akihiro Yamanaka and Kenji F. Tanaka for kindly providing us with Tph2-tTA and TetO-ChR2(C128S) mice. We would like to thank Dr. Hitomi Sasamori for her help in the breeding of transgenic mice. We would like to thank Drs. Mike Robinson and Kent Berridge for telling us how to conduct the surgery of oral infusion. We would like to thank Hitoshi Saito for his help in programming. We would like to thank Dr. Masaaki Sato for kindly lending us an infusion pump. We would like to thank Drs. Katsuyuki Kaneda and Satoshi Deyama for help on the CPP/CPA tests. We would like to thank Drs. Atsushi Miyawaki (pCSII-EF-Venus), Adam Cohen (CheRiff; addgene #51694), Karl Deisseroth (eArchT; addgene #35513), Douglas Kim and GENIE Project (GCaMP6s; addgene #40753), and Lin Tian (axon-GCaMP6s; addgene #112008) for providing us the constructs. This work was supported by Grants-in-Aid for Scientific Research from JSPS (to K.Nagayasu (JP20H04774, JP20K07064), to S.K. (JP18H04616, JP20H00491), to Y.O. (21K07473), to M.Y. (21H02668), to M.Kondo (JP22K11498), Grant-in-Aid for Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan (to H.K. (N-184403)), Grants-in-Aid for JSPS Fellows (to H.K. (JP20J12341), Y.N. (JP21J14215), and C.A. (JP21J21091)), AMED (to S.K. (JP20ak0101088h0003, JP21ak0101153h0001), to M.Kondo (JP21wm0525026, JP20lm0203007)), Smoking Research Foundation (to Y.O.), The Shimizu Foundation for Immunology and Neuroscience Grant (to K.Nagayasu), The Uehara Memorial Foundation (to K.Nagayasu), The Lotte Foundation (to K.Nagayasu), Takeda Science Foundation (to M.Kondo), SENSHIN Medical Research Foundation (M.Kondo). Funding Information: We would like to thank Dr. Hiroyuki Hasegawa for kindly gifting us anti-tryptophan hydroxylase 2 antibodies. We would like to thank Drs. Akihiro Yamanaka and Kenji F. Tanaka for kindly providing us with Tph2-tTA and TetO-ChR2(C128S) mice. We would like to thank Dr. Hitomi Sasamori for her help in the breeding of transgenic mice. We would like to thank Drs. Mike Robinson and Kent Berridge for telling us how to conduct the surgery of oral infusion. We would like to thank Hitoshi Saito for his help in programming. We would like to thank Dr. Masaaki Sato for kindly lending us an infusion pump. We would like to thank Drs. Katsuyuki Kaneda and Satoshi Deyama for help on the CPP/CPA tests. We would like to thank Drs. Atsushi Miyawaki (pCSII-EF-Venus), Adam Cohen (CheRiff; addgene #51694), Karl Deisseroth (eArchT; addgene #35513), Douglas Kim and GENIE Project (GCaMP6s; addgene #40753), and Lin Tian (axon-GCaMP6s; addgene #112008) for providing us the constructs. This work was supported by Grants-in-Aid for Scientific Research from JSPS (to K.Nagayasu (JP20H04774, JP20K07064), to S.K. (JP18H04616, JP20H00491), to Y.O. (21K07473), to M.Y. (21H02668), to M.Kondo (JP22K11498), Grant-in-Aid for Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan (to H.K. (N-184403)), Grants-in-Aid for JSPS Fellows (to H.K. (JP20J12341), Y.N. (JP21J14215), and C.A. (JP21J21091)), AMED (to S.K. (JP20ak0101088h0003, JP21ak0101153h0001), to M.Kondo (JP21wm0525026, JP20lm0203007)), Smoking Research Foundation (to Y.O.), The Shimizu Foundation for Immunology and Neuroscience Grant (to K.Nagayasu), The Uehara Memorial Foundation (to K.Nagayasu), The Lotte Foundation (to K.Nagayasu), Takeda Science Foundation (to M.Kondo), SENSHIN Medical Research Foundation (M.Kondo). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Appropriate processing of reward and aversive information is essential for survival. Although a critical role of serotonergic neurons in the dorsal raphe nucleus (DRN) in reward processing has been shown, the lack of rewarding effects with selective serotonin reuptake inhibitors (SSRIs) implies the presence of a discrete serotonergic system playing an opposite role to the DRN in the processing of reward and aversive stimuli. Here, we demonstrated that serotonergic neurons in the median raphe nucleus (MRN) of mice process reward and aversive information in opposite directions to DRN serotonergic neurons. We further identified MRN serotonergic neurons, including those projecting to the interpeduncular nucleus (5-HTMRN→IPN), as a key mediator of reward and aversive stimuli. Moreover, 5-HT receptors, including 5-HT2A receptors in the interpeduncular nucleus, are involved in the aversive properties of MRN serotonergic neural activity. Our findings revealed an essential function of MRN serotonergic neurons, including 5-HTMRN→IPN, in the processing of reward and aversive stimuli.

AB - Appropriate processing of reward and aversive information is essential for survival. Although a critical role of serotonergic neurons in the dorsal raphe nucleus (DRN) in reward processing has been shown, the lack of rewarding effects with selective serotonin reuptake inhibitors (SSRIs) implies the presence of a discrete serotonergic system playing an opposite role to the DRN in the processing of reward and aversive stimuli. Here, we demonstrated that serotonergic neurons in the median raphe nucleus (MRN) of mice process reward and aversive information in opposite directions to DRN serotonergic neurons. We further identified MRN serotonergic neurons, including those projecting to the interpeduncular nucleus (5-HTMRN→IPN), as a key mediator of reward and aversive stimuli. Moreover, 5-HT receptors, including 5-HT2A receptors in the interpeduncular nucleus, are involved in the aversive properties of MRN serotonergic neural activity. Our findings revealed an essential function of MRN serotonergic neurons, including 5-HTMRN→IPN, in the processing of reward and aversive stimuli.

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JO - Nature Communications

JF - Nature Communications

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M1 - 7708

ER -

Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion

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