Abstract
Central serotonin (5-HT) orchestrates myriad cognitive processes andlies at the core of many stress-related psychiatric illnesses. However, the basicrelationship between its brain-wide axonal projections and functional dynamics isnot known. Here we combine optogenetics and fMRI to produce a brain-wide 5-HT evokedfunctional map. We find that DRN photostimulation leads to an increase in thehemodynamic response in the DRN itself, while projection areas predominately exhibita reduction of cerebral blood volume mirrored by suppression of cortical deltaoscillations. We find that the regional distribution of post-synaptically expressed5-HT receptors better correlates with DRN 5-HT functional connectivity thananatomical projections. Our work suggests that neuroarchitecture is not the primarydeterminant of function for the DRN 5-HT. With respect to two 5-HT elevatingstimuli, we find that acute stress leads to circuit-wide blunting of the DRN output,while the SSRI fluoxetine noticeably enhances DRN functional connectivity. Thesedata provide fundamental insight into the brain-wide functional dynamics of the 5-HTprojection system.
Highlights
The central nervous system (CNS)’s expansive serotonergic (5-HT) circuit is amongst the most versatile and important neurotransmitter systems for emotional and cognitive processing
While no ChR2-eYFP-positive cell bodies were found outside the dorsal raphe nucleus (DRN) (Fig. 1b, c), axons co-expressing ChR2-eYFP and 5-HT were found terminating in the neocortex (Supplementary Figure 2), thalamus (Supplementary Figure 3), amygdala (Fig. 1d; Supplementary Figure 4), dorsal hippocampus (Fig. 1e; Supplementary Figure 5) and striatum (Supplementary Figure 6)
We investigated cellular and molecular factors determining functional connectivity of the DRN 5-HT circuit by comparing the wholebrain DRN/5-HT hemodynamic maps derived from optogenetic combined with functional magnetic resonance imaging (ofMRI) with the DRN/5-HT neuron projection density maps from the Allen Institute for Brain Science (AIBS)
Summary
The central nervous system (CNS)’s expansive serotonergic (5-HT) circuit is amongst the most versatile and important neurotransmitter systems for emotional and cognitive processing. Does the anatomical architecture of the 5-HT circuit correlate with its functional connectivity? To address these outstanding questions, we used optogenetic combined with functional magnetic resonance imaging (ofMRI)[5] to establish a whole-brain visualisation of the central 5-HT functional circuit in the live mouse. When examining the circuit following either acute stress or administration of fluoxetine, we observe opposite effects on DRN 5-HT functional connectivity, providing an elegant explanation at the circuit level for the behavioural divergence of these stimuli. Our observations underscore the power of ofMRI for characterizing large brain networks originating from subcortical nuclei, as well for analysing effects of acute stimuli on neuromodulatory systems
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