Brainwide mapping of endogenous serotonergic transmission via chemogenetic-fMRI

Abstract

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 ventrostriatal 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.

Oscillatory brain states govern spontaneous fMRI network dynamics

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Autism-associated 16p11.2 microdeletion impairs prefrontal functional connectivity in mouse and human

“…Brain slice electrophysiology was carried out as recently described (Giorgi et al, 2017) on young adult 16p11.2 + / + and 16p11.2 + /À mice (12 weeks old, n = 4 per group). Whole-cell patch-clamp recordings were made on pyramidal neurons of the layer V of the prefrontal cortex.…”

Paradoxical fMRI overconnectivity upon chemogenetic silencing of the prefrontal cortex

“…Leveraging the recent implementations of chemo-fMRI in the mouse 21 , we causally probed how cortical silencing affects brain-wide rsfMRI coupling. In contrast to theoretical 10 and experimental 8 evidence predicting that regional inactivation of a neural node would result in reduced functional synchronization with its direct anatomical targets, we found that both chronic and acute silencing of the PFC can counterintuitively increase rsfMRI connectivity within thalamo-cortical substrates of the mouse DMN, encompassing cortical and subcortical regions densely innervated by inactivated medial prefrontal areas.…”

“…Here we combine rsfMRI, neural and chemogenetic silencing (chemo-fMRI 21 ) and in vivo electrophysiology in the mouse to probe how inactivation of a cortical area causally affects rsfMRI coupling. Surprisingly, we find that chronic and acute neural silencing of the medial prefrontal cortex (PFC), a core component of the mouse default mode network DMN, 22 may lead to increased rsfMRI coupling between the silenced area and its thalamo-cortical terminals.…”