Ryu Ueno: Department of Neurosurgery, Yokohama City University, Yokohama, Japan. Electronic address: ryuryu08300@gmail.com.
Hajime Takase: Department of Neurosurgery, Yokohama City University, Yokohama, Japan. Electronic address: htakase@yokohama-cu.ac.jp.
Jun Suenaga: Department of Neurosurgery, Yokohama City University, Yokohama, Japan. Electronic address: suenaga@yokohama-cu.ac.jp.
Masao Kishimoto: Department of Neurosurgery, Yokohama City University, Yokohama, Japan. Electronic address: t146028b@yokohama-cu.ac.jp.
Yuji Kurihara: Molecular Medical Bioscience Laboratory, Department of Medical Life Science, Yokohama City University Graduate School of Medical Life Science, Yokohama, Japan. Electronic address: kuri_yg@yokohama-cu.ac.jp.
Kohtaro Takei: Molecular Medical Bioscience Laboratory, Department of Medical Life Science, Yokohama City University Graduate School of Medical Life Science, Yokohama, Japan. Electronic address: kohtaro@yokohama-cu.ac.jp.
Nobutaka Kawahara: Department of Neurosurgery, Yokohama City University, Yokohama, Japan.
Tetsuya Yamamoto: Department of Neurosurgery, Yokohama City University, Yokohama, Japan. Electronic address: y_neuros@yokohama-cu.ac.jp.
The adult mammalian central nervous system (CNS) rarely recovers from injury. Myelin fragments contain axonal growth inhibitors that limit axonal regeneration, thus playing a major role in determining neural recovery. Nogo receptor-1 (NgR1) and its ligands are among the inhibitors that limit axonal regeneration. It has been previously shown that the endogenous protein, lateral olfactory tract usher substance (LOTUS), antagonizes NgR1-mediated signaling and accelerates neuronal plasticity after spinal cord injury and cerebral ischemia in mice. However, it remained unclear whether LOTUS-mediated reorganization of descending motor pathways in the adult brain is physiologically functional and contributes to functional recovery. Here, we generated LOTUS-overexpressing transgenic (LOTUS-Tg) rats to investigate the role of LOTUS in neuronal function after damage. After unilateral pyramidotomy, motor function in LOTUS-Tg rats recovered significantly compared to that in wild-type animals. In a retrograde tracing study, labeled axons spanning from the impaired side of the cervical spinal cord to the unlesioned hemisphere of the red nucleus and sensorimotor cortex were increased in LOTUS-Tg rats. Anterograde tracing from the unlesioned cortex also revealed enhanced ipsilateral connectivity to the impaired side of the cervical spinal cord in LOTUS-Tg rats. Moreover, electrophysiological analysis showed that contralesional cortex stimulation significantly increased ipsilateral forelimb movement in LOTUS-Tg rats, which was consistent with the histological findings. According to these data, LOTUS overexpression accelerates ipsilateral projection from the unlesioned cortex and promotes functional recovery after unilateral pyramidotomy. LOTUS could be a future therapeutic option for CNS injury.
