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Retinal waves coordinate patterned activity throughout the developing visual system

Abstract

The morphological and functional development of the vertebrate nervous system is initially governed by genetic factors and subsequently refined by neuronal activity. However, fundamental features of the nervous system emerge before sensory experience is possible. Thus, activity-dependent development occurring before the onset of experience must be driven by spontaneous activity, but the origin and nature of activity in vivo remains largely untested. Here we use optical methods to show in live neonatal mice that waves of spontaneous retinal activity are present and propagate throughout the entire visual system before eye opening. This patterned activity encompassed the visual field, relied on cholinergic neurotransmission, preferentially initiated in the binocular retina and exhibited spatiotemporal correlations between the two hemispheres. Retinal waves were the primary source of activity in the midbrain and primary visual cortex, but only modulated ongoing activity in secondary visual areas. Thus, spontaneous retinal activity is transmitted through the entire visual system and carries patterned information capable of guiding the activity-dependent development of complex intra- and inter-hemispheric circuits before the onset of vision.

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Figure 1: Spontaneous waves of activity in retinal ganglion cell arbors in vivo.
Figure 2: Spontaneous waves of correlated activity among superior-colliculus neurons in vivo.
Figure 3: Retinal waves originate in the ventrotemporal retina and propagate bilaterally.
Figure 4: Retinal waves propagate simultaneously in the SC and visual cortex.
Figure 5: Retinal-wave-driven activity in V1 and extrastriate visual areas.
Figure 6: Retinal waves depend on cholinergic neurotransmission.

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Acknowledgements

We thank R. Sachdev and D. McCormick for Emx1-Cre:Ai38 mice, C. Chen for helpful advice on ganglion cell loading with calcium indicators and Y. Zhang for technical support. We would like to thank M. Colonnese and members of the Crair laboratory for valuable comments on the manuscript. This work was supported by US National Institutes of Health (NIH) grants P30 EY000785 and R01 EY015788 (to M.C.C.), T32 NS007224 (to J.A.), and T15 LM070506 and T32 EY017353 (to T.B.). This work was also supported by the family of William Ziegler III.

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Authors and Affiliations

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Contributions

Author Contributions J.B.A. and M.C.C. designed the experiments. J.B.A. carried out in vivo ganglion-cell-axon, collicular-neuron and visual-cortex imaging experiments and analysed the recordings. T.J.B. carried out intra-ocular ganglion-cell labelling and in vivo ganglion-cell-axon imaging experiments and analysed recordings. J.B.A. implemented analysis routines and analysed the data. J.B.A. and M.C.C. wrote the manuscript.

Corresponding author

Correspondence to Michael C. Crair.

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Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-9 and a Supplementary Discussion with Supplementary References. (PDF 12133 kb)

Supplementary Movie 1

The movie shows an example of retinal waves recorded in Calcium Green Dextran-labeled RGC axons within the superior colliculus using widefield CCD calcium imaging at P7. Movie is a 330 s long recording played back at 10x (50 fps) as ΔF/F. Field of view is 1.2 mm x 1.4 mm. (MOV 2811 kb)

Supplementary Movie 2

The movie shows an example of retinal waves recorded in OGB1AM-labeled superior colliculus neurons with 2P calcium imaging at P5. Movie depth was 100 µm below the pial surface and 609 s long, played back at 22x. Brief motor movements during the recording cause visible z-artefacts; wave activity was not analyzed during frames containing these artifacts. Field of view is 241 µm x 241 µm. (MOV 5176 kb)

Supplementary Movie 3

The movie shows an example of bilateral spatiotemporally correlated retinal waves recorded in Calcium Green Dextran-labeled RGC arbors with widefield CCD calcium imaging. Recording is of a single wave traveling throughout the rostralcaudal extent of both hemispheres over a period of 47 sec, played back at 16x as ΔF/F. Field of view is 1.2 mm x 1.2 mm. (MOV 427 kb)

Supplementary Movie 4

The movie shows an example of bilateral spatiotemporally correlated retinal wave recorded in OGB1-AM-labeled collicular neurons with widefield CCD calcium imaging. Recording is of a single wave traveling throughout the rostral-caudal extent of both hemispheres over a period of 28 sec, played back at 6x as ΔF/F. Field of view is 1.3 mm x 2.3 mm. (MOV 505 kb)

Supplementary Movie 5

The movie shows an example of a retinal wave propagating in primary visual cortex and superior colliculus simultaneously with secondary activations in extrastriate cortical regions at P6 with widefield CCD calcium imaging. Calcium signals in superior colliculus are from bulk labeling wih OGB1-AM and imaged through a cranial window and signals in cortex are from GCaMP3 expressing excitatory neurons imaged through the skull in Emx1-Ai38 mice. Recording is 16 s long, played back at 10x as ΔF/F. Field of view is 3.0 mm x 3.0 mm. (MOV 451 kb)

Supplementary Movie 6

The movie shows an example of a retinal wave propagating in primary visual cortex and superior colliculus in an Rx-Cre:Ai38 mouse at P4 with widefield CCD calcium imaging under control conditions (18 s long, played back at 10x as ΔF/F) and an example of typical activity patterns seen in the same animal after contralateral injection of 1 mM epibatidine intraocularly (18 s long, played back at 10x as ΔF/F). Calcium signals are from transcranial cortical GCaMP3 expression and from RGC axon GCaMP3 expression imaged through a cranial window above the SC. Field of view is 2.8 mm x 3.4 mm. (MOV 1373 kb)

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Ackman, J., Burbridge, T. & Crair, M. Retinal waves coordinate patterned activity throughout the developing visual system. Nature 490, 219–225 (2012). https://doi.org/10.1038/nature11529

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