Corticospinal-specific Shh overexpression in combination with rehabilitation promotes CST axonal sprouting and skilled motor functional recovery after ischemic stroke.

Ischemic stroke often leads to permanent neurological impairments, largely due to limited neuroplasticity in adult central nervous system. Here, we first showed that the expression of Sonic Hedgehog (Shh) in corticospinal neurons (CSNs) peaked at the 2nd postnatal week, when corticospinal synaptogenesis occurs. Overexpression of Shh in adult CSNs did not affect motor functions and had borderline effects on promoting the recovery of skilled locomotion following ischemic stroke. In contrast, CSNs-specific Shh overexpression significantly enhanced the efficacy of rehabilitative training, resulting in robust axonal sprouting and synaptogenesis of corticospinal axons into the denervated spinal cord, along with significantly improved behavioral outcomes. Mechanistically, combinatory treatment led to additional mTOR activation in CSNs when compared to that evoked by rehabilitative training alone. Taken together, our study unveiled a role of Shh, a morphogen involved in early development, in enhancing neuroplasticity, which significantly improved the outcomes of rehabilitative training. These results thus provide novel insights into the design of combinatory treatment for stroke and traumatic central nervous system injuries.

Rehabilitative training paired with peripheral stimulation promotes motor recovery after ischemic cerebral stroke.

Spontaneous recovery of ischemic stroke is very limited and often results in the loss of motor and sensory function. Till now, rehabilitative training is the most widely accepted therapy to improve long-term outcome. However, its effectiveness is often suboptimal, largely due to a sharp decline of neuroplasticity in adults. In this study, we hypothesized that a combination of proprioceptive stimulation and rehabilitative training will promote neuroplasticity and functional recovery post injury. To test this hypothesis, we first established a photothrombotic stroke model that lesions the hindlimb sensorimotor cortex. Next, we demonstrated that injecting Cre-dependent AAV-retro viruses into the dorsal column of PV-Cre mice achieves specific and efficient targeting of proprioceptors. With chemogenetics, this method enables chronic activation of proprioceptors. We then assessed effects of combinatorial treatment on motor and sensory functional recovery. Our results showed that pairing proprioceptive stimulation with rehabilitative training significantly promoted skilled motor, but not tactile sensory functional recovery. This further led to significant improvement when compared to rehabilitation training or proprioceptor stimulation alone. Mechanistically, combinatorial treatment promoted cortical layer V neuronal mTOR activity and sprouting of corticospinal axon into the area where proprioceptive afferents terminate in the denervated side of the spinal cord. Serving as a proof of principle, our study thus provided novel insights into the application of combining proprioceptive stimulation and rehabilitative training to improve functional recovery of ischemic stroke and other traumatic brain or spinal cord injuries.

Knock down of lncRNA H19 promotes axon sprouting and functional recovery after cerebral ischemic stroke.

Ischemic stroke is a leading cause of irreversible brain damages and disabilities. In the past decade, much attention has been focused on exploring effective strategies to promote circuit reorganization and functional recovery post injury. Here, we showed that the expression level of a long non-coding RNA (lncRNA H19) is bilaterally increased in the sensorimotor cortex after a cerebral ischemia induced by middle cerebral artery occlusion (MCAO). Knock down of contralaterally elevated H19 robustly enhanced the midline-crossing sprouting of the intact corticospinal axons in the spinal cord. Furthermore, H19 knockdown mice showed significant improvement on the performance of the food pellet retrieval assay, a skilled, cortical dependent motor task. Mechanistically, lncRNA H19 inhibition increased IGF1R expression and activated IGF1 mediated mTOR pathway. Our research thereby provided novel insights into identifying therapeutic targets for ischemic stroke.