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However, the molecular and cellular mechanisms underlying cerebral blood flow reductions are not well understood. Here, by combining a multimodal imaging platform with a genetically encoded calcium indicator, we simultaneously measured the effects of acute cocaine on neuronal and astrocytic activity, tissue oxygenation, hemodynamics and vascular diameter changes in the mouse cerebral cortex. Our results showed that cocaine constricted blood vessels (measured by vessel diameter \u03a6 changes), decreasing cerebral total blood volume (HbT) and temporally reducing tissue oxygenation. Cellular imaging showed that the mean astrocytic Ca<jats:sup>2+<\/jats:sup> dependent fluorescence <jats:inline-formula><jats:alternatives><jats:tex-math>$$(\\Delta {F\/F}_{{{{\\rm{Ca}}}^{2+}}{\\mbox{-}{{{\\rm{G(A)}}}}}})$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                  <mml:mrow>\n                    <mml:mo>(<\/mml:mo>\n                    <mml:mrow>\n                      <mml:mi>\u0394<\/mml:mi>\n                      <mml:msub>\n                        <mml:mrow>\n                          <mml:mi>F<\/mml:mi>\n                          <mml:mo>\/<\/mml:mo>\n                          <mml:mi>F<\/mml:mi>\n                        <\/mml:mrow>\n                        <mml:mrow>\n                          <mml:msup>\n                            <mml:mrow>\n                              <mml:mi>Ca<\/mml:mi>\n                            <\/mml:mrow>\n                            <mml:mrow>\n                              <mml:mn>2<\/mml:mn>\n                              <mml:mo>+<\/mml:mo>\n                            <\/mml:mrow>\n                          <\/mml:msup>\n                          <mml:mstyle>\n                            <mml:mtext>-<\/mml:mtext>\n                          <\/mml:mstyle>\n                          <mml:mi>G(A)<\/mml:mi>\n                        <\/mml:mrow>\n                      <\/mml:msub>\n                    <\/mml:mrow>\n                    <mml:mo>)<\/mml:mo>\n                  <\/mml:mrow>\n                <\/mml:math><\/jats:alternatives><\/jats:inline-formula> increase in response to cocaine was weaker but longer lasting than the mean neuronal Ca<jats:sup>2+<\/jats:sup> dependent fluorescence <jats:inline-formula><jats:alternatives><jats:tex-math>$$(\\Delta {F\/F}_{{{{\\rm{Ca}}}^{2+}}{\\mbox{-}{{{\\rm{G(N)}}}}}})$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                  <mml:mrow>\n                    <mml:mo>(<\/mml:mo>\n                    <mml:mrow>\n                      <mml:mi>\u0394<\/mml:mi>\n                      <mml:msub>\n                        <mml:mrow>\n                          <mml:mi>F<\/mml:mi>\n                          <mml:mo>\/<\/mml:mo>\n                          <mml:mi>F<\/mml:mi>\n                        <\/mml:mrow>\n                        <mml:mrow>\n                          <mml:msup>\n                            <mml:mrow>\n                              <mml:mi>Ca<\/mml:mi>\n                            <\/mml:mrow>\n                            <mml:mrow>\n                              <mml:mn>2<\/mml:mn>\n                              <mml:mo>+<\/mml:mo>\n                            <\/mml:mrow>\n                          <\/mml:msup>\n                          <mml:mstyle>\n                            <mml:mtext>-<\/mml:mtext>\n                          <\/mml:mstyle>\n                          <mml:mi>G(N)<\/mml:mi>\n                        <\/mml:mrow>\n                      <\/mml:msub>\n                    <\/mml:mrow>\n                    <mml:mo>)<\/mml:mo>\n                  <\/mml:mrow>\n                <\/mml:math><\/jats:alternatives><\/jats:inline-formula> changes. Interestingly, while cocaine-induced <jats:inline-formula><jats:alternatives><jats:tex-math>$$\\Delta {F\/F}_{{{{\\rm{Ca}}}^{2+}}{\\mbox{-}{{{\\rm{G(N)}}}}}}$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                  <mml:mi>\u0394<\/mml:mi>\n                  <mml:msub>\n                    <mml:mrow>\n                      <mml:mi>F<\/mml:mi>\n                      <mml:mo>\/<\/mml:mo>\n                      <mml:mi>F<\/mml:mi>\n                    <\/mml:mrow>\n                    <mml:mrow>\n                      <mml:msup>\n                        <mml:mrow>\n                          <mml:mi>Ca<\/mml:mi>\n                        <\/mml:mrow>\n                        <mml:mrow>\n                          <mml:mn>2<\/mml:mn>\n                          <mml:mo>+<\/mml:mo>\n                        <\/mml:mrow>\n                      <\/mml:msup>\n                      <mml:mstyle>\n                        <mml:mtext>-<\/mml:mtext>\n                      <\/mml:mstyle>\n                      <mml:mi>G(N)<\/mml:mi>\n                    <\/mml:mrow>\n                  <\/mml:msub>\n                <\/mml:math><\/jats:alternatives><\/jats:inline-formula> increase was temporally correlated with tissue oxygenation change, the <jats:inline-formula><jats:alternatives><jats:tex-math>$$\\Delta {F\/F}_{{{{\\rm{Ca}}}^{2+}}{\\mbox{-}{{{\\rm{G(A)}}}}}}$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                  <mml:mi>\u0394<\/mml:mi>\n                  <mml:msub>\n                    <mml:mrow>\n                      <mml:mi>F<\/mml:mi>\n                      <mml:mo>\/<\/mml:mo>\n                      <mml:mi>F<\/mml:mi>\n                    <\/mml:mrow>\n                    <mml:mrow>\n                      <mml:msup>\n                        <mml:mrow>\n                          <mml:mi>Ca<\/mml:mi>\n                        <\/mml:mrow>\n                        <mml:mrow>\n                          <mml:mn>2<\/mml:mn>\n                          <mml:mo>+<\/mml:mo>\n                        <\/mml:mrow>\n                      <\/mml:msup>\n                      <mml:mstyle>\n                        <mml:mtext>-<\/mml:mtext>\n                      <\/mml:mstyle>\n                      <mml:mi>G(A)<\/mml:mi>\n                    <\/mml:mrow>\n                  <\/mml:msub>\n                <\/mml:math><\/jats:alternatives><\/jats:inline-formula> elevation after cocaine was in temporal correspondence with the long-lasting decrease in arterial blood volumes. To determine whether the temporal association between astrocytic activation and cocaine induced vasoconstriction reflected a causal association we inhibited astrocytic Ca<jats:sup>2+<\/jats:sup> using GFAP-DREADD(Gi). Inhibition of astrocytes attenuated the vasoconstriction resulting from cocaine, providing evidence that astrocytes play a critical role in cocaine\u2019s vasoconstrictive effects in the brain. These results indicate that neurons and astrocytes play different roles in mediating neurovascular coupling in response to cocaine. Our findings implicate neuronal activation as the main driver of the short-lasting reduction in tissue oxygenation and astrocyte long-lasting activation as the driver of the persistent vasoconstriction with cocaine. Understanding the cellular and vascular interaction induced by cocaine will be helpful for future putative treatments to reduce cerebrovascular pathology from cocaine use.<\/jats:p>","DOI":"10.1038\/s42003-022-03877-w","type":"journal-article","created":{"date-parts":[[2022,9,12]],"date-time":"2022-09-12T08:02:58Z","timestamp":1662969778000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Cocaine\u2019s cerebrovascular vasoconstriction is associated with astrocytic Ca2+ increase in mice"],"prefix":"10.1038","volume":"5","author":[{"given":"Yanzuo","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueming","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4863-4398","authenticated-orcid":false,"given":"Kicheon","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6668-0908","authenticated-orcid":false,"given":"Nora D.","family":"Volkow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingtian","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8957-4366","authenticated-orcid":false,"given":"Congwu","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,9,9]]},"reference":[{"key":"3877_CR1","unstructured":"Council, N. 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