@article{68e9b09390a94e9a940ade90b294f460,
title = "Microglial activation elicits a negative affective state through prostaglandin-mediated modulation of striatal neurons",
abstract = "Microglia are activated in many neurological diseases and have been suggested to play an important role in the development of affective disorders including major depression. To investigate how microglial signaling regulates mood, we used bidirectional chemogenetic manipulations of microglial activity in mice. Activation of microglia in the dorsal striatum induced local cytokine expression and a negative affective state characterized by anhedonia and aversion, whereas inactivation of microglia blocked aversion induced by systemic inflammation. Interleukin-6 signaling and cyclooxygenase-1 mediated prostaglandin synthesis in the microglia were critical for the inflammation-induced aversion. Correspondingly, microglial activation led to a prostaglandin-dependent reduction of the excitability of striatal neurons. These findings demonstrate a mechanism by which microglial activation causes negative affect through prostaglandin-dependent modulation of striatal neurons and indicate that interference with this mechanism could milden the depressive symptoms in somatic and psychiatric diseases involving microglial activation.",
keywords = "DREADDs, Microglia, anhedonia, aversion, depression, interleukin-6, neuroinflammation, prostaglandin, striatum",
author = "Klawonn, {Anna M.} and Michael Fritz and Silvia Castany and Marco Pignatelli and Carla Canal and Fredrik Simil{\"a} and Tejeda, {Hugo A.} and Julia Levinsson and Maarit Jaarola and Johan Jakobsson and Juan Hidalgo and Markus Heilig and Antonello Bonci and David Engblom",
note = "Funding Information: This work was supported by the Swedish Medical Research Council (including a postdoc fellowship to A.M.K.), the Knut and Alice Wallenberg Foundation , the Swedish Brain Foundation , the Link{\"o}ping Parkinson Foundation , the Lars Hierta Memorial Foundation , and the County Council of {\"O}sterg{\"o}tland . J.H. acknowledges the support of SAF2014-56546-R and RTI2018-101105-B-I00 . C.C. was supported by a PhD fellowship; B18P0023 . We thank Lindsay De Biase for generous support in the planning and implementation of the electrophysiology experiments. We also thank Joanna Zajdel and Anton Forsberg for contributing to the immunohistochemistry experiments. We thank Markus Schwaninger for providing the Slco1c1-creER line, Michel Vierboom for providing brain tissue from rhesus macaques, and Henrik Druid and Kanar Alkass for providing the human brain samples. Funding Information: This work was supported by the Swedish Medical Research Council (including a postdoc fellowship to A.M.K.), the Knut and Alice Wallenberg Foundation, the Swedish Brain Foundation, the Link?ping Parkinson Foundation, the Lars Hierta Memorial Foundation, and the County Council of ?sterg?tland. J.H. acknowledges the support of SAF2014-56546-R and RTI2018-101105-B-I00. C.C. was supported by a PhD fellowship; B18P0023. We thank Lindsay De Biase for generous support in the planning and implementation of the electrophysiology experiments. We also thank Joanna Zajdel and Anton Forsberg for contributing to the immunohistochemistry experiments. We thank Markus Schwaninger for providing the Slco1c1-creER line, Michel Vierboom for providing brain tissue from rhesus macaques, and Henrik Druid and Kanar Alkass for providing the human brain samples. A.M.K. M.F. and D.E. were responsible for the overall study design. Stereotaxic surgeries and behavioral experiments were primarily done by A.M.K. and M.F. but some experiments were performed by S.C. A.M.K. and M.P. performed the electrophysiological recordings with input from H.A.T. S.C. A.M.K. F.S. and J.L. were responsible for the histological analysis. S.C. performed the quantification of the histological data. M.F. S.C. M.J. and A.M.K. performed the qPCR experiments. J.J. provided viral vectors and input on how to use them. C.C. performed the Luminex experiments with input from J.H. who also provided the IL6-floxed mouse line. M.J. was responsible for the ELISA experiments, genotyping, and colony maintenance. A.B. and M.H. provided important input for the design of the study. The manuscript was written by A.M.K. M.F. and D.E. All authors read and commented on the manuscript. The authors declare no competing interests Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2021",
month = feb,
day = "9",
doi = "10.1016/j.immuni.2020.12.016",
language = "English",
volume = "54",
pages = "225--234.e6",
journal = "Immunity",
issn = "1074-7613",
number = "2",
}