A critical period for auditory thalamocortical connectivity

Journal name:
Nature Neuroscience
Volume:
14,
Pages:
1189–1194
Year published:
DOI:
doi:10.1038/nn.2882
Received
Accepted
Published online

Abstract

Neural circuits are shaped by experience during periods of heightened brain plasticity in early postnatal life. Exposure to acoustic features produces age-dependent changes through largely unresolved cellular mechanisms and sites of origin. We isolated the refinement of auditory thalamocortical connectivity by in vivo recordings and day-by-day voltage-sensitive dye imaging in an acute brain slice preparation. Passive tone-rearing modified response strength and topography in mouse primary auditory cortex (A1) during a brief, 3-d window, but did not alter tonotopic maps in the thalamus. Gene-targeted deletion of a forebrain-specific cell-adhesion molecule (Icam5) accelerated plasticity in this critical period. Consistent with its normal role of slowing spinogenesis, loss of Icam5 induced precocious stubby spine maturation on pyramidal cell dendrites in neocortical layer 4 (L4), identifying a primary locus of change for the tonotopic plasticity. The evolving postnatal connectivity between thalamus and cortex in the days following hearing onset may therefore determine a critical period for auditory processing.

At a glance

Figures

  1. Developmental cortical map reorganization in mouse A1.
    Figure 1: Developmental cortical map reorganization in mouse A1.

    (ac) Representative A1 best frequency maps from the left hemisphere of young adult mice (P32–39) reared in a normal sound environment (a) or after 7-kHz tone exposure between P11–15 (b) or P16–20 (c). Circle denotes multi-unit recording site and hue represents best frequency (color scale). Triangles indicate non-A1 recording sites and x's indicate non-responsive sites. Scale bar represents 0.25 mm. Dark and light gray lines represent branches of the middle cerebral artery and inferior branches of the rhinal vein, respectively. (d) Sample frequency response areas of normalized firing rates as a function of tone frequency and level. Recordings obtained from caudal, intermediate and rostral zones of A1 from mice reared in a normal sound environment (top) or with 7-kHz tones between P11–15 (middle) or P16–20 (bottom). Vertical blue lines indicate best frequency. (e) Percentage of recording sites of all best frequency measurements in normally reared mouse A1 (open bars; n = 18, 15, 12, 20, 26 and 2 sites for each of the six categories (cat.)) or those reared with 7-kHz tones between P11–15 (gray bars; n = 27, 18, 15, 19, 14 and 0 sites) or P16–20 (black bars, n = 14, 9, 9, 14, 16 and 2 sites). Best frequencies are grouped into 0.5-octave bins centered on the x axis frequency. (f) Best frequency distributions segregated by rearing condition and topographic location. The percentages of best frequency sites are represented by circle diameter. Scale bar denotes a diameter equaling 50% of the distribution. (g) Best frequency values (mean ± s.e.m.) for each rearing group and topographic position. *P < 0.05 (t test).

  2. Thalamic tonotopy remains stable despite reorganization of A1 maps.
    Figure 2: Thalamic tonotopy remains stable despite reorganization of A1 maps.

    (a) In vivo recordings from MGBv (gray shading) with a multichannel silicon probe inserted at an angle matching the plane of thalamocortical slices. Inset, schematic depicting position of recording sites relative to cytoarchitectonic boundaries of MGBv. (b) Representative frequency response areas recorded from a lateral (left) and medial (right) recording site in MGBv. All conventions match those in Figure 1d. (c) Examples of raw multi-unit traces recorded with a tungsten microelectrode used for A1 mapping (upper) or silicon probe used for MGBv mapping (lower). Spikes were registered when signal amplitude exceeded a threshold line set at 4 s.d. from the mean of a 5-s running average (indicated by gray line). Scale bars represent 1 s and 0.1 mV. (d) Images of coronal section through MGBv reacted for cytochrome oxidase. High-power image depicts the location of two lesions made inside and outside of the MGBv boundary (black outline). Scale bars represent 0.5 mm. (e) Percentage of recording sites of all best frequency measurements from normally reared mouse MGBv (open bars; n = 9, 19, 10, 17, 41 and 5 sites for each of the six categories) and those reared with 7-kHz tones between P11–15 (gray bars; n = 21, 21, 14, 31, 50 and 14 sites). (f) Best frequency values (mean ± s.e.m.) measured at lateral (0.05 mm past the lateral MGBv boundary) or medial loci (0.2 mm past the lateral MGBv boundary), as well as averaged overall.

  3. Topography and developmental window for A1 response strengthening at P12-15.
    Figure 3: Topography and developmental window for A1 response strengthening at P12–15.

    (a) Schematic of the six MGBv stimulus (stim) sites (colored arrows) and 18 L4 locations analyzed in A1. Sample traces of ΔF/F at two different L4 loci (8 and 13) as a function of time following a 1-ms stimulus pulse to MGBv site 1 (blue) or 5 (yellow). P12 control mouse. Scale bars represent 100 ms and 0.1% ΔF/F. (b) Normalized (norm) peak ΔF/F as a function of stimulus site for three age groups (mean ± s.e.m.; P8–12, n = 13; P13–15, n = 16; P16–20, n = 16). *P < 0.05, **P < 0.01 (t test) between dark gray and black. (c) Peak ΔF/F location in L4 as a function of MGBv stimulus site. Inset, topographic slope (mean ± s.e.m.) for the three age groups.

  4. Critical period for experience-dependent topographic refinement at P12-15.
    Figure 4: Critical period for experience-dependent topographic refinement at P12–15.

    (a,b) Normalized (norm.) maximal ΔF/F across L4 loci in response to different MGBv stimulus sites for P16–20 mice raised in a normal acoustic environment (left, n = 16) or exposed to a 7-kHz tone from P8 (right, n = 13). Color code indicates MGBv stimulus site as in Figure 3a. (c) Normalized peak ΔF/F, defined as the maximum ΔF/F amplitude across all L4 loci, and location of L4 peak ΔF/F in response to different MGBv stimulus site for P16–20 control and 7-kHz exposed mice. Inset, topographic slopes. Data are mean ± s.e.m., *P < 0.05 (t test). (d) Schedule of tone exposure windows and recording (arrows). (e) Topographic slopes (median ± s.e.m.) for control mice (none, n = 9) and those exposed to 7 kHz during three time windows (P8–11, n = 8; P12–15, n = 8; P16–19, n = 5). #P < 0.05, **P < 0.01 (Mann-Whitney U test).

  5. Columnar shift of thalamocortical connectivity up to L4 through the critical period.
    Figure 5: Columnar shift of thalamocortical connectivity up to L4 through the critical period.

    (a) Nissl stain of a P20 thalamocortical slice for columnar analysis (red boxes). Black arrows denote approximate borders between layers I/II, layers IV/V and layer VI/white matter. Scale bar represents 125 μm. Normalized (norm.) ΔF/F and latency with distance from pia for three age groups (mean ± s.e.m.; P8–12, n = 13; P13–15, n = 15; P16–20, n = 11). *P < 0.05, **P < 0.01 (t test) between dark gray and black. (b) Sample upper L4 cortical response at P10 in normal (black) and high X2+ (green) ACSF. Scale bars represent 100 ms and 0.2% ΔF/F. Response reduction (median ± s.e.m.) in high X2+ for three age groups (P8–12, n = 6; P13–15, n = 8; P16–20, n = 4). #P < 0.05 (Mann-Whitney U test).

  6. Forebrain-specific gene deletion accelerates thalamocortical plasticity.
    Figure 6: Forebrain-specific gene deletion accelerates thalamocortical plasticity.

    (a) Icam5 normally slows dendritic spine maturation21. (b) Icam5 expression at P13 in the auditory thalamocortical slice. Note the absence of immunostaining in control MGBv and throughout Icam5−/− brain. Scale bars represent 1 mm. (c) Normalized (norm.) peak ΔF/F as a function of MGBv stimulus site in Icam5−/− mice for three age groups (median ± s.e.m.; P8–12, n = 8; P13–15, n = 10; P16–20, n = 9). **P < 0.01 (Mann-Whitney U test) between dark gray and black. (d) Topographic slope (median ± s.e.m.) for mice without (none; wild type (WT), n = 15; Icam5−/−, n = 9) or after 7-kHz exposure between P12–13 (wild type, n = 9; Icam5−/−, n = 7), P13–14 (Icam5−/−, n = 9) or P14–15 (Icam5−/−, n = 9). *P < 0.05 (Mann-Whitney U test).

  7. Stubby spine density increases through the critical period.
    Figure 7: Stubby spine density increases through the critical period.

    (a) Sample DiI-labeled upper L4 pyramidal cell. The white circle denotes a radius of 100 μm around the somata, in which spines were counted. Scale bar represents 20 μm (top). High-power image of dendrites at P13 revealing mushroom (yellow arrows) and stubby spines (green arrows). Scale bar represents 5 μm (bottom). (b) Spine density in P13 wild-type (n = 6) and Icam5−/− mice (n = 7 neurons). (c) Spine density (median ± s.e.m.) in P13 (n = 6) and P16 wild-type mice (n = 7 neurons). **P < 0.01 (Mann-Whitney U test).

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Affiliations

  1. Center for Brain Science, Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.

    • Tania Rinaldi Barkat &
    • Takao K Hensch
  2. Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts, USA.

    • Daniel B Polley

Contributions

T.R.B. performed all of the in vitro experiments and analysis. D.B.P. performed or supervised the in vivo experiments and analysis. T.R.B., D.B.P. and T.K.H. designed the study and wrote the paper.

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The authors declare no competing financial interests.

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