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Oxytocin mediates early experience–dependent cross-modal plasticity in the sensory cortices


Sensory experience is critical to development and plasticity of neural circuits. Here we report a new form of plasticity in neonatal mice, where early sensory experience cross-modally regulates development of all sensory cortices via oxytocin signaling. Unimodal sensory deprivation from birth through whisker deprivation or dark rearing reduced excitatory synaptic transmission in the correspondent sensory cortex and cross-modally in other sensory cortices. Sensory experience regulated synthesis and secretion of the neuropeptide oxytocin as well as its level in the cortex. Both in vivo oxytocin injection and increased sensory experience elevated excitatory synaptic transmission in multiple sensory cortices and significantly rescued the effects of sensory deprivation. Together, these results identify a new function for oxytocin in promoting cross-modal, experience-dependent cortical development. This link between sensory experience and oxytocin is particularly relevant to autism, where hypersensitivity or hyposensitivity to sensory inputs is prevalent and oxytocin is a hotly debated potential therapy.

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Figure 1: Whisker deprivation from birth significantly reduced excitatory synaptic transmission in layer II/III pyramidal neurons of the S1 barrel field and cross-modally in other sensory cortices.
Figure 2: Whisker deprivation from birth significantly reduced visually evoked responses for neurons in V1.
Figure 3: Dark rearing from birth significantly reduced excitatory synaptic transmission in layer II/III pyramidal neurons of the primary visual cortex and cross-modally in other sensory cortices.
Figure 4: Sensory deprivation from birth reduced oxytocin level at P14.
Figure 5: Sensory deprivation from birth reduced oxytocin release.
Figure 6: Oxytocin application significantly increased excitatory synaptic transmission in S1 layer II/III pyramidal neurons via OXTR-mediated signaling.
Figure 7: In vivo oxytocin injection rescued the effect of sensory deprivation, whereas its antagonist reduced excitatory synaptic transmission.
Figure 8: Environmental enrichment rescued the effect of sensory deprivation.

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We thank S. Young (US National Institute of Mental Health) for the oxytocin knockout mice, V. Grinevich (Max Planck Institute, Heidelberg, Germany) for the AAV-OXT-Venus construct, Y. Lu, X. Zeng and S. He for technical assistance, and colleagues at ION and members of the Yu laboratory for suggestions and comments. This work was supported by grants from the Ministry of Science and Technology (2011CBA00400) to X.Y. and H.Y., the National Natural Science Foundation of China (31125015 and 31321091) to X.Y., the China Postdoctoral Science Foundation (2013M540393) and Postdoctor Research Program of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (2013KIP306) to S.-J.L.

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Authors and Affiliations



J.-J.Z., S.-J.L. and X.Y. designed the study and wrote the paper. J.-J.Z. performed and analyzed all in vitro electrophysiology experiments; S.-J.L. performed and analyzed biochemistry and immunohistochemistry experiments, with the help of W.-Y. M. and X.-D.Z.; X.-D.Z. performed stereotaxic injections with the help of J.-J.Z.; D.Z. performed in vivo electrophysiology experiments; D.Z. and H.Y. analyzed in vivo electrophysiology experiments. All authors edited the paper.

Corresponding author

Correspondence to Xiang Yu.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 The effect of whisker deprivation on inhibitory synaptic transmission and early excitatory synaptic transmission in the sensory cortices.

(a,d) Representative mIPSC recordings (left) and average waveforms (right) for conditions as indicated from S1 (a) and V1 (d). (b,c) Whisker-deprivation (WD) did not significantly affect mIPSC frequencies [b, bar graphs: Ctrl, 1.04 ± 0.14 Hz, WD, 0.83 ± 0.09 Hz, P = 0.22, t(29) = 1.24; cumulative distributions, P = 0.29] or amplitudes [c, bar graphs: Ctrl, 26.33 ± 1.91 pA, WD, 28.37 ± 2.62 pA, P = 0.52, t(29) = 0.65; cumulative distributions: P = 0.58] in S1. (e,f) Whisker-deprivation did not significantly affect mIPSC frequencies [e, bar graphs: Ctrl, 1.47 ± 0.16 Hz, WD, 1.32 ± 0.13 Hz, P = 0.49, t(23) = 0.69; cumulative distributions: P = 0.45] or amplitudes [f, bar graphs: Ctrl, 26.96 ± 2.37 pA, WD, 30.88 ± 3.14 pA, P = 0.32, t(23) = 1.02; cumulative distributions: P = 0.12] in V1. (g,h) Whisker-deprivation reduced mEPSC frequencies at P7 in both S1 [g, Ctrl, 0.48 ± 0.06 Hz, WD, 0.31 ± 0.02 Hz, P = 0.018, t(21) = 2.58] and V1 [h, Ctrl, 0.38 ± 0.05 Hz, WD, 0.18 ± 0.02 Hz, P = 0.002, t(20) = 3.57]. (i,j) Dark-rearing (DR) reduced mEPSC frequencies at P7 in both S1 [i, Ctrl, 0.42 ± 0.10 Hz, DR, 0.11 ± 0.02 Hz, P = 0.003, t(35) = 3.18] and V1 [j, Ctrl, 0.42 ± 0.11 Hz, DR, 0.07 ± 0.01 Hz, P = 0.003, t(39) = 3.15]. Error bars denote s.e.m.; “n” as denoted inside bar graphs. *P < 0.05, **P < 0.01, using unpaired two-tailed Student's t-tests for bar graphs and Kolmogorov-Smirnov two-sample tests for cumulative distributions.

Supplementary Figure 2 Changes in the level of hypothalamic neuropeptides under dark-rearing and whisker-deprivation conditions.

(a) Microarray results showing changes in the mRNA level of multiple neuropeptides in the hypothalamus of dark-reared mice at P14, as compared to controls; n = 2 for each condition. (b,c) Real-time qPCR results showing changes in the mRNA level of neuropeptides from the hypothalamus in dark-reared (b, n = 4 for each condition) or whisker-deprived (c, n = 4 or 9 for each condition) mice at P14. Error bars denote s.e.m.; “n” represents the number of mice. *P < 0.05, **P < 0.01, ***P < 0.001, using paired t-test.

Supplementary Figure 3 Immunolabeling oxytocin neurons in the PVN and apoptosis assay under sensory-deprivation conditions.

(a) Display of a full set of sections containing oxytocin-positive neurons from the PVN; every 6th section (30 μm thick) was immunolabeled and counted. Scale bar: 200 μm. (b) Co-localization of oxytocin (red) and neurophysin I (green) in the mouse brain. Scale bar: 200 μm. (c-e) Representative immunofluorescence double-staining images of neurophysin I (green), TUNEL (red) and overlay (merge) in the PVN of Ctrl, whisker-deprived and dark-reared mice. Negative: negative control for TUNEL staining. Positive: positive control for TUNEL staining. Quantitation of TUNEL-positive neurons: 0/681 neurons for whisker-deprived mice, 0/746 for dark-reared mice and 0/1422 for combined controls. Scale bar: 200 μm. (f) AAV-OXT-Venus expression (green) was specific in oxytocin neurons (red, oxytocin-antibody staining). Scale bar: 200 μm. (g) Representative images of oxytocin immunoreactive neurons and fibers amplified using the Tyramide Signal Amplification systems. Left: coronal section of the whole brain, scale bar: 1 mm. Right: zoomed image of the PVN, showing fibers of oxytocin neurons projecting towards the 3rd ventricle, V: ventricle, scale bar: 40 μm.

Supplementary Figure 4 Retrograde tracing successfully labeled known direct projections to the primary somatosensory cortex in developing mice.

(a) Representative image of coronal brain slice from a P14 mouse injected with the retrograde tracer CTB (green). The site of injection is marked using an arrow. (b) Zoomed image of the contralateral cortex, showing neurons clearly labeled with CTB. (c) Zoomed image of the thalamus, showing neurons clearly labeled with CTB (green). Mice were injected with CTB at P9 and sacrificed at P14-15. Scale bar: 200 μm.

Supplementary Figure 5 Retrograde tracing successfully labeled known direct projections from PVN oxytocin neurons to the central amygdala of adult mice.

(a) Representative images (left, combined DIC and green fluorescence; right, green fluorescence alone) of coronal brain slices showing the site of CTB injection (green) in central amygdala (CeA). (b-d) Representative images of brain slices containing CeA-projecting oxytocin neurons. Location of sections is indicated by their bregma positions, and the positions of the zoomed areas are as indicated. Neurons co-labeling with oxytocin (red) and CTB (green) are indicated by arrows. CTB was injected into the central amygdala of adult female mice, which were sacrificed 7 days following injection. Scale bar:100 μm.

Supplementary Figure 6 Developmental expression profile of oxytocin and oxytocin receptor as well as acute effects of oxytocin on synaptic transmission.

(a,b) Developmental expression pattern of oxytocin peptide in the blood plasma [a, P <0.001, F(6, 39) = 13.50] and oxytocin mRNA in the hypothalamus [b, P < 0.001, F(6, 22) = 20.90]. (c) The effect of different concentrations of oxytocin on mEPSC frequencies in S1 at P14 mice [Ctrl, 0.78 ± 0.08 Hz, 0.1 nM OXT, 0.83 ± 0.12 Hz, 1 nM OXT, 1.30 ± 0.23 Hz, 10 nM OXT, 1.40 ± 0.12 Hz, 100 nM OXT, 1.56 ± 0.14 Hz, 1,000 nM OXT, 2.07 ± 0.30 Hz, P < 0.001, F(5, 62) = 6.78]. (d) Bath application of oxytocin significantly reduced mEPSC frequencies in S1 in adult, 2 month old mice [left, Ctrl, 3.95 ± 0.81 Hz, OXT, 1.90 ± 0.29 Hz, P = 0.019, t(16) = 2.60, unpaired two-tailed Student's t-tests], without affecting mEPSC amplitudes [right, Ctrl, 13.81 ± 2.06 pA, OXT, 12.44 ± 1.30 pA, P = 0.57, t(16) = 0.58, unpaired two-tailed Student's t-tests]. (e) Developmental expression pattern of oxytocin receptor mRNA in the PFC, S1 and V1 [P < 0.001, F(2, 9) = 31.62]. (f) Both Oxtr-RNAi-1 (pSuper-RNAi-1) and Oxtr-RNAi-2 (pSuper-RNAi-2) were effective in lowering the level of over-expressed OXTR (HA-mOXTR) in HEK 293T cells. GAPDH was used as the loading control. (g) Representative recordings of paired-pulse ratios for conditions as indicated. (h) Bath application of oxytocin did not affect paired-pulse ratios in S1 at P14 (P > 0.05, unpaired two-tailed Student's t-tests). Error bars denote s.e.m.; “n” as denoted inside bar graphs. *P < 0.05, **P < 0.01, ***P < 0.001, using one-way ANOVA unless otherwise specified.

Supplementary Figure 7 Environmental enrichment from birth significantly increased inhibitory synaptic transmission in layer II/III pyramidal neurons of S1 and V1.

(a) Illustration of standard and environmentally enriched (EE) housings. (b,e) Representative mIPSC recordings (left) and average waveforms (right) for conditions as indicated from S1 (b) and V1 (e). (c,d) Environmental enrichment significantly increased mIPSC frequencies in S1 at P14 [c, bar graphs: Ctrl, 1.59 ± 0.23 Hz, EE, 3.90 ± 0.58 Hz, P < 0.001, t(34) = 3.69; cumulative distributions: P < 0.001], without affecting mEPSC amplitudes [d, bar graphs: Ctrl, 30.79 ± 2.06 pA, EE, 28.87 ± 1.62 pA, P = 0.47, t(34) = 0.73; cumulative distributions: P = 0.42]. (f,g) Environmental enrichment significantly increased mIPSC frequencies in V1 at P14 [f, bar graphs: Ctrl, 1.37 ± 0.19 Hz, EE, 2.57 ± 0.28 Hz, P < 0.01, t(21) = 3.68; cumulative distributions: P < 0.001], without affecting mEPSC amplitudes [g, bar graphs: Ctrl, 24.70 ± 1.12 pA, EE, 25.15 ± 1.60 pA, P = 0.82, t(21) = 0.24; cumulative distributions: P = 0.84]. Error bars denote s.e.m.; “n” as denoted inside bar graphs. **P < 0.01, ***P < 0.001, using unpaired two-tailed Student's t-tests for bar graphs and Kolmogorov-Smirnov two-sample tests for cumulative distributions.

Supplementary Figure 8 Full-length images of immunoblots presented in the main figures.

Full-length images of cropped immunoblots presented in Fig. 1m (top), Fig. 3f (middle) and Fig. 6h (bottom) are shown.

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Zheng, JJ., Li, SJ., Zhang, XD. et al. Oxytocin mediates early experience–dependent cross-modal plasticity in the sensory cortices. Nat Neurosci 17, 391–399 (2014).

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