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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References
Buffelli, M. et al. Genetic evidence that relative synaptic efficacy biases the outcome of synaptic competition. Nature 424, 430–434 (2003)
Marder, E. & Rehm, K. J. Development of central pattern generating circuits. Curr. Opin. Neurobiol. 15, 86–93 (2005)
Petersson, P., Waldenström, A., Fåhraeus, C. & Schouenborg, J. Spontaneous muscle twitches during sleep guide spinal self-organization. Nature 424, 72–75 (2003)
Sanes, J. R. & Lichtman, J. W. Development of the vertebrate neuromuscular junction. Annu. Rev. Neurosci. 22, 389–442 (1999)
Katz, L. C. & Shatz, C. J. Synaptic activity and the construction of cortical circuits. Science 274, 1133–1138 (1996)
Meister, M., Wong, R. O., Baylor, D. A. & Shatz, C. J. Synchronous bursts of action potentials in ganglion cells of the developing mammalian retina. Science 252, 939–943 (1991)
Wong, R. O., Meister, M. & Shatz, C. J. Transient period of correlated bursting activity during development of the mammalian retina. Neuron 11, 923–938 (1993)
Feller, M. B., Wellis, D. P., Stellwagen, D., Werblin, F. S. & Shatz, C. J. Requirement for cholinergic synaptic transmission in the propagation of spontaneous retinal waves. Science 272, 1182–1187 (1996)
Penn, A. A., Riquelme, P. A., Feller, M. B. & Shatz, C. J. Competition in retinogeniculate patterning driven by spontaneous activity. Science 279, 2108–2112 (1998)
Stellwagen, D. & Shatz, C. J. An instructive role for retinal waves in the development of retinogeniculate connectivity. Neuron 33, 357–367 (2002)
McLaughlin, T., Torborg, C. L., Feller, M. B. & O’Leary, D. D. M. Retinotopic map refinement requires spontaneous retinal waves during a brief critical period of development. Neuron 40, 1147–1160 (2003)
Chandrasekaran, A. R., Plas, D. T., Gonzalez, E. & Crair, M. C. Evidence for an instructive role of retinal activity in retinotopic map refinement in the superior colliculus of the mouse. J. Neurosci. 25, 6929–6938 (2005)
Huberman, A. D., Speer, C. M. & Chapman, B. Spontaneous retinal activity mediates development of ocular dominance columns and binocular receptive fields in v1. Neuron 52, 247–254 (2006)
Chalupa, L. M. Retinal waves are unlikely to instruct the formation of eye-specific retinogeniculate projections. Neural Dev. 4, 25 (2009)
Feller, M. B. Retinal waves are likely to instruct the formation of eye-specific retinogeniculate projections. Neural Dev. 4, 24 (2009)
Maffei, L. & Galli-Resta, L. Correlation in the discharges of neighboring rat retinal ganglion cells during prenatal life. Proc. Natl Acad. Sci. USA 87, 2861–2864 (1990)
Hanganu, I. L., Ben-Ari, Y. & Khazipov, R. Retinal waves trigger spindle bursts in the neonatal rat visual cortex. J. Neurosci. 26, 6728–6736 (2006)
Colonnese, M. T. & Khazipov, R. “Slow activity transients” in infant rat visual cortex: a spreading synchronous oscillation patterned by retinal waves. J. Neurosci. 30, 4325–4337 (2010)
Hofbauer, A. & Dräger, U. C. Depth segregation of retinal ganglion cells projecting to mouse superior colliculus. J. Comp. Neurol. 234, 465–474 (1985)
Bansal, A. et al. Mice lacking specific nicotinic acetylcholine receptor subunits exhibit dramatically altered spontaneous activity patterns and reveal a limited role for retinal waves in forming ON and OFF circuits in the inner retina. J. Neurosci. 20, 7672–7681 (2000)
Stafford, B. K., Sher, A., Litke, A. M. & Feldheim, D. A. Spatial-temporal patterns of retinal waves underlying activity-dependent refinement of retinofugal projections. Neuron 64, 200–212 (2009)
Ford, K. J., Félix, A. L. & Feller, M. B. Cellular mechanisms underlying spatiotemporal features of cholinergic retinal waves. J. Neurosci. 32, 850–863 (2012)
Mooney, R., Penn, A. A., Gallego, R. & Shatz, C. J. Thalamic relay of spontaneous retinal activity prior to vision. Neuron 17, 863–874 (1996)
Weliky, M. & Katz, L. C. Correlational structure of spontaneous neuronal activity in the developing lateral geniculate nucleus in vivo. Science 285, 599–604 (1999)
Blankenship, A. G. & Feller, M. B. Mechanisms underlying spontaneous patterned activity in developing neural circuits. Nature Rev. Neurosci. 11, 18–29 (2010)
Elstrott, J. et al. Direction selectivity in the retina is established independent of visual experience and cholinergic retinal waves. Neuron 58, 499–506 (2008)
Rochefort, N. L. et al. Development of direction selectivity in mouse cortical neurons. Neuron 71, 425–432 (2011)
Zhang, J., Ackman, J. B., Xu, H.-P. & Crair, M. C. Visual map development depends on the temporal pattern of binocular activity in mice. Nature Neurosci. 15, 298–307 (2011)
Gastinger, M. J., Tian, N., Horvath, T. & Marshak, D. W. Retinopetal axons in mammals: emphasis on histamine and serotonin. Curr. Eye Res. 31, 655–667 (2006)
Müller, M. & Holländer, H. A small population of retinal ganglion cells projecting to the retina of the other eye. An experimental study in the rat and the rabbit. Exp. Brain Res. 71, 611–617 (1988)
Takahashi, M., Sugiuchi, Y. & Shinoda, Y. Commissural mirror-symmetric excitation and reciprocal inhibition between the two superior colliculi and their roles in vertical and horizontal eye movements. J. Neurophysiol. 98, 2664–2682 (2007)
Lewis, J. W. & Olavarria, J. F. Two rules for callosal connectivity in striate cortex of the rat. J. Comp. Neurol. 361, 119–137 (1995)
Crair, M. C., Gillespie, D. C. & Stryker, M. P. The role of visual experience in the development of columns in cat visual cortex. Science 279, 566–570 (1998)
Wang, Q. & Burkhalter, A. Area map of mouse visual cortex. J. Comp. Neurol. 502, 339–357 (2007)
Zariwala, H. A. et al. A Cre-dependent GCaMP3 reporter mouse for neuronal imaging in vivo. J. Neurosci. 32, 3131–3141 (2012)
Dräger, U. C. & Hubel, D. H. Topography of visual and somatosensory projections to mouse superior colliculus. J. Neurophysiol. 39, 91–101 (1976)
Huberman, A. D., Stellwagen, D. & Chapman, B. Decoupling eye-specific segregation from lamination in the lateral geniculate nucleus. J. Neurosci. 22, 9419–9429 (2002)
Rossi, F. M. et al. Requirement of the nicotinic acetylcholine receptor β2 subunit for the anatomical and functional development of the visual system. Proc. Natl Acad. Sci. USA 98, 6453–6458 (2001)
Pfeiffenberger, C. et al. Ephrin-As and neural activity are required for eye-specific patterning during retinogeniculate mapping. Nature Neurosci. 8, 1022–1027 (2005)
Rebsam, A., Petros, T. J. & Mason, C. A. Switching retinogeniculate axon laterality leads to normal targeting but abnormal eye-specific segregation that is activity dependent. J. Neurosci. 29, 14855–14863 (2009)
Sun, C., Speer, C. M., Wang, G.-Y., Chapman, B. & Chalupa, L. M. Epibatidine application in vitro blocks retinal waves without silencing all retinal ganglion cell action potentials in developing retina of the mouse and ferret. J. Neurophysiol. 100, 3253–3263 (2008)
Wong, R. O. Retinal waves and visual system development. Annu. Rev. Neurosci. 22, 29–47 (1999)
Warland, D. K., Huberman, A. D. & Chalupa, L. M. Dynamics of spontaneous activity in the fetal macaque retina during development of retinogeniculate pathways. J. Neurosci. 26, 5190–5197 (2006)
Chiu, C. & Weliky, M. Spontaneous activity in developing ferret visual cortex in vivo. J. Neurosci. 21, 8906–8914 (2001)
Vanhatalo, S. et al. Slow endogenous activity transients and developmental expression of K+-Cl− cotransporter 2 in the immature human cortex. Eur. J. Neurosci. 22, 2799–2804 (2005)
Tolonen, M., Palva, J. M., Andersson, S. & Vanhatalo, S. Development of the spontaneous activity transients and ongoing cortical activity in human preterm babies. Neuroscience 145, 997–1006 (2007)
Wiesel, T. N. & Hubel, D. H. Ordered arrangement of orientation columns in monkeys lacking visual experience. J. Comp. Neurol. 158, 307–318 (1974)
Rakic, P. Prenatal genesis of connections subserving ocular dominance in the rhesus monkey. Nature 261, 467–471 (1976)
Triplett, J. W. et al. Retinal input instructs alignment of visual topographic maps. Cell 139, 175–185 (2009)
Adams, D. L. & Horton, J. C. Capricious expression of cortical columns in the primate brain. Nature Neurosci. 6, 113–114 (2003)
Swindell, E. C. et al. Rx-Cre, a tool for inactivation of gene expression in the developing retina. Genesis 44, 361–363 (2006)
Kreitzer, A. C., Gee, K. R., Archer, E. A. & Regehr, W. G. Monitoring presynaptic calcium dynamics in projection fibers by in vivo loading of a novel calcium indicator. Neuron 27, 25–32 (2000)
Dhande, O. S. & Crair, M. C. Transfection of mouse retinal ganglion cells by in vivo electroporation. J. Vis. Exp. 50 e2678 10.3791/2678 (2011)
Stosiek, C., Garaschuk, O., Holthoff, K. & Konnerth, A. In vivo two-photon calcium imaging of neuronal networks. Proc. Natl Acad. Sci. USA 100, 7319–7324 (2003)
Kerr, J. N. D., Greenberg, D. & Helmchen, F. Imaging input and output of neocortical networks in vivo. Proc. Natl Acad. Sci. USA 102, 14063–14068 (2005)
Garaschuk, O., Milos, R.-I. I. & Konnerth, A. Targeted bulk-loading of fluorescent indicators for two-photon brain imaging in vivo. Nature Protocols 1, 380–386 (2006)
Greenberg, D. S. & Kerr, J. N. D. Automated correction of fast motion artifacts for two-photon imaging of awake animals. J. Neurosci. Methods 176, 1–15 (2009)
Cossart, R., Aronov, D. & Yuste, R. Attractor dynamics of network UP states in the neocortex. Nature 423, 283–288 (2003)
Gonzalez, R. C., Woods, R. E. & Eddins, S. L. Digital Image Processing Using MATLAB (Gatesmark Publishing, 2009)
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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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.
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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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DOI: https://doi.org/10.1038/nature11529
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