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Sensory deprivation after focal ischemia in mice accelerates brain remapping and improves functional recovery through Arc-dependent synaptic plasticity

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Science Translational Medicine  31 Jan 2018:
Vol. 10, Issue 426, eaag1328
DOI: 10.1126/scitranslmed.aag1328
  • Fig. 1 Whisker deprivation accelerates right forepaw remapping after photothrombosis.

    (A) Schematic representation of the experimental groups used in the study: WT, wild-type mice; Arc, Arc knockout mice; Control, whiskers intact; Depriv, whiskers trimmed. In the OIS field of view (dashed circle), the area subjected to photothrombosis (S1FP, blue) and whisker barrel cortex (S1WB, yellow) is shown. (B) Timeline illustrates behavioral testing, OIS imaging, and whisker trimming. (C) Activation density heat maps projected onto a white light cortical image shows the area activated by right forepaw stimulation at baseline (Pre) and 1 (WK1), 4 (WK4), and 8 (WK8) weeks after photothrombosis. The whisker barrel cortex, delineated using whisker stimulation–evoked mapping with OIS imaging, is outlined in black. (D) Mean activation intensity (calculated for individual mice) after right forepaw stimulation for each group over the recovery time course. Intensity response is determined for each mouse before being group-averaged. *,+P ≤ 0.05, **,‡‡P ≤ 0.01, ###,‡‡‡P ≤ 0.001 compared to baseline using repeated-measures analysis of variance (ANOVA). WT-Control, n = 11; WT-Depriv, n = 10; Arc-Control, n = 8; Arc-Depriv, n = 7.

  • Fig. 2 Whisker deprivation accelerates and enhances behavioral recovery after right S1FP photothrombosis.

    (A) Cylinder rearing test shows forepaw use during exploratory behavior. (B) Graph shows limb use asymmetry before (Pre) and 1 (WK1), 3 (WK3), 5 (WK5), and 7 (WK7) weeks after photothrombosis in the experimental groups described in Fig. 1A. *,‡P ≤ 0.05, ***,+++,###,‡‡‡P ≤ 0.001 compared to baseline time point (Pre), using repeated-measures ANOVA with Newman-Keuls multiple pairwise comparisons. WT-Control, n = 22; WT-Depriv, n = 16; Arc-Control, n = 7; Arc-Depriv, n = 7.

  • Fig. 3 Regions of remapping demonstrate increased dendritic spine density.

    (A) Cortical dendritic spines (inset, photomicroph of Golgi-Cox–stained spines) were counted at perilesional and distant regions in relation to the area of photothrombosis (blue). Mean spine density is compared between the four groups of mice (WT-Control, WT-Depriv, Arc-Control, and Arc-Depriv) at the distant site (B) as well as at anterior (C) and posterior (D) perilesional sites. Statistical comparisons were performed using ANOVA with Bonferroni correction (*P ≤ 0.05; **P ≤ 0.01). WT-Control, n = 5; WT-Depriv, n = 5; Arc-Control, n = 4; Arc-Depriv, n = 4.

  • Fig. 4 Whisker deprivation–induced remapping is stable beyond the deprivation period.

    (A) WT mice were subjected to right S1FP (R. S1FP) photothrombosis. Half of the mice underwent right whisker trimming every other day for the first 8 weeks of the experiment; thereafter, trimming was halted and whiskers were allowed to regrow. (B) Limb behavior and OIS imaging were performed at the times indicated. (C to H) Activation density heat maps projected onto a white light cortical image show right S1FP maps, 8 (C and D) and 12 weeks (E and F) after photothrombosis, and right S1WB maps 12 weeks after photothrombosis (G and H) in WT-Control (C, E, and G) and WT-Depriv (D, F, and H) groups. RFP, right forepaw; WB, whisker barrel. (I to O) Activation heat maps projected onto a white light cortical image showing >65% density response for each map. Map identity is indicated by the label in each image, and dark blue represents overlap between the maps. The >65% threshold was used only for display; statistical comparisons were independent of any threshold. Spatial distribution difference: *P < 0.0071 (Bonferroni-corrected); n.s., not significant (see fig. S13 and Materials and Methods for more details). WT-Control, n = 11; WT-Depriv, n = 11. (P) Line graph showing the differences in limb use asymmetry before (Pre) and 1 (WK1), 3 (WK3), 5 (WK5), 7 (WK7), and 11 (WK11) weeks after right S1FP photothrombosis in WT-Control and WT-Depriv mice. *P ≤ 0.05, **P ≤ 0.01, ***, +++P ≤ 0.001; n.s., not significant compared to baseline time point (Pre), using repeated-measures ANOVA with Newman-Keuls multiple pairwise comparisons. WT-Control, n = 11; WT-Depriv, n = 8.

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/10/426/eaag1328/DC1

    Fig. S1. Arc gene deletion does not affect infarct volume.

    Fig. S2. Arc gene deletion does not alter perilesional reactive astrocytosis.

    Fig. S3. Full-range activation heat maps mirror thresholded activation maps.

    Fig. S4. Mean oxy-Hb intensity maps are similar to activation heat maps.

    Fig. S5. P value maps show accelerated remapping into the whisker barrel cortex insensory-deprived mice.

    Fig. S6. Baseline right S1FP activation intensity is similar in all groups.

    Fig. S7. Baseline forepaw activation is similar in location for all groups of mice.

    Fig. S8. Left S1FP and right hindpaw (S1HP) activations remain intact before and after injury.

    Fig. S9. Left S1FP activation remains intact throughout injury and recovery.

    Fig. S10. Right S1FP remaps after focal ischemia, but left S1FP remains stable throughout thetime course.

    Fig. S11. Whisker deprivation does not affect limb use symmetry.

    Fig. S12. Dendritic spine density is lower in perilesional cortex compared to distant corticalregions.

    Fig. S13. Right S1FP maps remain stable after whisker regrowth.

    Fig. S14. Right S1WB area is smaller in WT-Depriv compared to WT-Control groups.

    Fig. S15. Oxy-Hb contrast demonstrates the greatest signal-to-noise ratio of all spectralcomponents.

  • Supplementary Material for:

    Sensory deprivation after focal ischemia in mice accelerates brain remapping and improves functional recovery through Arc-dependent synaptic plasticity

    Andrew W. Kraft, Adam Q. Bauer, Joseph P. Culver, Jin-Moo Lee*

    *Corresponding author. Email: leejm{at}wustl.edu

    Published 31 January 2018, Sci. Transl. Med. 10, eaag1328 (2018)
    DOI: 10.1126/scitranslmed.aag1328

    This PDF file includes:

    • Fig. S1. Arc gene deletion does not affect infarct volume.
    • Fig. S2. Arc gene deletion does not alter perilesional reactive astrocytosis.
    • Fig. S3. Full-range activation heat maps mirror thresholded activation maps.
    • Fig. S4. Mean oxy-Hb intensity maps are similar to activation heat maps.
    • Fig. S5. P value maps show accelerated remapping into the whisker barrel cortex in sensory-deprived mice.
    • Fig. S6. Baseline right S1FP activation intensity is similar in all groups.
    • Fig. S7. Baseline forepaw activation is similar in location for all groups of mice.
    • Fig. S8. Left S1FP and right hindpaw (S1HP) activations remain intact before and after injury.
    • Fig. S9. Left S1FP activation remains intact throughout injury and recovery.
    • Fig. S10. Right S1FP remaps after focal ischemia, but left S1FP remains stable throughout the time course.
    • Fig. S11. Whisker deprivation does not affect limb use symmetry.
    • Fig. S12. Dendritic spine density is lower in perilesional cortex compared to distant cortical regions.
    • Fig. S13. Right S1FP maps remain stable after whisker regrowth.
    • Fig. S14. Right S1WB area is smaller in WT-Depriv compared to WT-Control groups.
    • Fig. S15. Oxy-Hb contrast demonstrates the greatest signal-to-noise ratio of all spectral components.

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