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Astrocytes modulate cerebral blood flow and neuronal response to cocaine in prefrontal cortex

Molecular Psychiatry volume 29, pages 820–834 (2024)Cite this article

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Abstract

Cocaine affects both cerebral blood vessels and neuronal activity in brain. Cocaine can also disrupt astrocytes, which modulate neurovascular coupling—a process that regulates cerebral hemodynamics in response to neuronal activation. However, separating neuronal and astrocytic effects from cocaine’s direct vasoactive effects has been challenging, partially due to limitations of neuroimaging techniques able to differentiate vascular from neuronal and glial effects at high temporal and spatial resolutions. Here, we used a newly-developed multi-channel fluorescence and optical coherence Doppler microscope (fl-ODM) that allows for simultaneous measurements of neuronal and astrocytic activities (reflected by the intracellular calcium changes in neurons Ca2+N and astrocytes Ca2+A, respectively) alongside their vascular interactions in vivo to address this challenge. Using green and red genetically-encoded Ca2+ indicators differentially expressed in astrocytes and neurons, fl-ODM enabled concomitant imaging of large-scale astrocytic and neuronal Ca2+ fluorescence and 3D cerebral blood flow velocity (CBFv) in vascular networks in the mouse cortex. We assessed cocaine’s effects in the prefrontal cortex (PFC) and found that the CBFv changes triggered by cocaine were temporally correlated with astrocytic Ca2+A activity. Chemogenetic inhibition of astrocytes during the baseline state resulted in blood vessel dilation and CBFv increases but did not affect neuronal activity, suggesting modulation of spontaneous blood vessel’s vascular tone by astrocytes. Chemogenetic inhibition of astrocytes during a cocaine challenge prevented its vasoconstricting effects alongside the CBFv decreases, but it also attenuated the neuronal Ca2+N increases triggered by cocaine. These results document a role of astrocytes both in regulating vascular tone and consequently blood flow, at baseline and for modulating the vasoconstricting and neuronal activation responses to cocaine in the PFC. Strategies to inhibit astrocytic activity could offer promise for ameliorating vascular and neuronal toxicity from cocaine misuse.

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Fig. 1: In vivo imaging of NGV interactions.
Fig. 2: Illustration of time-lapse images to derive Ca2+N, Ca2+A fluorescence and local CBFv changes in response to acute cocaine in mouse PFC.
Fig. 3: Comparisons of cocaine’s effects on neuronal Ca2+N, astrocytic Ca2+A fluorescence and vascular CBFv in the PFC (n = 7 mice).
Fig. 4: Effects of DREADDS(Gi) activation on the NGV interactions.
Fig. 5: Comparisons of cocaine-induced Ca2+N, Ca2+A and CBFv changes with vs without DREADDS(Gi) activation.

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Correspondence and requests for additional materials should be addressed to Yingtian Pan.

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Acknowledgements

This work was supported in part by National Institutes of Health (NIH) grants RF1DA048808 (YP, CD), 2R01 DA029718 (CD, YP), R21 DA057699 (YP, CD) and NIH’s Intramural Program of NIAAA (NDV). The authors would like to thank A. Li for participating in system development, K. Clair for immunostaining and discussion on mCherry control experiment, and also to NIDA’s Drug Supply Program for providing cocaine used in this study.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, 11794, USA

    Congwu Du, Kichon Park, Yueming Hua, Yanzuo Liu & Yingtian Pan

  2. National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20857, USA

    Nora D. Volkow

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  1. Congwu Du
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  2. Kichon Park
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  3. Yueming Hua
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  4. Yanzuo Liu
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  5. Nora D. Volkow
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  6. Yingtian Pan
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Contributions

CD, NDV, and YP designed the research; KP and YH carried out the in vivo experiments and participated in image processing and data analysis (equal contribution). CD, NDV, and YP contributed to data interpretation, result discussions, and manuscript writing.

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Correspondence to Yingtian Pan.

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Du, C., Park, K., Hua, Y. et al. Astrocytes modulate cerebral blood flow and neuronal response to cocaine in prefrontal cortex. Mol Psychiatry 29, 820–834 (2024). https://doi.org/10.1038/s41380-023-02373-9

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