Research ArticleNEUROSCIENCE

Awake functional MRI detects neural circuit dysfunction in a mouse model of autism

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Science Advances  05 Feb 2020:
Vol. 6, no. 6, eaav4520
DOI: 10.1126/sciadv.aav4520
  • Fig. 1 NBS detect global hypoconnectivity in 15q dup mice.

    (A) Group-averaged connectivity matrices (Pearson correlation coefficients) in WT-saline (bottom, n = 15) and 15q dup-saline groups (top, n = 10). Color bar represents the Pearson correlation coefficient. (B) Network of reduced connectivity in the 15q dup-saline group identified with the NBS (P = 0.001). Connections are colored according to effect size (Cohen’s d). (C) Box plot showing distribution of network-averaged connectivity in WT-saline and 15q dup-saline groups. Connectivity averaged over the connections comprising the network in (A). Circles indicate medians, and boxes indicate 25th and 75th percentiles. (D) Extent to which individual regions are affected by the network of reduced connectivity in the 15q dup group. Strength is the sum of effects sizes across all connections associated with a given region. Strength is averaged between contralateral regions. CC, anterior cingulate cortex; mPFC, medial prefrontal cortex; SC, somatosensory cortex; IC, insular cortex; Pir, piriform; RSC, retrosplenial cortex; NAc, nucleus accumbens; AMG, amygdala; Hip, hippocampus; BNST, bed nucleus and stria terminus; Hyp, hypothalamus.

  • Fig. 2 Distinct BOLD response to odor stimulation between WT and 15q dup-saline mice.

    (A) Schematic of odor presentation system. (B) Photo of dedicated mouse odor mask. (Photo credit: T. Tsurugizawa, Ajinomoto Co. Inc.) (C) Schedule of odor stimulation task. (D) Significant BOLD response to other-odor stimulation in WT-saline (n = 15) or 15q dup-saline mice [n = 10; P < 0.05, false discovery rate (FDR)–corrected at the cluster level]. (E) Significant BOLD response to other-odor stimulation in WT-saline compared to 15q dup-saline (P < 0.05, FDR-corrected at the cluster level). Color bar represents the t statistic value.

  • Fig. 3 FA and structural connectivity in 15q dup mice.

    (A) Group-averaged FA maps in WT (top, n = 10) and 15q dup mice (middle, n = 12) and differences of FA between WT and 15q dup groups (bottom). Color bar, FA value and ΔFA. (B) Averaged FA values within each ROI in WT (n = 10) and 15q dup mice (n = 12). (C) Mean FA and (D) EW structural connectivity in the same ROIs as functional connectivity in WT (bottom) and 15q dup (top) groups. Color bar, FA or EW.

  • Fig. 4 Decreased brain serine and restored social behavior by acute DCS treatment in 15q dup mice.

    (A) Changes in amino acid concentrations between WT and 15q dup mice (n = 6 in each group). The mean level of WT-saline was set to 1. Ce, cerebellum; FC, frontal cortex. (B and C) Quantification of l- and d-serine concentrations in the frontal cortex. Mice that were 1 to 3 weeks postnatal were used for this analysis (n = 4, 7, and 10 15q dup and n = 9, 6, and 7 WT mice of ages 1, 2, and 3 weeks, respectively). The mean level for WT was set to 100%. Values are expressed with means ± SEM. *P < 0.05, **P < 0.01 significantly different from WT mice by Student’s t test. (D) Reciprocal social interaction test after administration of DCS or saline (WT-saline, n = 11; WT-DCS, n = 11; 15q dup-saline, n = 10; 15q dup-DCS, n = 12). (E) Novelty-induced anxiety in open-field test after administration of DCS or saline (WT-saline, n = 8; WT-DCS, n = 9; 15q dup-saline, n = 9; 15q dup-DCS, n = 10). (F) Adult USV calls after administration of DCS or saline (WT-saline, n = 8; WT-DCS, n = 9; 15q dup-saline, n = 9; 15q dup-DCS, n = 10). Values are expressed with means ± SEM. *P < 0.05, **P < 0.01; N.S., not significant following Tukey-Kramer procedure.

  • Fig. 5 Acute DCS treatment partially normalized rsfMRI functional connectivity in 15q dup mice.

    (A) Group-averaged connectivity matrices (Pearson correlation coefficients) for WT (top) and 15q dup (bottom) groups. Top right matrices show the group administered saline, and bottom left matrices show the group administered DCS. (B) Box plot comparing whole-brain–averaged (i.e., global) connectivity between WT and 15q dup groups administered saline or DCS. The P values indicated are for a two-sample t test performed on whole-brain–averaged connectivity. (C) Network of reduced connectivity in the 15q dup group identified with the NBS (P < 0.01). Connections are colored according to effect size (Cohen’s d). (D) Box plot showing distribution of network-averaged connectivity in WT and 15q dup groups, stratified according to administration of DCS and saline. (E) Extent to which individual regions showed reversal of connectivity reductions following administration of DCS. Strength is the sum of effects sizes across all connections associated with a given region. Strength is averaged between contralateral regions.

  • Fig. 6 Acute DCS treatment partially normalized odor fMRI response in 15q dup mice.

    (A) Significant BOLD response to other-odor stimulation in 15q dup-DCS (n = 10) and WT-DCS (n = 10) groups (P < 0.05, FDR-corrected at the cluster level). (B) Significant BOLD response to other-odor stimulation in 15q dup-DCS compared to 15q dup-saline (P < 0.05, FDR-corrected at the cluster level). (C) Total number of gray matter voxels with a significant BOLD response (P < 0.05, FDR-corrected at the cluster level) to other-odor stimulation.

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/6/6/eaav4520/DC1

    Fig. S1. Awake fMRI system and physiological parameters.

    Fig. S2. EEG recording.

    Fig. S3. Head motion parameters.

    Fig. S4. Similar BOLD response to odor stimulation in the olfactory bulb between WT and 15q dup-saline mice.

    Fig. S5. Common ICA components in WT and 15q dup mice.

    Fig. S6. DMN in WT and 15q dup mice.

    Fig. S7. Modular decomposition of functional connectivity networks and comparison of within-module–averaged connectivity.

    Table S1. Amino acid concentration in hindbrain in WT and 15q dup mice.

    Table S2. Amino acid concentration in forebrain in WT and 15q dup mice.

  • Supplementary Materials

    This PDF file includes:

    • Fig. S1. Awake fMRI system and physiological parameters.
    • Fig. S2. EEG recording.
    • Fig. S3. Head motion parameters.
    • Fig. S4. Similar BOLD response to odor stimulation in the olfactory bulb between WT and 15q dup-saline mice.
    • Fig. S5. Common ICA components in WT and 15q dup mice.
    • Fig. S6. DMN in WT and 15q dup mice.
    • Fig. S7. Modular decomposition of functional connectivity networks and comparison of within-module–averaged connectivity.
    • Table S1. Amino acid concentration in hindbrain in WT and 15q dup mice.
    • Table S2. Amino acid concentration in forebrain in WT and 15q dup mice.

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