NIDA IRP Technology Resource Initiative Featured Paper

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

Authors

Congwu Du, Kichon Park, Yueming Hua, Yanzuo Liu, Nora D Volkow, Yingtian Pan

Paper presented by Dr. Zilu Ma and selected by the NIDA TDI Paper of the Month Committee

Publication Brief Description

Cocaine disrupts multiple components of the neuro-glio-vascular (NGV) network in the brain, but distinguishing its effects on neurons, astrocytes, and blood vessels has remained a technical challenge due to their interactions. This study introduces a novel fl-ODM imaging system capable of capturing synchronized calcium activity in neurons and astrocytes alongside 3D cerebral blood flow velocity at high spatial and temporal resolution. Using this tool, this study demonstrates that astrocytes play a central role in mediating cocaine-induced vasoconstriction and modulating neuronal responses. Chemogenetic inhibition of astrocytic activity blunted both vascular and neuronal effects of cocaine, highlighting astrocytes as key regulators of neurovascular function and potential therapeutic targets. This technology provides a powerful platform for dissecting complex cellular interactions in vivo, with broad implications for studying brain function and pathology.

Du, Congwu; Park, Kichon; Hua, Yueming; Liu, Yanzuo; Volkow, Nora D; Pan, Yingtian

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

In: Mol Psychiatry, vol. 29, no. 3, pp. 820–834, 2024, ISSN: 1476-5578.

Abstract | Links

@article{pmid38238549,

title = {Astrocytes modulate cerebral blood flow and neuronal response to cocaine in prefrontal cortex},

author = {Congwu Du and Kichon Park and Yueming Hua and Yanzuo Liu and Nora D Volkow and Yingtian Pan},

url = {https://pubmed.ncbi.nlm.nih.gov/38238549/},

doi = {10.1038/s41380-023-02373-9},

issn = {1476-5578},

year  = {2024},

date = {2024-03-01},

urldate = {2024-03-01},

journal = {Mol Psychiatry},

volume = {29},

number = {3},

pages = {820--834},

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 Ca and astrocytes Ca, respectively) alongside their vascular interactions in vivo to address this challenge. Using green and red genetically-encoded Ca indicators differentially expressed in astrocytes and neurons, fl-ODM enabled concomitant imaging of large-scale astrocytic and neuronal Ca 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 Ca 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 Ca 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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

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 Ca and astrocytes Ca, respectively) alongside their vascular interactions in vivo to address this challenge. Using green and red genetically-encoded Ca indicators differentially expressed in astrocytes and neurons, fl-ODM enabled concomitant imaging of large-scale astrocytic and neuronal Ca 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 Ca 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 Ca 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.