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. Giorgi et al. combined chemogenetics and functional magnetic resonance imaging (chemo-fMRI) to establish causation between serotonin release and regional functional activity. They show that endogenous serotonergic transmission does not affect global brain activity but selectively activates a set of target regions that serve as primary effectors of this modulatory system.

Brain-wide Mapping of Endogenous Serotonergic Transmission via Chemogenetic fMRI

GIORGI, ANDREA
Primo
;
MIGLIARINI, SARA;MADDALONI, GIACOMO;RATTO, GIAN MICHELE;PASQUALETTI, MASSIMO
Ultimo
2017-01-01

Abstract

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. Giorgi et al. combined chemogenetics and functional magnetic resonance imaging (chemo-fMRI) to establish causation between serotonin release and regional functional activity. They show that endogenous serotonergic transmission does not affect global brain activity but selectively activates a set of target regions that serve as primary effectors of this modulatory system.
2017
Giorgi, Andrea; Migliarini, Sara; Galbusera, Alberto; Maddaloni, Giacomo; Mereu, Maddalena; Margiani, Giulia; Gritti, Marta; Landi, Silvia; Trovato, Francesco; Bertozzi, Sine Mandrup; Armirotti, Andrea; Ratto, GIAN MICHELE; De Luca, Maria Antonietta; Tonini, Raffaella; Gozzi, Alessandro; Pasqualetti, Massimo
File in questo prodotto:
File Dimensione Formato  
CELL-REPORTS-D-17-00992.pdf

accesso aperto

Descrizione: articolo completo
Tipologia: Documento in Post-print
Licenza: Creative commons
Dimensione 5.16 MB
Formato Adobe PDF
5.16 MB Adobe PDF Visualizza/Apri
Giorgi_etal_CellReports_2017_extended.pdf

accesso aperto

Descrizione: Articolo full text pdf
Tipologia: Versione finale editoriale
Licenza: Creative commons
Dimensione 5.01 MB
Formato Adobe PDF
5.01 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/876059
Citazioni
  • ???jsp.display-item.citation.pmc??? 39
  • Scopus 59
  • ???jsp.display-item.citation.isi??? 54
social impact