Cell Reports
Volume 21, Issue 4, 24 October 2017, Pages 910-918
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Brain-wide Mapping of Endogenous Serotonergic Transmission via Chemogenetic fMRI

https://doi.org/10.1016/j.celrep.2017.09.087Get rights and content
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Highlights

  • We describe a combination of chemogenetics and mouse fMRI (chemo-fMRI)

  • Chemogenetic release of serotonin activates a set of primary regional effectors

  • Systemic serotonin boosting results in widespread deactivation

  • Chemo-fMRI can be used to causally manipulate evoked and intrinsic brain activity

Summary

Serotonin-producing neurons profusely innervate brain regions via long-range projections. However, it remains unclear whether and how endogenous serotonergic transmission specifically influences regional or global functional activity. We combined designed receptors exclusively activated by designed drugs (DREADD)-based chemogenetics and functional magnetic resonance imaging (fMRI), an approach we term “chemo-fMRI,” to causally probe the brain-wide substrates modulated by endogenous serotonergic activity. We describe the generation of a conditional knockin mouse line that, crossed with serotonin-specific Cre-recombinase mice, allowed us to remotely stimulate serotonergic neurons during fMRI scans. We show that endogenous stimulation of serotonin-producing neurons does not affect global brain activity but results in region-specific activation of a set of primary target regions encompassing corticohippocampal and ventrostriatal areas. By contrast, pharmacological boosting of serotonin levels produced widespread fMRI deactivation, plausibly reflecting the mixed contribution of central and perivascular constrictive effects. Our results identify the primary functional targets of endogenous serotonergic stimulation and establish causation between activation of serotonergic neurons and regional fMRI signals.

Keywords

DREADD
connectivity
clozapine
CNO
CBV
dopamine
citalopram
pharmacokinetics

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