A groundbreaking study led by Prof. Liu Kai from the Hong Kong University of Science and Technology (HKUST) has unveiled a novel intracranial optic tract injury model, shedding light on the intricate mechanisms of functional axonal rewiring following central nervous system (CNS) injury. This innovative research, published in Nature Communications in March 2025, marks a significant milestone in understanding the complex processes involved in CNS regeneration.
The adult mammalian CNS has long been known for its limited capacity to repair itself after injury, primarily due to the challenges associated with axonal regeneration and the rebuilding of functional connections with target neurons. While previous research has focused on enhancing axonal regeneration, the lack of models capable of achieving functional connectivity after complete injury has hindered progress in uncovering the mechanisms of functional circuit reconstruction.
To address these limitations, Prof. Liu and his team introduced the intracranial pre-olivary pretectal nucleus (OPN) optic tract injury model, known as pre-OPN OTI. This model involves microsurgery to apply mechanical pressure between the lateral geniculate nucleus (LGN) and the OPN, specifically targeting retinal ganglion cell (RGC) axons. Unlike traditional models, the pre-OPN OTI model offers several advantages, including reduced surgical complexity, proximity to the target nucleus (OPN) for studying targeted axonal regeneration, and the use of the pupillary light reflex (PLR) as a quantitative measure of functional recovery.
Through a series of experiments utilizing the pre-OPN OTI model, the research team discovered that knocking out the Pten/Socs3 genes in RGCs while expressing CNTF significantly enhanced axonal regeneration to the OPN and facilitated the reformation of functional synapses. This was supported by various imaging techniques, including super-resolution microscopy, electron microscopy, trans-synaptic viral tracing, and electrophysiological recordings, all confirming the restoration of synaptic transmission and partial recovery of the PLR.
Moreover, the study identified intrinsically photosensitive RGCs (ipRGCs) as the key subtype responsible for mediating functional recovery, with regenerated axons reconnecting precisely to their original targets. The team also proposed a dual-intervention strategy involving axonal regeneration and synaptic enhancement, which accelerated regeneration efficiency and functional recovery, offering promising results for improving outcomes in CNS repair.
The pre-OPN OTI model represents a significant advancement in CNS regeneration research, emphasizing the critical role of specific neuronal subtypes in functional circuit reconstruction. By validating the potential application of dual-intervention strategies, this work not only deepens our understanding of CNS regeneration mechanisms but also provides valuable insights for developing precision therapies targeting neural injuries and neurodegenerative diseases.
In conclusion, the study conducted by Prof. Liu and his team at HKUST represents a pivotal contribution to the field of neuroscience, offering new perspectives on CNS repair and regeneration. The findings from this research have the potential to pave the way for innovative therapeutic approaches aimed at addressing neural injuries and neurodegenerative conditions in the future.
