A High-Resolution <i>In Vivo</i> Atlas of the Human Brain's Serotonin System

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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-HT _1A, 5-HT _1B, 5-HT _2A, and 5-HT ₄) 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.

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Author and article information

Journal

Journal ID (nlm-ta): J Neurosci

Journal ID (iso-abbrev): J. Neurosci

Journal ID (hwp): jneuro

Journal ID (pmc): jneurosci

Journal ID (publisher-id): J. Neurosci

Title: The Journal of Neuroscience

Publisher: Society for Neuroscience

ISSN (Print): 0270-6474

ISSN (Electronic): 1529-2401

Publication date (Print): 4 January 2017

Publication date PMC-release: 4 July 2017

Volume: 37

Issue: 1

Pages: 120-128

Affiliations

[1] ¹Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Rigshospitalet,

[2] ²Faculty of Health and Medical Sciences,

[3] ³Department of Public Health, Section of Biostatistics, and

[4] ⁴PET and Cyclotron Unit, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark,

[5] ⁵Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts 02129, and

[6] ⁶Harvard Medical School, Boston, Massachusetts 02115

Author notes

Correspondence should be addressed to Gitte M. Knudsen, MD, DMSc, Neurobiology Research Unit, Rigshospitalet, 9 Blegdamsvej, Section 6931, DK-2100 Copenhagen, Denmark. gmk@ 123456nru.dk

Author contributions: V.B., P.M.F., C.S., D.N.G., and G.M.K. designed research; V.B. and L.H. performed research; V.B., M.G., L.F., and B.O. analyzed data; V.B., M.G., L.F., B.O., L.H., P.M.F., C.S., D.N.G., and G.M.K. wrote the paper.