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Developing the practice of neurons for real life
When a mouse runs forward across the forest floor, the landscape it traverses flows backward. Ge et al. show that the developing mouse retina exerts in advance what the eyes have to process later when the mouse moves. Spontaneous waves of retinal activity circulate in the same pattern that would be produced a few days later by actual movement in the environment. This spontaneous patterned activity refines the responsiveness of cells in the brain’s superior colliculus, which receive neural signals from the retina to process directional information.
Science, abd0830, this issue p. eabd0830
Structured summary
INTRODUCTION
Fundamental characteristics of the mouse visual system circuitry appear before the onset of vision, allowing the mouse to perceive objects and detect visual movement immediately after opening the eyes. It is not well understood how the visual system of the mouse manages to self-organize when the eyes are opened without structured external sensory input. In the absence of a sensory impulse, the developing retina generates spontaneous activity in the form of propagating waves. Previous work has shown that spontaneous retinal waves provide the correlated activity needed to refine the development of raw topographic maps in downstream visual areas, such as retinotopy and eye-specific segregation, but it is not. clear whether the waves also convey information that instructs the development of -ordering visual response properties, such as direction selectivity, upon eye opening.
REASONING
Spontaneous retinal waves exhibit changing stereotypical spatiotemporal patterns throughout development. To characterize the spatiotemporal properties of waves during development, we used wide-field one-photon calcium imaging of retinal axons projecting to the superior colliculus in awake neonatal mice. We identified a consistent spread bias that occurred during a transient window of development shortly before the eyes were opened. Using quantitative analysis, we investigated whether directionally polarized retinal waves convey relevant ethological information for future visual inputs. To understand the origin of directional retinal waves, we used pharmacological, optogenetic and genetic strategies to identify the retinal circuits underlying the propagation bias. Finally, to assess the role of directional retinal waves in visual system development, we used pharmacological and genetic strategies to chronically manipulate wave directionality and used two-photon calcium imaging to measure responses to visual movement. in the superior colliculus of the midbrain immediately after opening the eyes.
RESULTS
We found that spontaneous retinal waves in mice exhibit a distinct propagation bias in the temporal-nasal direction during a transient window of development (postnatal day 8 to day 11). The spatial geometry of the directional wave flow aligns strongly with the optical flow pattern generated by forward self-movement, a dominant natural optical flow pattern after eye opening. We identified an intrinsic asymmetry in the retinal circuit that imposed wave propagation bias involving the same circuit elements required for motion detection in the adult retina, in particular the asymmetric inhibition of starburst amacrine cells by γ acid. -aminobutyric acid type A (GABAA) receivers. Finally, the manipulation of directional retinal waves, either by the chronic administration of gabazine to block GABAergic inhibition, or by the specific mutation of the star-shaped amacrine cells of the FRMD7 gene, altered the development of visual movement responses in superior colliculus neurons downstream of the retina.
CONCLUSION
Our results show that spontaneous activity in the developing retina before the onset of vision is structured to convey information essential to the development of visual response properties before the onset of visual experience. Spontaneous retinal waves simulate future optical flow patterns produced by forward movement in space, due to an asymmetric retinal circuitry that has a conserved evolutionary link with motion sensing circuitry in the mature retina. In addition, ethologically relevant information relayed by directional retinal waves improves the development of higher-order visual function in the downstream visual system before the eyes are opened. These results provide insight into the activity-dependent mechanisms that regulate the self-organization of brain circuits before the onset of sensory experience.
(A) Imaging of retinal axonal activity reveals propagation bias in spontaneous retinal waves (scale bar, 500 μm). (B) Cartoon representation of wave flow vectors projected onto visual space. The vectors (black arrows) align with the optical flow pattern (red arrows) generated by the forward self-motion. (VS) Asymmetric GABAergic inhibition in the retina mediates wave directionality. (D) Developmental manipulation of wave directivity disrupts selective directional responses in superior colliculus neurons downstream to eye opening.
Abstract
The ability to perceive and respond to environmental stimuli emerges in the absence of sensory experience. Spontaneous retinal activity prior to eye opening guides the refinement of retinotopy and eye-specific segregation in mammals, but its role in the development of higher-order visual response properties remains unclear. Here, we describe a transient window in neonatal mouse development during which the spatial propagation of spontaneous retinal waves resembles the optical flow pattern generated by forward self-movement. We show that wave directionality requires the same circuit components that form the adult selective retinal circuit, and that chronic disruption of wave directionality alters the development of selective directional responses of superior colliculus neurons. These data demonstrate how the developing visual system models spontaneous activity to simulate ethologically relevant characteristics of the outside world and thereby instruct self-organization.
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