Abstract
In response to cortical stroke and unilateral corticospinal tract degeneration, compensatory sprouting of spared corticospinal fibers is associated with recovery of skilled movement in rodents. To date, little is known about the molecular mechanisms orchestrating this spontaneous rewiring. In this study, we provide insights into the molecular changes in the spinal cord tissue after large ischemic cortical injury in adult female mice, with a focus on factors that might influence the reinnervation process by contralesional corticospinal neurons. We mapped the area of cervical gray matter reinnervation by sprouting contralesional corticospinal axons after unilateral photothrombotic stroke of the motor cortex in mice using anterograde tracing. The mRNA profile of this reinnervation area was analyzed using whole-genome sequencing to identify differentially expressed genes at selected time points during the recovery process. Bioinformatic analysis revealed two phases of processes: early after stroke (4–7 d post-injury), the spinal transcriptome is characterized by inflammatory processes, including phagocytic processes as well as complement cascade activation. Microglia are specifically activated in the denervated corticospinal projection fields in this early phase. In a later phase (28–42 d post-injury), biological processes include tissue repair pathways with upregulated genes related to neurite outgrowth. Thus, the stroke-denervated spinal gray matter, in particular its intermediate laminae, represents a growth-promoting environment for sprouting corticospinal fibers originating from the contralesional motor cortex. This dataset provides a solid starting point for future studies addressing key elements of the post-stroke recovery process, with the goal to improve neuroregenerative treatment options for stroke patients.SIGNIFICANCE STATEMENT We show that the molecular changes in the spinal cord target tissue of the stroke-affected corticospinal tract are mainly defined by two phases: an early inflammatory phase during which microglia are specifically activated in the target area of reinnervating corticospinal motor neurons; and a late phase during which growth-promoting factors are upregulated which can influence the sprouting response, arborization, and synapse formation. By defining for the first time the endogenous molecular machinery in the stroke-denervated cervical spinal gray matter with a focus on promotors of axon growth through the growth-inhibitory adult CNS, this study will serve as a basis to address novel neuroregenerative treatment options for chronic stroke patients.
Highlights
Stroke is a leading cause of neurological disability and often impairs motor and sensory systems, resulting in a severely decreasedReceived Oct. 3, 2018; revised March 22, 2019; accepted March 28, 2019
Statement We show that the molecular changes in the spinal cord target tissue of the stroke-affected corticospinal tract are mainly defined by two phases: an early inflammatory phase during which microglia are activated in the target area of reinnervating corticospinal motor neurons; and a late phase during which growth-promoting factors are upregulated which can influence the sprouting response, arborization, and synapse formation
At 4 dpi, all stroked animals showed a strong deficit in limb placement and targeting as detected by a reduction in success score and an increase in the number of forelimb foot faults compared with baseline
Summary
Stroke is a leading cause of neurological disability and often impairs motor and sensory systems, resulting in a severely decreased. Received Oct. 3, 2018; revised March 22, 2019; accepted March 28, 2019. I.S. contributed unpublished reagents/analytic tools; J.K., M.M., I.S., N.H., V.B.C.S., and M.D.R. analyzed data; J.K. wrote the paper. We thank all members quality of life (Murphy and Corbett, 2009). Functional improvements are most considerable within the first few weeks to months of the Schwab laboratory, in particular Anna-Sophia Wahl, Oliver Weinmann, and Benjamin Ineichen, for technical advice and fruitful discussions. Kaiser et al The Spinal Transcriptome after Cortical Stroke
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