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A High-Resolution in Vivo Atlas of the Human Brain's Benzodiazepine

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A High-Resolution in Vivo Atlas of the Human Brain's Benzodiazepine bioRxiv preprint doi: https://doi.org/10.1101/2020.04.10.035352; this version posted April 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. 1 A High-Resolution In Vivo Atlas of the Human 2 Brain’s Benzodiazepine Binding Site of GABAA Receptors 3 Running Title: A High-Resolution Atlas of the Human Brain’s BZ binding site of GABAAR 4 5 Martin Nørgaard1,2**, Vincent Beliveau5**, Melanie Ganz1,3, Claus Svarer1, Lars H Pinborg1,2, 6 Sune H Keller6, Peter S Jensen1, Douglas N. Greve4, Gitte M. Knudsen1,2* 7 8 1 Neurobiology Research Unit & CIMBI, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark 9 2 Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark 10 3 University of Copenhagen, Department of Computer Science, Copenhagen, Denmark 11 4 Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 12 Boston, MA, USA 13 5 Medical University of Innsbruck, Department of Neurology, Innsbruck, Austria 14 6 Department of Clinical Physiology, Nuclear Medicine and PET, Righospitalet, Copenhagen, Denmark 15 16 * Corresponding author: 17 Professor Gitte Moos Knudsen 18 Neurobiology Research Unit, Section 6931, Rigshospitalet 19 9 Blegdamsvej 20 DK-2100 Copenhagen 21 +45 3545 6720 22 [email protected] 23 24 ** These authors contributed equally 25 26 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.04.10.035352; this version posted April 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. 27 ABSTRACT 28 Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human brain and 29 plays a key role in several brain functions and neuropsychiatric disorders such as anxiety, epilepsy, 30 and depression. The binding of benzodiazepines to the benzodiazepine receptor sites (BZR) located 31 on GABAA receptors (GABAARs) potentiates the inhibitory effect of GABA leading to the 32 anxiolytic, anticonvulsant and sedative effects used for treatment of those disorders. However, the 33 function of GABAARs and the expression of BZR protein is determined by the GABAAR subunit 34 stoichiometry (19 genes coding for individual subunits), and it remains to be established how the 35 pentamer composition varies between brain regions and individuals. 36 Here, we present a quantitative high-resolution in vivo atlas of the human brain BZRs, generated on 37 the basis of [11C]flumazenil Positron Emission Tomography (PET) data. Next, based on 38 autoradiography data, we transform the PET-generated atlas from binding values into BZR protein 39 density. Finally, we examine the brain regional association with mRNA expression for the 19 40 subunits in the GABAAR, including an estimation of the minimally required expression of mRNA 41 levels for each subunit to translate into BZR protein. 42 This represents the first publicly available quantitative high-resolution in vivo atlas of the spatial 43 distribution of BZR densities in the healthy human brain. The atlas provides a unique 44 neuroscientific tool as well as novel insights into the association between mRNA expression for 45 individual subunits in the GABAAR and the BZR density at each location in the brain. 46 47 Key words: GABA, PET, Atlas, Autoradiography, mRNA, benzodiazepine binding site 48 49 50 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.04.10.035352; this version posted April 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. 51 INTRODUCTION 52 Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human brain and 53 is a key component in several brain functions and in neuropsychiatric disorders, including anxiety, 54 epilepsy, and depression [1]. The GABAA receptor (GABAAR) is a pentameric complex that 55 functions as a ligand-gated chloride ion channel and it is the target of several pharmacological 56 compounds such as anesthetics, antiepileptics, and hypnotics. 57 Benzodiazepines are well-known for their sedative, anticonvulsive and anxiolytic effects. They act 58 as positive allosteric modulators via the benzodiazepine binding sites (BZR) which are located 59 between the α1,2,3,5 and g1-3 subunits in the pentameric constellation of the postsynaptic ionotropic 60 GABAAR. In total, 19 subunits (a1-6, b1-3, g1-3, r1-3, d, e, q, p) have currently been identified, and 61 the constellation of subunits to form GABAARs, and consequently the expression of and affinity to 62 the BZR site, has been shown to differ between individuals, between brain regions, and across the 63 life span [1]. 64 High-resolution quantitative human brain atlases of e.g., receptors represent a highly valuable 65 reference tool in neuroimaging research to inform about the in vivo 3-dimensional distribution and 66 density of specific targets. On the basis of high-resolution PET neuroimaging data from 210 healthy 67 individuals, Beliveau et al. 2017 [2] created a quantitative high-resolution atlas of the serotonin 68 system (four receptors, and the serotonin transporter), providing a valuable reference for researchers 69 studying human brain disorders, or effects of pharmacological interventions on the serotonin system 70 that may subsequently down- or upregulate the receptors. Because the functional organization of 71 receptor systems may be different than commonly defined structural organizations (e.g. Brodmann 72 [3]), it is important to define and use the organization of the receptor systems modulating brain 73 function not only to capture a more refined view of the brain [4], but also to provide insights in 74 novel brain parcellations. 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.04.10.035352; this version posted April 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. 75 Here, we present the first quantitative PET-based high-resolution in vivo 3D human brain atlas 76 of the distribution of BZRs; an atlas to serve as a reference in future studies. Based on 77 autoradiography data, we transform the PET generated atlas into brain regional protein densities of 78 BZR and compare it to the mRNA expression for individual subunits in the GABAAR, using the 79 Allen Human Brain Atlas [5]. 80 81 METHODS 82 Study participants and neuroimaging 83 Sixteen healthy participants (9 females; mean age ± SD: 26.6 ± 8 years, range 19-46 years) were 84 included in the study [6]. The study was approved by the Regional Ethics Committee (KF 85 01280377), and all subjects provided written informed consent prior to participation, in accordance 86 with The Declaration of Helsinki II. Data from 10 individuals have entered a previous paper (Feng 87 et al. 2016 [7]) where more detailed accounts of the methods can be found. The participants were 88 scanned between 1 and 3 times with the High-Resolution Research Tomograph (HRRT, 89 CTI/Siemens) PET scanner at Rigshospitalet (Copenhagen, Denmark) with the radioligand 90 [11C]flumazenil (26 unique PET scans in total). After an initial transmission scan [8], the 91 radioligand was given either as an intravenous bolus injection or as a bolus-infusion, and a PET 92 emission scan was conducted over 90 minutes, starting at the time of injection. PET data was 93 reconstructed into 35 frames (6x5, 10x15, 4x30, 5x120, 5x300, 5x600 seconds) with isotropic 94 voxels of 1.2 mm using a 3D-ordered subset expectation maximum and point spread function 95 modelling (3D-OSEM-PSF) (16 subsets, 10 iterations) with [137Cs]transmission scan-based 96 attenuation correction and no postfiltering [9-11]. Arterial sampling was also performed and the 97 arterial input function was corrected for radiometabolites [7]. The reconstructed PET data were 98 motion corrected using the reconcile procedure in AIR (v. 5.2.5, http://loni.usc.edu/Software/AIR), 4 bioRxiv preprint doi: https://doi.org/10.1101/2020.04.10.035352; this version posted April 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. 99 and our criterion for acceptable motion was a median movement less than 3 mm across frames. The 100 PET tracer injection protocols carried out for each subject are listed in Table S1 in the 101 supplementary. 102 An isotropic T1-weigthed MP-RAGE was acquired for all participants (matrix size = 256 x 256 x 103 192; voxel size = 1 mm; TR/TE/TI = 1550/3.04/800 ms; flip angle = 9°) using either a Magnetom 104 Trio 3T or a 3T Verio MR scanner (both Siemens Inc.). Furthermore, an isotropic T2-weighted 105 sequence (matrix size 256 x 256 x 176; voxel size = 1 mm; TR/TE = 3200/409 ms; flip angle = 106 120˚) was acquired for all participants. All acquired MRI’s were corrected for gradient 107 nonlinearities [12] and examined to ensure absence of structural abnormalities. 108 The MR data was processed using FreeSurfer (v.6.0) [13], and co-registered to the PET data using a 109 rigid transformation and a normalized mutual information cost function.
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