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However, the NG2 promoter cannot target NG2 glia and mural cells separately. This has been an obstacle for NG2 glia\u2010specific manipulation. Here, we developed transgenic mice in which either cell type can be targeted using the NG2 promoter. We selected a tetracycline\u2010controllable gene induction system for cell type\u2010specific transgene expression, and generated NG2\u2010tetracycline transactivator (tTA) transgenic lines. We crossed tTA lines with the tetO\u2010ChR2 (channelrhodopsin\u20102)\u2010EYFP line to characterize tTA\u2010dependent transgene induction. We isolated two unique NG2\u2010tTA mouse lines: one that induced ChR2\u2010EYFP only in mural cells, likely due to the chromosomal position effect of NG2\u2010tTA insertion, and the other that induced it in both cell types. We then applied a Cre\u2010mediated set\u2010subtraction strategy to the latter case and eliminated ChR2\u2010EYFP from mural cells, resulting in NG2 glia\u2010specific transgene induction. We further demonstrated that tTA\u2010dependent ChR2 expression could manipulate cell function. Optogenetic mural cell activation decreased cerebral blood flow, as previously reported, indicating that tTA\u2010mediated ChR2 expression was sufficient to impact cellular function. ChR2\u2010mediated depolarization was observed in NG2 glia in acute hippocampal slices. In addition, ChR2\u2010mediated depolarization of NG2 glia inhibited their proliferation but promoted their differentiation in juvenile mice. Since the tTA\u2013tetO combination is expandable, the mural cell\u2013specific NG2\u2010tTA line and the NG2 glia\u2010specific NG2\u2010tTA line will permit us to conduct observational and manipulation studies to examine in vivo function of these cells separately.<\/jats:p>","DOI":"10.1002\/glia.24273","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T13:14:48Z","timestamp":1664284488000},"page":"317-333","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Separate optogenetic manipulation of Nerve\/glial antigen 2 (NG2) glia and mural cells using the NG2 promoter"],"prefix":"10.1002","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9019-2699","authenticated-orcid":false,"given":"Mitsuhiro","family":"Oishi","sequence":"first","affiliation":[{"name":"Division of Brain Sciences Keio University School of Medicine  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Passlick","sequence":"additional","affiliation":[{"name":"Institute of Cellular Neurosciences Medical Faculty, University of Bonn  Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0549-6346","authenticated-orcid":false,"given":"Yoshihiko","family":"Yamazaki","sequence":"additional","affiliation":[{"name":"Department of Physiology Yamagata University School of Medicine  Yamagata Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miyuki","family":"Unekawa","sequence":"additional","affiliation":[{"name":"Department of Neurology Keio University School of Medicine  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruka","family":"Adachi","sequence":"additional","affiliation":[{"name":"Division of Brain Sciences Keio University School of Medicine  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mayumi","family":"Yamada","sequence":"additional","affiliation":[{"name":"Research Center for Dynamic Living Systems, Graduate School of Biostudies Kyoto University  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Itaru","family":"Imayoshi","sequence":"additional","affiliation":[{"name":"Research Center for Dynamic Living Systems, Graduate School of Biostudies Kyoto University  Kyoto Japan"},{"name":"Institute for Frontier Life and Medical Sciences Kyoto University  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshifumi","family":"Abe","sequence":"additional","affiliation":[{"name":"Division of Brain Sciences Keio University School of Medicine  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2579-8357","authenticated-orcid":false,"given":"Christian","family":"Steinh\u00e4user","sequence":"additional","affiliation":[{"name":"Institute of Cellular Neurosciences Medical Faculty, University of Bonn  Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2511-0057","authenticated-orcid":false,"given":"Kenji F.","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Division of Brain Sciences Keio University School of Medicine  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,9,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2019.02.017"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109427"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1006\/mcne.1999.0827"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/35012083"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2247"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.09.066"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0928-12.2012"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.20769"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.06.035"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(07)00562-3"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22859"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-018-0261-2"},{"key":"e_1_2_8_14_1","volume-title":"The mouse brain in stereotaxic coordinates (compact 3R)","author":"Franklin K. 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