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| Home > Publications database > Hierarchical organization of the serotonergic system: A multi-tracer PET study on healthy subjects |
| Abstract | FZJ-2014-00690 |
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2013
Abstract: Introduction The serotonergic system is a highly diverse composition of various pre- and postsynaptic receptor subtypes and the serotonin transporter. Previous in vivo and postmortem studies revealed a rather distinct distribution pattern of these proteins throughout the human brain [1-2]. The cerebral cortex has often been subdivided into numerous areas characterized by structural, functional and cytoarchitectonic features [3] while protein-based organizations schemes are lacking. In the current study we propose a new organizational model of the brain based on protein distributions of the serotonergic system including the major inhibitory (5-HT1A and 5-HT1B), the major excitatory (5-HT2A) receptors and the transporter (SERT) of healthy subjects. Methods Dynamic PET scans were performed in 95 healthy subjects (age=28.0±6.9 years; 59% males) divided into 4 groups using the selective radioligands [carbonyl-11C]WAY100635 for 5-HT1A, [18F]altanserin for 5-HT2A, [11C]P943 for 5-HT1B and [11C]DASB for SERT. After motion correction and spatial normalization in SPM8 dynamic PET scans were quantified from radioactivity concentrations by a multi-linear reference tissue model (MRTM2; 5HT1A, 5-HT1B, SERT; BPND) and a bolus/infusion approach (5HT2A; BPP) in PMOD 3.3. A standard template in MNI stereotactic space served for ROI delineation. The ROI template based on the macro-anatomical criteria according to AAL (automated anatomical labeling) including 52 regions [4]. Similarities between receptor distribution patterns were analyzed by means of a hierarchical cluster analysis using Euclidean distances in combination with the Ward-linkage method as implemented in R2.15.0. All values were z-transformed across areas prior to analysis in order to establish equal weight between the protein bindings. Results Receptor densities as represented by binding potentials were computed for all ROIs. Hierarchical cluster analysis of group-average BP values revealed two main protein-distinct clusters. The first exclusively comprised subcortical areas such as the raphe nuclei, thalamus, pallidum, caudate nucleus, putamen, midbrain, and striatum, whereas in the second the remaining cortical areas were aggregated. Of note is the strikingly pronounced dissimilarity between these two clusters given by the high distance. In the cortical cluster occipital, parietal and frontal ROIs displayed closer similarities than temporal ROIs. Basal ganglia ROIs showed shorter Euclidean distance than raphe nuclei in the subcortical cluster. XIth International Conference on Quantification of Brain Function with PET, May 20-23, 2013, Shanghai, China Discussion We quantified in vivo PET data of 4 key proteins of the serotonergic system and subsequently used a data-driven approach to identify brain regions of similar features within the serotonergic system. Interestingly, spatially distant ROIs such as the subcortical areas were identified with close molecular similarity in contrast to cortical ROIs as given by the large Euclidean distance between these two clusters. The two clusters found were in accordance with the familiar classification of cortical und subcortical ROIs. Furthermore, temporal ROIs but also some frontal ROIs (ACC, Insula) exert a similar role as opposed to the remaining lobes. This result reflects an explicit hierarchical organization of the serotonergic system and emphasizes functions and interactions of the binding proteins beyond topologies.
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