Molecular Signatures of Id2- and Ascl4-Induced Wiring of Adult Hippocampal Neurons

While circuit formation is generally thought to be absent in the adult brain, there is evidence that the adult brain retains a considerable capacity for neuronal wiring. Among other findings, molecular programming by basic helix-loop-helix (bHLH) proteins can reactivate axon growth in adult neurons, allowing the investigation of the mechanisms and potential of adult brain rewiring. Here, we analyzed proteomic and transcriptomic changes during Id2-induced (a bHLH transcriptional regulator) and Ascl4-induced (a bHLH transcription factor) feedback and feedforward wiring in the hippocampus of adult male and female mice. We find that Id2 and Ascl4 share a molecular cascade through the transcription factor Stat1 and coregulate a set of proteins that may constitute a core program for adult wiring. Unexpectedly, we also identify shared molecular changes that do not originate directly from the programmed neurons, but from endothelial cells and microglia. Taken together, our results suggest that adult brain wiring is regulated by specific molecular programs and dynamic interactions between the wiring neurons and the circuit environment.