(This article was originally published on EurekAlert! on March 28, 2025)
A research team led by Prof. LIU Kai from the Division of Life Science and Department of Chemical and Biological Engineering at the Hong Kong University of Science and Technology (HKUST) has established an innovative intracranial pre-olivary pretectal nucleus (OPN) optic tract injury model (pre-OPN OTI), shedding light on crucial mechanisms of functional axonal rewiring following central nervous system injury.
The adult mammalian central nervous system (CNS) has a low capacity to repair itself after injury, primarily because axons often fail to regenerate and rebuild functional connections with target neurons. Existing research mainly focuses on enhancing axonal regeneration, but there are limited models that can achieve functional connectivity after complete injury, and the mechanisms of functional circuit reconstruction remain unclear. To tackle these challenges, the research team led by Prof. Liu, introduces the intracranial pre-OPN OTI model, in a study titled “Functional optic tract rewiring via subtype- and target-specific axonal regeneration and presynaptic activity enhancement” published in Nature Communications in March 2025.
The pre-OPN OTI model involves microsurgery to apply mechanical pressure between the lateral geniculate nucleus (LGN) and the OPN, injuring retinal ganglion cell (RGC) axons. This method has several advantages over traditional models: it avoids the need for cortical tissue removal, reducing surgical complexity; the injury site is close to the target nucleus (OPN), facilitating studies on targeted axonal regeneration; it uses the pupillary light reflex (PLR) as a quantitative measure of functional recovery; and it ensures high survival rates of RGCs post-injury for long-term observation; it represents a complete axonal injury model, with all recovered function stemming from regenerated axons.
The team found that knocking out the Pten/Socs3 genes in RGCs while expressing CNTF significantly enhances axonal regeneration to the OPN (Figure 2) and the reformation of functional synapses. Key evidence includes super-resolution microscopy showing colocalization of presynaptic (Bassoon) and postsynaptic (Homer1) markers; electron microscopy confirming the formation of synaptic structures between regenerated axons and OPN neurons; trans-synaptic viral tracing and electrophysiological recordings validating restored synaptic transmission; and partial recovery of the PLR indicating functional reconnection. Importantly, intrinsically photosensitive RGCs (ipRGCs) were identified as the key subtype mediating functional recovery, with regenerated axons reconnecting precisely to their original targets.
To further enhance regeneration efficiency and functional recovery, the team proposed a dual-intervention strategy of "axonal regeneration & synaptic enhancement." The knockdown of the lipid metabolism gene Lipin1, along with Pten/Socs3 knockout and CNTF expression, accelerated axonal regeneration, and reduced PLR recovery time from 6 to 3 months. Additionally, overexpression of melanopsin was adopted to increase RGC photosensitivity or enhancement of presynaptic voltage-gated calcium channel activity further optimized synaptic signal transmission, significantly improving functional outcomes.
The pre-OPN OTI model is a valuable tool for CNS repair research, clarifying the critical role of specific neuronal subtypes in functional circuit reconstruction and validating the potential application of dual-intervention strategies. This work deepens our understanding of CNS regeneration mechanisms and offers new insights for developing precision therapies targeting neural injuries and neurodegenerative diseases.
This study was led by Prof. Liu’s team at HKUST, in collaboration with Prof. WANG Yiwen’s team from the Department of Electronic and Computer Engineering and the Department of Chemical and Biological Engineering, and researchers from multiple institutions including Prof. JIANG Liwen and Prof. DUAN Liting from CUHK, Prof. YUNG Wing-Ho from CityU, and Dr. MA Yuqian from USTC. Co-first authors of the article include Dr. ZHANG Xin, Research Assistant Professor YANG Chao, and ZHANG Chengle (PhD student) from the Division of Life Science, with Prof. Liu serving as the corresponding author. The research was supported by grants from the Hong Kong Research Grant Council, Innovation and the Technology Commission, the National Natural Science Foundation of China, and others.
