The display of patterned spontaneous activity is an emergent property of the immature nervous system that is thought to mediate synaptic competition and instruct self- organization in many developing neural circuits. In the visual system, isolated (in vitro) preparations of developing retina exhibit propagating electrical activiy amongst neighboring retinal ganglion cells (RGCs), termed 'retinal waves'. Since RGCs relay visual information to higher order structures in the central nervous system, retinal waves are thought to play a key role in activity-dependent refinement of topographic neural maps in the superior colliculus (SC), lateral geniculate nucleus (LGN), and visual cortex (VCtx). However, the role of retinal waves in neural circuit development remains remarkably controversial, in part because their existence has never been demonstrated in vivo. Previous work using extracellular microelectrode recording techniques in vivo demonstrated limited and local correlated spiking between pairs of embryonic rat RGCs, but no assessment of wave activity has been undertaken in vivo, likely because of the methodological challenges associated with recording from a large cohort of RGCs in neonatal animals. In this proposal, we use a highly novel imaging approach to examine and characterize spontaneous activity throughout the visual neuraxis, including RGCs, the SC and VCtx, in neonatal mice in vivo. We seek to establish whether traveling waves of spontaneous activity occur in awake, behaving neonatal mice, and examine the spatiotemporal properties of waves throughout the developing visual system during the first two weeks after birth. Our preliminary data indicates that spontaneous retinal waves are present for at least a week of development in vivo and exhibit a similar profile of spatiotemporal properties as those described previously in vitro. Moreover, retinal waves generate matched activity patterns in the midbrain and visual cortex. Given the remarkable fidelity of retinal waves during the period prior to eye opening in mice we report here in vivo, together with previous work demonstrating that spontaneous waves within macaque retina are present in vitro before birth, it seems likely that the visual system experiences patterned activation by retinal waves for a substantial gestational period during human fetal development that may be crucial for shaping the functional maturation of neural circuits before the onset of sensory experience. In all, these experiments are designed to investigate the properties and role of patterned spontaneous activity in vivo in the development of neural circuits in the mammalian visual system.

Public Health Relevance

We are interested in understanding how complex brain circuits develop. We focus on the visual system, as its function is relatively well understood and it is especially important to human behavior. We are particularly interested in understanding the mechanisms leading to the devastating visual deficits associated with the emergence of Amblyopia and Strabismus during development. Our experiments also have the potential to help develop techniques to restore visual function following eye trauma or disease, such as glaucoma or age related macular degeneration.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY023105-03S1
Application #
9145839
Study Section
Special Emphasis Panel (SPC)
Program Officer
Greenwell, Thomas
Project Start
2013-02-01
Project End
2018-01-31
Budget Start
2015-09-30
Budget End
2016-01-31
Support Year
3
Fiscal Year
2015
Total Cost
$50,296
Indirect Cost
$2,081
Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06510
Seabrook, Tania A; Burbridge, Timothy J; Crair, Michael C et al. (2017) Architecture, Function, and Assembly of the Mouse Visual System. Annu Rev Neurosci 40:499-538
Thompson, Andrew; Gribizis, Alexandra; Chen, Chinfei et al. (2017) Activity-dependent development of visual receptive fields. Curr Opin Neurobiol 42:136-143
Crair, Michael C; Mason, Carol A (2016) Reconnecting Eye to Brain. J Neurosci 36:10707-10722
Xu, Hong-Ping; Burbridge, Timothy J; Ye, Meijun et al. (2016) Retinal Wave Patterns Are Governed by Mutual Excitation among Starburst Amacrine Cells and Drive the Refinement and Maintenance of Visual Circuits. J Neurosci 36:3871-86
Xu, Hong-Ping; Burbridge, Timothy J; Chen, Ming-Gang et al. (2015) Spatial pattern of spontaneous retinal waves instructs retinotopic map refinement more than activity frequency. Dev Neurobiol 75:621-40
Burbridge, Timothy J; Xu, Hong-Ping; Ackman, James B et al. (2014) Visual circuit development requires patterned activity mediated by retinal acetylcholine receptors. Neuron 84:1049-64
Ackman, James B; Crair, Michael C (2014) Role of emergent neural activity in visual map development. Curr Opin Neurobiol 24:166-75
Ribic, Adema; Liu, Xinran; Crair, Michael C et al. (2014) Structural organization and function of mouse photoreceptor ribbon synapses involve the immunoglobulin protein synaptic cell adhesion molecule 1. J Comp Neurol 522:900-20
Li, Hong; Fertuzinhos, Sofia; Mohns, Ethan et al. (2013) Laminar and columnar development of barrel cortex relies on thalamocortical neurotransmission. Neuron 79:970-86
Ackman, James B; Burbridge, Timothy J; Crair, Michael C (2012) Retinal waves coordinate patterned activity throughout the developing visual system. Nature 490:219-25