Serotonin regulation of behaviour via large-scale neuromodulation of serotonin receptor networks

Abstract

Although we understand how serotonin receptors function at the single-cell level, what role different serotonin receptors play in regulating brain-wide activity and, in turn, human behaviour, remains unknown. Here, we developed transcriptomic-neuroimaging mapping to characterise brain-wide functional signatures associated with specific serotonin receptors: serotonin receptor networks (SRNs). Probing SRNs with optogenetics-fMRI and pharmacology in mice, we show that activation of dorsal raphe serotonin neurons differentially modulates the amplitude and functional connectivity of different SRNs, showing that receptors’ spatial distributions can confer specificity not only at the local, but also at the brain-wide, network-level. In humans, using resting state fMRI, different sets of SRNs are linked to different behavioural phenotypes. These results provide compelling evidence that heterogeneous brain-wide distributions of different serotonin receptor types may underpin behaviourally-distinct modes of serotonin regulation. This suggests that dorsal raphe serotonin neurons may regulate multiple aspects of human behaviour via modulation of large-scale receptor networks.

Structural and neurophysiological alterations in Parkinson’s disease are aligned with cortical neurochemical systems

“…Inhibition of norepinephrine reuptake improves motor learning in healthy adults 44 . Serotonin is also a potent modulator of several cortical neurochemical systems and brain networks 45,46 . However, noradrenergic, serotonergic, and cholinergic dysfunction are more often related to cognitive than motor deficits in PD 22,30,32,41,[47][48][49] .…”

From Neurotransmitters to Networks: Transcending Organisational Hierarchies with Molecular-informed Functional Imaging

“…The resulting molecular-enriched networks can be compared between groups (e.g., patients vs controls), conditions (e.g., rest vs naturalistic stimuli), or states (e.g., drug vs placebo) as well as correlated with variables of interest (eg: clinical, 13 psychometric, or pharmacokinetic measures). This approach integrating molecular information into fMRI networks has been recently extended to gene expression data and used to examine receptor-enriched networks in both mice and humans using gene expression data from the Allen Mouse/Human Brain atlases to derive so-called "serotonin receptor networks (SRNs)" (Salvan et al, 2022).…”

“…One unexplored avenue is the use of blocking studies, within which the effects of a drug on molecular networks can be examined with and without an antagonist to the primary target, providing a causal manipulation of the system of interest which should be reflected in the molecular networks. Another option would be to utilise manipulations of molecular systems within animal models, as recently done by Salvan and colleagues (Salvan et al, 2022) to show that pharmacological and optogenetic manipulation of the serotonergic system modulates the SRNs in a receptor sub-system-specific manner. A similar study has also recently shown that the serotonin receptor gene expression patterns explain a large proportion of the variance in the BOLD signal following optogenetic stimulation of the dorsal raphe (Hamada et al, 2022).…”

“…Despite offering initial insights through ease of use, the spatial correlation analyses described above are limited in their ability to exploit the rich spatiotemporal dynamics of brain-wide BOLD fluctuations. In order to overcome this, novel analytical approaches have been developed to enrich fMRI data with the molecular information provided by PET and SPECT imaging (Cercignani et al, 2021;Dipasquale et al, 2020Dipasquale et al, , 2019Lawn et al, 2022aLawn et al, , 2022bDaniel Martins et al, 2022;Wong et al, 2022), and gene expression data from the AHBA (Salvan et al, 2022). Compared to the spatial correlation analyses, the derivation and analyses of molecular-enriched networks offers two key benefits.…”