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. 2017 Jan 4;37(1):120-128.
doi: 10.1523/JNEUROSCI.2830-16.2016.

A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System

Vincent Beliveau  1   2 , Melanie Ganz  1 , Ling Feng  1 , Brice Ozenne  1   3 , Liselotte Højgaard  2   4 , Patrick M Fisher  1 , Claus Svarer  1 , Douglas N Greve  5   6 , Gitte M Knudsen  7   2
Affiliations

A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System

Vincent Beliveau et al. J Neurosci. .

Abstract

The serotonin (5-hydroxytryptamine, 5-HT) system modulates many important brain functions and is critically involved in many neuropsychiatric disorders. Here, we present a high-resolution, multidimensional, in vivo atlas of four of the human brain's 5-HT receptors (5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4) and the 5-HT transporter (5-HTT). The atlas is created from molecular and structural high-resolution neuroimaging data consisting of positron emission tomography (PET) and magnetic resonance imaging (MRI) scans acquired in a total of 210 healthy individuals. Comparison of the regional PET binding measures with postmortem human brain autoradiography outcomes showed a high correlation for the five 5-HT targets and this enabled us to transform the atlas to represent protein densities (in picomoles per milliliter). We also assessed the regional association between protein concentration and mRNA expression in the human brain by comparing the 5-HT density across the atlas with data from the Allen Human Brain atlas and identified receptor- and transporter-specific associations that show the regional relation between the two measures. Together, these data provide unparalleled insight into the serotonin system of the human brain.

Significance statement: We present a high-resolution positron emission tomography (PET)- and magnetic resonance imaging-based human brain atlas of important serotonin receptors and the transporter. The regional PET-derived binding measures correlate strongly with the corresponding autoradiography protein levels. The strong correlation enables the transformation of the PET-derived human brain atlas into a protein density map of the serotonin (5-hydroxytryptamine, 5-HT) system. Next, we compared the regional receptor/transporter protein densities with mRNA levels and uncovered unique associations between protein expression and density at high detail. This new in vivo neuroimaging atlas of the 5-HT system not only provides insight in the human brain's regional protein synthesis, transport, and density, but also represents a valuable source of information for the neuroscience community as a comparative instrument to assess brain disorders.

Keywords: 5-HT; MRI; PET; atlas; autoradiography; mRNA.

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Figures

Figure 1.
Figure 1.
Regional BPND and Bmax values for the five 5-HT targets: 5-HTT, 5-HT1AR, 5-HT1BR, 5-HT2AR, and 5-HT4R (A–E). The regions in the PET image space were combined to match the regions used by Varnäs et al. (2004) and Bonaventure et al. (2000) in their autoradiography measurement. The regressions (fixed through 0.0) are shown as black, dashed lines and the Pearson's (R) and Spearman's (S) correlation coefficients are reported. **p < 0.001. Dorsal raphe, median raphe, and globus pallidus for 5-HTT and dorsal raphe for 5-HT1AR were excluded from the regressions and marked with + on the figure (see Materials and Methods).
Figure 2.
Figure 2.
Average density (Bmax) maps for five 5-HT targets on the common FreeSurfer surface (left hemisphere; lateral view, upper and medial view, lower). Color scaling was individually adjusted to highlight features of the distributions.
Figure 3.
Figure 3.
Average density (Bmax) maps for the five 5-HT targets in the common MNI152 space (coronal, upper, z = 8 mm and sagittal, lower, x = −3 mm). Color scaling was individually adjusted to highlight features of the distributions.
Figure 4.
Figure 4.
Density values (Bmax) of the five 5-HT targets in FreeSurfer defined brain regions. Median raphe is not reported for 5-HTT due the irreversible kinetic of the TACs (see Material and Methods).
Figure 5.
Figure 5.
Regional density values (Bmax) and mRNA levels for the five 5-HT targets: 5-HTT, 5-HT1AR, 5-HT1BR, 5-HT2AR, and 5-HT4R (A–E). Subcortical data are shown in color and cortical data are shown in black. The regression lines are shown as black dashed lines and the Pearson's (R) and Spearman's (S) correlation coefficients are reported. *p < 0.01; ** p < 0.001. In C and D, a line was fitted to cortical regions (black) only. Dorsal raphe, median raphe, and globus pallidus for 5-HTT and dorsal raphe for 5-HT1AR were excluded from the regressions and marked with + on the figure (see Material and Methods).
Figure 6.
Figure 6.
Average density (Bmax) maps for five 5-HT targets on the inflated common FreeSurfer surface (left hemisphere; lateral view, upper and medial view, lower).
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