RT Journal Article
SR Electronic
T1 Brainwide mapping of endogenous serotonergic transmission via chemogenetic-fMRI
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 122770
DO 10.1101/122770
A1 Andrea Giorgi
A1 Sara Migliarini
A1 Marta Gritti
A1 Alberto Galbusera
A1 Giacomo Maddaloni
A1 Maria Antonietta De Luca
A1 Raffaella Tonini
A1 Alessandro Gozzi
A1 Massimo Pasqualetti
YR 2017
UL http://biorxiv.org/content/early/2017/04/03/122770.abstract
AB Serotonergic transmission affects behaviours and neuro-physiological functions via the orchestrated recruitment of distributed neural systems. It is however unclear whether serotonin’s modulatory effect entails a global regulation of brainwide neural activity, or is relayed and encoded by a set of primary functional substrates. Here we combine DREADD-based chemogenetics and mouse fMRI, an approach we term “chemo-fMRI”, to causally probe the brainwide substrates modulated by phasic serotonergic activity. We describe the generation of a conditional knock-in mouse line that, crossed with serotonin-specific Cre-recombinase mice, allowed us to remotely stimulate serotonergic neurons during fMRI scans. We show that chemogenetic stimulation of the serotonin system does not affect global brain activity, but results in region-specific activation of a set of primary target regions encompassing parieto-cortical, hippocampal, and midbrain structures, as well as ventro-striatal components of the mesolimbic reward systems. Many of the activated regions also exhibit increased c-Fos immunostaining upon chemogenetic stimulation in freely-behaving mice, corroborating a neural origin for the observed functional signals. These results identify a set of regional substrates that act as primary functional targets of endogenous serotonergic stimulation, and establish causation between phasic activation of serotonergic neurons and regional fMRI signals. They further highlight a functional cross-talk between serotonin and mesolimbic dopamine systems hence providing a novel framework for understanding serotonin dependent functions and interpreting data obtained from human fMRI studies of serotonin modulating agents.