Mapping the axolotl brain and its regeneration

The Axolotl is an extraordinary model system to study regeneration in tetrapods. Remarkably, the axolotl is

able to regenerate parts of the brain after major injury, however the molecular mechanisms that orchestrate

regeneration are unclear, and the completeness of functional circuit and behavioral recovery is unknown. Our

vision is to develop the axolotl model system to rigorously study central nervous system regeneration, and

use discoveries from the axolotl to design novel strategies for regenerating mammalian tissues. The mapping

of brain cell types and connections in the axolotl will also have a profound impact on the understanding of

vertebrate brain organization and evolution.

In AxoBrain, we will integrate scale-crossing technologies to map the axolotl brain at molecular, cellular

and circuit resolution, and establish assays to understand how brain cells respond to damage and behavioral

circuits regenerate. Our project will be achieved through the following objectives: 1) We will generate a

spatiotemporal multiomic atlas of the axolotl brain at single cell resolution. 2) We will generate a

connectome of the axolotl retino-tectal-hindbrain circuit and develop behavioral and circuit functional assays

in response to visual stimulation. 3) We will establish injury assays and assess regeneration through

behavioral, connectomic and single-cell multiomic analysis. 4) Finally, we will apply CRISPR perturbation

screens with single-cell genomic readout in vivo and in vitro to identify modulators of regeneration.

AxoBrain utilizes quantitative and state-of-the-art methods to explore how the axolotl can regenerate neural

circuitry after injury. We have assembled a team with synergistic skill sets that will be required to achieve

our vision. This project is a groundbreaking starting point to rigorously investigate how mammals have lost

regeneration capabilities over evolution, and will serve as a springboard to design novel strategies for

regenerating