Research ArticleFUNCTIONAL NEUROIMAGING

Structural-functional connectivity deficits of neocortical circuits in the Fmr1−/y mouse model of autism

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Science Advances  20 Nov 2015:
Vol. 1, no. 10, e1500775
DOI: 10.1126/sciadv.1500775
  • Fig. 1 Reduced structural integrity of the corpus callosum in Fmr1−/y mice.

    DTI was performed on adult Fmr1−/y and wild type (WT) mice to measure the FA of the corpus callosum. Tensor images were collectively acquired in several horizontal planes from +2.0 to −4.0 mm from the bregma, with an interplane distance of 0.5 mm (WT, n = 12; Fmr1−/y, n = 7). FA values were measured on individual planes and grouped into the splenium/FMJ of the corpus callosum, EC, the Genu/Body of the corpus callosum, and the FMI of the corpus callosum. (A) Color-coded heat maps of the FA values showing the average (of all WT and Fmr1−/y animals) of one plane from each group (from anterior to posterior). Warm colors indicate fiber tracts with strong diffusion coherence. (B) The FA values were significantly reduced in Fmr1−/y mice in the FMI (P = 3.5 × 10−5) and the splenium/FMJ (P = 0.0069). Data are means ± SEM. **P < 0.01 (Fmr1−/y compared with WT). Statistical significance was determined using multiple t tests corrected for multiple comparisons using the Holm-Sidak method with α = 0.05.

  • Fig. 2 Reorganization of inputs to V1 of Fmr1−/y mice.

    (A) Summary image showing the localization of all retrogradely (input; green) and anterogradely (local; red) labeled neurons of all WT (upper panel; n = 3) and Fmr1−/y (lower panel; n = 3) mice within a 3D model. Scale bar, 1 mm. (B) Average distance of the retrogradely labeled cells from the injection site in Fmr1−/y and WT mice (***P < 0.0001, Mann-Whitney test). (C) The relative FLN (in percentage of total) plotted as a function of distance to the injection site indicates a significant change in the distribution (***P < 0.0001, Kolmogorov-Smirnov test). (C′) In particular, the FLN with a distance of less than 0.5 mm is increased in Fmr1−/y mice (P = 0.0242, unpaired t test). (D) FLN expressed as a function of brain area showing an increased number of local inputs (from V1) in Fmr1−/y mice compared to WT mice (P = 1.57 × 10−5, multiple t tests corrected for multiple comparisons using the Holm-Sidak method with α = 0.05). Ctx, cortical areas; Vi, visual cortex; V1, primary Vi; V2, secondary Vi; V2L, lateral V2; V2MM, mediomedial V2; V2ML, mediolateral V2; Motor, motor cortex; Som, somatosensory cortex; RS, retrosplenial cortex; CG, cingulate cortex; Au, auditory cortex; Thal, thalamus; ON, other nuclei. (E) The average distance of the local input (within V1) is decreased in the Fmr1−/y mice (P < 0.0001, Mann-Whitney test). (F) The distribution of the local input (within V1) shows that the fraction 0 to 400 μm is increased, whereas the fraction above 600-μm distance is decreased (***P < 0.0001, Kolmogorov-Smirnov test). All data are means ± SEM.

  • Fig. 3 Functional decoupling of neocortical brain areas in Fmr1−/y mice.

    Brain graph showing the network connectivity of nodes (blue spheres) via edges (lines, color-coded for their Z score), indicating the strength of the connections. (A to D) fMRI measurements under light isoflurane anesthesia revealed a reduced functional connectivity between a number of neocortical brain areas in the Fmr1−/y (A and B; n = 7) compared to WT (C and D; n = 10) mice. In particular, the intrahemispheric connections are strongly affected (A and C), whereas the homotopic interhemispheric connectivity is only partially affected (for example, Mo-Mo; B and D). HC, hippocampus; Mo, motor cortex; S1, primary somatosensory cortex; V1, primary visual cortex; CPu, caudate putamen.

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/1/10/e1500775/DC1

    Fig. S1. High-field 11.7-T DT-MRI measurements of the white and gray matter of adult Fmr1−/y and wild-type littermate mice.

    Fig. S2. Tracing of the input to V1.

    Fig. S3. Schematic representation of the experimental strategy for the 3D anatomical registration of projection neurons into V1.

    Fig. S4. Functional connectivity matrix of wild-type and Fmr1−/y mice.

    Movie S1. Slice view and 3D view, illustrating the 3D mouse brain model with the combined positions of all retrogradely (input; green) and anterogradely (local; red) labeled neurons in wild-type mice.

    Movie S2. Slice view and 3D view, illustrating the 3D mouse brain model with the combined positions of all retrogradely (input; green) and anterogradely (local; red) labeled neurons in Fmr1−/y mice.

  • Supplementary Materials

    This PDF file includes:

    • Fig. S1. High-field 11.7-T DT-MRI measurements of the white and gray matter of adult Fmr1−/y and wild-type littermate mice.
    • Fig. S2. Tracing of the input to V1.
    • Fig. S3. Schematic representation of the experimental strategy for the 3D anatomical registration of projection neurons into V1.
    • Fig. S4. Functional connectivity matrix of wild-type and Fmr1−/ymice.
    • Legends for movies S1 and S2

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    Other Supplementary Material for this manuscript includes the following:

    • Movie S1 (.mp4 format). Slice view and 3D view, illustrating the 3D mouse brain model with the combined positions of all retrogradely (input; green) and anterogradely (local; red) labeled neurons in wild-type mice.
    • Movie S2 (.mp4 format). Slice view and 3D view, illustrating the 3D mouse brain model with the combined positions of all retrogradely (input; green) and anterogradely (local; red) labeled neurons in Fmr1−/y mice.

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