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Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging.

ABSTRACT: Background:The serotonin (5-HT) system has long been implicated in autism spectrum disorder (ASD) as indicated by elevated whole blood and platelet 5-HT, altered platelet and brain receptor and transporter binding, and genetic linkage and association findings. Based upon work in genetically modified mice, 5-HT is known to influence several aspects of brain development, but systematic neuroimaging studies have not previously been reported. In particular, the 5-HT transporter (serotonin transporter, SERT; 5-HTT) gene, Slc6a4, has been extensively studied. Methods:Using a 7-T MRI and deformation-based morphometry, we assessed neuroanatomical differences in an Slc6a4 knockout mouse on a C57BL/6 genetic background, along with an Slc6a4 Ala56 knockin mouse on two different genetic backgrounds (129S and C57BL/6). Results:Individually (same sex, same background, same genotype), the only differences found were in the female Slc6a4 knockout mouse; all the others had no significant differences. However, an analysis of variance across the whole study sample revealed a significant effect of Slc6a4 on the amygdala, thalamus, dorsal raphe nucleus, and lateral and frontal cortices. Conclusions:This work shows that an increase or decrease in SERT function has a significant effect on the neuroanatomy in 5-HT relevant regions, particularly the raphe nuclei. Notably, the Slc6a4 Ala56 knockin alone appears to have an insignificant, but suggestive, effect compared to the KO, which is consistent with Slc6a4 function. Despite the small number of 5-HT neurons and their localization to the brainstem, it is clear that 5-HT plays an important role in neuroanatomical organization.

SUBMITTER: Ellegood J

PROVIDER: S-EPMC5894125 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging.

Ellegood Jacob J Yee Yohan Y Kerr Travis M TM Muller Christopher L CL Blakely Randy D RD Henkelman R Mark RM Veenstra-VanderWeele Jeremy J Lerch Jason P JP

Molecular autism 20180410

<h4>Background</h4>The serotonin (5-HT) system has long been implicated in autism spectrum disorder (ASD) as indicated by elevated whole blood and platelet 5-HT, altered platelet and brain receptor and transporter binding, and genetic linkage and association findings. Based upon work in genetically modified mice, 5-HT is known to influence several aspects of brain development, but systematic neuroimaging studies have not previously been reported. In particular, the 5-HT transporter (serotonin tr ...[more]

PMID: 29651330

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Project description:Localised signal voids in diffusion-weighted (DW) images of skeletal muscle have been postulated to occur as a result of muscle fibre contraction and relaxation. We investigated the contrast mechanism of these signal voids using a combination of modelling and experimental measurements by employing DW and phase contrast (PC) imaging sequences. The DW signal and PC signal were simulated for each time point of a theoretical muscle twitch. The model incorporated compaction (simulating actively contracting muscle fibres) and translation (simulating passively moving surrounding fibres). The model suggested that the DW signal depended on contraction time and compaction whereas the PC signal depended on contraction time, compaction and translation. In a retrospective study, we tested this model with subgroup analyses on 10 healthy participants. Electrical nerve stimulation was used to generate muscle twitches in lower leg muscles; the resulting force was measured using an MR-compatible force transducer. At current levels causing a visible muscle twitch (~13 mA), the width of the first signal drop in the DW signal (mean ± SD: 103 ± 20 ms) was comparable with the force contraction time (93 ± 34 ms; intraclass correlation coefficient [ICC] = 0.717, P = .010). At current levels activating single motor units (~9 mA), the contraction time determined from the DW signal was 75 ± 13 ms and comparable with the PC contraction time (81 ± 15 ms; ICC = 0.925, P = .001). The maximum positive velocity was 0.55 ± 0.26 cm/s and the displacement was 0.20 ± 0.10 mm. Voxel-wise analysis revealed localised DW changes occurring together with more widespread phase changes. In conclusion, local signal attenuations in DW images following muscle fibre activation are primarily caused by compaction. The PC sequence also detects translating muscle tissue being passively pulled. The magnitude of the changes in DW and PC images depends on the twitch's contractile properties and percentage contraction. DW imaging and PC imaging can therefore measure twitch profiles of skeletal muscle fibres.

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Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging.

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Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging.

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