Assembly and repair of eye-to-brain connections

Abstract

Vision is the sense humans rely on most to navigate the world and survive. A tremendous amount of research has focused on understanding the neural circuits for vision and the developmental mechanisms that establish them. The eye-to-brain, or 'retinofugal' pathway remains a particularly important model in these contexts because it is essential for sight, its overt anatomical features relate to distinct functional attributes and those features develop in a tractable sequence. Much progress has been made in understanding the growth of retinal axons out of the eye, their selection of targets in the brain, the development of laminar and cell type-specific connectivity within those targets, and also dendritic connectivity within the retina itself. Moreover, because the retinofugal pathway is prone to degeneration in many common blinding diseases, understanding the cellular and molecular mechanisms that establish connectivity early in life stands to provide valuable insights into approaches that re-wire this pathway after damage or loss. Here we review recent progress in understanding the development of retinofugal pathways and how this information is important for improving visual circuit regeneration.

Figure 1:. RGC axon pathfinding and target selection

(A) Retinal ganglion cells extend axons away from the periphery due to repulsive influences from chondroitin sulfate proteoglycans (CSPG, purple) and grow towards the optic disk. Netrin 1 expressed by glial cells at the optic disc (green) provides local attractive cues and enables axons to exit the eye, into the optic nerve. (B) Schematic of the optic nerve reaching the optic chiasm, a midline choice point for RGC axons. EphrinB2 expressed at the midline repels EphB1 expressing RGC axons to form ipsilateral projections (green), while Sema6D/NrCAM/PlexinA1 complex directs other RGCs to cross at the chiasm and form the contralateral projections (magenta). (C) Schematic showing the anatomical position of the eye, optic nerve, and optic tracts projecting to targets in the brain. After crossing the chiasm, the contralateral projection ascends into the brain to form the main optic tract (green). A smaller bundle projects into the SCN at the base of the hypothalamus, forming the retinohypothalamic tract. Two bundles deviate from the tract however – the inferior fasciculus of the accessory optic tract (ifAOT, purple), extends at the base of the brain to project to the MTN. While another bundle continues from the main optic tract and dives down to form the superior fasciculus of the AOT (sfAOT, pink). (D) Birth order of RGCs determines their target-selection and exploration. Early-born RGCs extend axon branches into many targets (yellow lines). Axons born shortly after (blue) extend to a few different targets while the early born axons retract some connections (yellow dotted lines). The later-born axons project directly to their targets without much exploration (green).

Figure 2:. Molecular mechanisms regulate axon projections to specific targets

Cadherin 6 (Cdh6) RGCs (yellow) grow to Cdh6 expressing target cells in the OPN. Contactin-4 (CNTN4+) expressing RGCs (blue) act with their co-receptor amyloid precursor protein (APP) to regulate branch formation of direction-selcective ganglion cells (DSGC) in the NOT. Sema6A expressing DSGCs (green) enter the MTN by interacting with Plexin A2/A4 expressed by cells in the MTN.

Figure 3:. Laminar specification of RGC dendrites in the inner plexiform layer

(A) Schematic showing the layers of the mouse retina and the different types of cells present in each layer. (B) A particular type of RGC, the W3B-RGC (blue) dendrites receive inputs from VGlut3 (vesicular glutamate transporter 3) amacrine cells (purple). Both W3B-RGCs and VG3-AC express sidekick 2 (Sdk2), thus binding via homophilic interactions. (C) Sema6A expressing RGCs (pink) received dendritic inputs from PlexinA4 expressing dopaminergic amacrine cells (light blue) in the OFF sublamina of the inner plexiform layer. OFF starburst amacrine cells (SAC) expressing Plexin A2 (dark blue) are repelled by Sema6A-PlexinA2 expressing ON SACs (teal) thus specifying laminar depth in SACs.

Figure 4:. Developmentally informed regenerative strategies

(A) Schematic to show how injury impacts the optic nerve. Injured RGCs start dying within two weeks and cannot regenerate their axons without therapeutic intervention. Silencing neural activity using chemogenetic approaches, reduces the survival of RGCs. (B) Combinatorial approaches that increase neural activity and mTOR signaling in RGCs (pink circles) promote regenerated axons to reinnervate visual targets in the brain (pink lines).