Cocaine’s cerebrovascular vasoconstriction is associated with astrocytic Ca2+ increase in mice

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

doi:10.1038/s42003-022-03877-w

Cited by 10 publications

(12 citation statements)

References 63 publications

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“…Analysis of temporal correlations showed that cocaine-induced Ca 2+ A increases had strong negative correlations with the CBFv decreases. These ndings are in agreement with our recent results obtained in separate groups of animals 35 . In that study we used single virus containing GCaMP6f (not jRGECO1a) delivered into the somatosensory cortex and reported that cocaine-induced neuronal Ca 2+ N increases recovered by 30min followed by a downshoot similar to our observations in this study but in the PFC (Fig.…”

Section: Ca 2+supporting

confidence: 94%

“…It also allowed us to control for group variability. For example, in our prior study using separate groups of mice, the amplitude of cocaineinduced Ca 2+ A was 3 fold lower than that of the Ca 2+ N response 35 , whereas in the current study that measured them in the same animals there were no differences between the peak values of Ca 2+ A and Ca 2+ N (i.e., 2.97±0.42% vs 2.46±0.42%, p=0.82). This discrepancy likely re ects differences between the groups (i.e., WT vs GFAP-cre mice) in our prior study.…”

Section: Ca 2+contrasting

confidence: 82%

“…3a above). In our previous study we also showed that cocaine-induced Ca 2+ N changes were inversely correlated with temporal changes in tissue oxygenation 35 . The duration of neuronal activation in response to cocaine observed here and in our prior study is consistent with the pharmacokinetics of intravenous cocaine in the brain [36][37][38] and to the duration of striatal dopamine increases 39 .…”

Section: Ca 2+mentioning

confidence: 70%

“…The inverse association between Ca 2+ N and tissue oxygenation indicates that cocaine's effects on neuronal activation and deactivation underly the changes in tissue oxygenation and might also underlie the reductions in brain glucose metabolism reported during cocaine withdrawal 40,41 . Although we had observed that the lasting increases in Ca 2+ A induced by cocaine were associated with vasoconstriction as assessed via quanti cation of vessel diameter changes 35 , the measurements of Ca 2+ A and Ca 2+ N changes were done in separate groups of mice, whereas in the current study the -ODM enabled us to assess the dynamic Ca 2+ A and Ca 2+ N responses simultaneously in the same animals. This was crucial for assessing the role of astrocytes in mediating the neuronal responses to cocaine alongside vascular function.…”

Section: Ca 2+mentioning

confidence: 89%

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

Pan

Park³

et al. 2023

Preprint

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Cocaine affects both cerebral blood vessels and neuronal activity in brain. Cocaine can also disrupt astrocytes, which are involved in neurovascular coupling process that modulates cerebral hemodynamics in response to neuronal activity. However, separating neuronal and astrocytic effects from cocaine’s direct vasoactive effects is challenging, partially due to limitations of neuroimaging techniques 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 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 cocaine challenge prevented its vasoconstricting effects alongside the CBFv decreases but also attenuated the neuronal Ca2 +N increases triggered by cocaine. These results document a role of astrocytes both in regulating vascular tone of blood flow at baseline and for mediating the vasoconstricting responses to cocaine as well as its neuronal activation in the PFC. Strategies to inhibit astrocytic activity could offer promise for ameliorating vascular and neuronal toxicity from cocaine misuse.

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Section: Ca 2+supporting

confidence: 94%

Section: Ca 2+contrasting

confidence: 82%

Section: Ca 2+mentioning

confidence: 70%

Section: Ca 2+mentioning

confidence: 89%

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

Pan

Park³

et al. 2023

Preprint

Self Cite

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“…The mice in the cocaine abuse/use model showed elevated BP and aortic stiffness 30 . Cocaine abuse has been shown to induce vasoconstriction [43][44][45][46][47] . Ca 2+ plays a central role in excitation-contraction coupling in vascular SMCs among other functions (reviewed in 48 ).…”

Section: Cocaine and CM Treatment Increase Intracellular Free Calcium...mentioning

confidence: 99%

MicroRNA-423-5p Mediates Cocaine-Induced Smooth Muscle Cell Contraction by Targeting Cacna2d2

Dykxhoorn

Wang

Ferreira³

et al. 2023

Preprint

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Background: Cocaine abuse increases the risk of atherosclerotic cardiovascular disease (CVD) and causes acute coronary syndromes (ACS) and hypertension (HTN). Significant research has explored the role of the sympathetic nervous system mediating the cocaine effects on the cardiovascular (CV) system. However, the response of the sympathetic nervous system alone is insufficient to completely account for the CV consequences seen in cocaine users. Here, we examined the role of microRNAs (miRNAs) in mediating the effect of cocaine on the CV system. MiRNAs regulate many important biological processes and have been associated with both response to cocaine and CV disease development. Multiple miRNAs have altered expression in the CV system (CVS) upon cocaine exposure. Herein, we examined the role of microRNA-423-5p and the downstream signaling events in regulating cocaine-induced mouse aortic smooth muscle cell (SMC) contraction. Methods: To understand the molecular mechanisms underlying the cocaine response in the CV system, we studied the role of miRNA-423-5p and its target Cacna2d2 in the regulation of intracellular calcium concentration and SMC contractility, a critical factor in the modulation of blood pressure (BP). We used in vivo models to evaluate BP and aortic stiffness. Results: In vitro, Cocaine treatment decreased miR-423-5p expression and increased Cacna2d2 expression, which led to elevated intracellular calcium concentrations and increased SMC contractility. Overexpression of miR-423-5p, silencing of its target Cacna2d2, and treatment with a calcium channel blocker reversed the elevated SMC contractility caused by cocaine. In contrast, suppression of miR-423-5p increased the intracellular calcium concentration and SMC contractibility. In vivo, overexpression of miR-423-5p ameliorated the increase in BP and aortic stiffness associated with cocaine use. Conclusions: MiR-423-5p regulates SMC contraction by modulating Cacna2d2 expression increasing intracellular calcium concentrations. Modulation of miR-423-5p—Cacna2d2—Calcium transport pathway may represent a novel therapeutic strategy to improve cocaine-induced hypertension and aortic stiffness.

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Chemogenetic modulation of astrocytes and microglia: State‐of‐the‐art and implications in neuroscience

Bossuyt

Herrewegen

Nestor

et al. 2023

Glia

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Insights into the role astrocytes and microglia play in normal and diseased brain functioning has expanded drastically over the last decade. Recently, chemogenetic tools have emerged as cutting-edge techniques, allowing targeted and spatiotemporal precise manipulation of a specific glial cell type. As a result, significant advances in astrocyte and microglial cell function have been made, showing how glial cells can intervene in central nervous system (CNS) functions such as cognition, reward and feeding behavior in addition to their established contribution in brain diseases, pain, and CNS inflammation. Here, we discuss the latest insights in glial functions in health and disease that have been made through the application of chemogenetics. We will focus on the manipulation of intracellular signaling pathways induced by activation of the designer receptors exclusively activated by designer drugs (DREADDs) in astrocytes and microglia. We will also elaborate on some of the potential pitfalls and the translational potential of the DREADD technology.

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Cocaine’s cerebrovascular vasoconstriction is associated with astrocytic Ca2+ increase in mice

Cited by 10 publications

References 63 publications

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

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

MicroRNA-423-5p Mediates Cocaine-Induced Smooth Muscle Cell Contraction by Targeting Cacna2d2

Chemogenetic modulation of astrocytes and microglia: State‐of‐the‐art and implications in neuroscience

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