TY - JOUR
T1 - Spinal astrocytes in superficial laminae gate brainstem descending control of mechanosensory hypersensitivity
AU - Kohro, Yuta
AU - Matsuda, Tsuyoshi
AU - Yoshihara, Kohei
AU - Kohno, Keita
AU - Koga, Keisuke
AU - Katsuragi, Ryuichi
AU - Oka, Takaaki
AU - Tashima, Ryoichi
AU - Muneta, Sho
AU - Yamane, Takuya
AU - Okada, Shota
AU - Momokino, Kazuya
AU - Furusho, Aogu
AU - Hamase, Kenji
AU - Oti, Takumi
AU - Sakamoto, Hirotaka
AU - Hayashida, Kenichiro
AU - Kobayashi, Ryosuke
AU - Horii, Takuro
AU - Hatada, Izuho
AU - Tozaki-Saitoh, Hidetoshi
AU - Mikoshiba, Katsuhiko
AU - Taylor, Verdon
AU - Inoue, Kazuhide
AU - Tsuda, Makoto
N1 - Funding Information:
We thank E. Sakaguchi for starting the initial experiment for rAAV, and the University of Pennsylvania vector core for providing pZac2.1, pAAV2/5, pAAV2/9 and pAd DeltaF6 plasmids. This work was supported by JSPS KAKENHI grant numbers JP19H05658, 19K22500 (to M.T.), JP16K18885, JP18K14821 (to Y.K.), JP25117013 (to K.I.), by the Core Research for Evolutional Science and Technology (CREST) program from the Japan Agency for Medical Research and Development (AMED) under grant number JP20gm0910006 (to M.T.), by the Practical Research Project for Allergic Diseases and Immunology (Research on Allergic Diseases and Immunology) from AMED under grant number JP17ek0410034 (to M.T.), the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under grant number JP20am0101091 (to M.T.), JP20am0101120 (to R. Kobayashi, T.H. and I.H.), by Naito Foundation (to Y.K. and M.T.), and by The Nakatomi Foundation (to M.T.). The authors appreciate Shiseido Co., Ltd., for their technical support for the measurement of d-serine. T.M. and K.Y. were research fellows of the JSPS (15J03522 and 19J21063, respectively).
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Astrocytes are critical regulators of CNS function and are proposed to be heterogeneous in the developing brain and spinal cord. Here we identify a population of astrocytes located in the superficial laminae of the spinal dorsal horn (SDH) in adults that is genetically defined by Hes5. In vivo imaging revealed that noxious stimulation by intraplantar capsaicin injection activated Hes5+ SDH astrocytes via α1A-adrenoceptors (α1A-ARs) through descending noradrenergic signaling from the locus coeruleus. Intrathecal norepinephrine induced mechanical pain hypersensitivity via α1A-ARs in Hes5+ astrocytes, and chemogenetic stimulation of Hes5+ SDH astrocytes was sufficient to produce the hypersensitivity. Furthermore, capsaicin-induced mechanical hypersensitivity was prevented by the inhibition of descending locus coeruleus–noradrenergic signaling onto Hes5+ astrocytes. Moreover, in a model of chronic pain, α1A-ARs in Hes5+ astrocytes were critical regulators for determining an analgesic effect of duloxetine. Our findings identify a superficial SDH-selective astrocyte population that gates descending noradrenergic control of mechanosensory behavior.
AB - Astrocytes are critical regulators of CNS function and are proposed to be heterogeneous in the developing brain and spinal cord. Here we identify a population of astrocytes located in the superficial laminae of the spinal dorsal horn (SDH) in adults that is genetically defined by Hes5. In vivo imaging revealed that noxious stimulation by intraplantar capsaicin injection activated Hes5+ SDH astrocytes via α1A-adrenoceptors (α1A-ARs) through descending noradrenergic signaling from the locus coeruleus. Intrathecal norepinephrine induced mechanical pain hypersensitivity via α1A-ARs in Hes5+ astrocytes, and chemogenetic stimulation of Hes5+ SDH astrocytes was sufficient to produce the hypersensitivity. Furthermore, capsaicin-induced mechanical hypersensitivity was prevented by the inhibition of descending locus coeruleus–noradrenergic signaling onto Hes5+ astrocytes. Moreover, in a model of chronic pain, α1A-ARs in Hes5+ astrocytes were critical regulators for determining an analgesic effect of duloxetine. Our findings identify a superficial SDH-selective astrocyte population that gates descending noradrenergic control of mechanosensory behavior.
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U2 - 10.1038/s41593-020-00713-4
DO - 10.1038/s41593-020-00713-4
M3 - Article
C2 - 33020652
AN - SCOPUS:85092109238
SN - 1097-6256
VL - 23
SP - 1376
EP - 1387
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 11
ER -