Measuring and Modelling the Emergence of Order in the Mouse Retinocollicular Projection

Abstract

In the formation of retinotopic maps both experimental and theoretical work implicate guidance molecules and patterned neuronal activity. A common view is that molecular cues define and activity cues refine mappings. Important insights have come from studies of the retinocollicular projection in transgenic mice, in which cues have been modified either in isolation or in combination. Mostly these have generated descriptions of endpoint mappings. The dynamics of map formation remain under-explored experimentally and computationally. We have quantified changes in the ordering of the mouse retinocollicular projection with age after making local collicular injections of fluorescent microspheres. Contour analysis shows that, at birth (P0), cells from over 80% of the retina converge on a given collicular locus; this percentage falls gradually to P4 then rapidly approaches adult values by P12. Paired injections reveal how the segregation of labelled cells depends both on injection site separation and relative orientation and also age. At P0, large anterior-posterior separations failed to produce segregated label: segregation improved with a similar timecourse to convergence to reach near adult-values by P12. An implementation of a combined activity-molecular model captures these segregation dynamics.

The developmental dynamics were then studied in the nAChR-β2^−/− mouse, which has altered patterns of retinal activity in the first postnatal week that results in a more diffuse adult retinal projection. Surprisingly, both measures of map refinement (convergence and segregation) remain largely constant and imprecise in the first postnatal week – only subsequently does the projection begin to refine. Substituting nAChR-β2^−/− activity patterns for wild-type patterns [5] into the model failed to capture the biology: refinement was initially faster. By reducing the relative importance of the gradients’ contribution to the model energy (to 15% of normal) we were able to mimic the delayed refinement observed in vivo. Our model therefore predicts the altered activity patterns may affect readout of guidance cues.