The role of sensorimotor afferent feedback in mediating functional recovery after spinal cord injury

Spinal cord injury (SCI) leads to permanent deficits in sensory and motor function due to the physical disruption of descending and ascending pathways. As a consequence, spinal circuits below the level of lesion remain in an intact, but inactive state. A number of studies have shown that epidural electrical stimulation (EES) of the lumbar spinal cord can reactivate these spinal circuits after SCI. EES reversed paralysis of lower limbs in rodent and primate models of SCI as well as in a number of clinical case studies. However, although the positive effects of EES have been documented, little is known about the neural circuits through which EES enables motor pattern formation after SCI.

In the first part of this thesis, we examined the neural circuits activated by EES. In the past, modeling experiments highlighted a pivotal role for large-diameter, myelinated afferent circuits in mediating the facilitating effects of EES after SCI. Using calcium imaging and chemogenetic inactivation experiments, we confirmed that EES primarily recruits proprioceptive and low-threshold mechanoreceptor feedback circuits. We next sought to exploit this knowledge to specifically enhance the effects of EES. We found that alpha2a receptors are prominently expressed on proprioceptive afferent neurons in DRGs, whereas alpha2c receptors are located on low-threshold mechanoreceptor interneurons in the dorsal spinal horn. Based on this knowledge, we built a computational model that identified beneficial and detrimental interactions between EES and noradrenergic circuits. This understanding guided the design of a circuit-specific, electrochemical neuromodulation that specifically gated the effects of EES towards proprioceptive feedback circuits and re-established locomotion in paralyzed mice and rats.

The second part of this thesis uncovers the impact of movement on sensory afferent pathways. For this, mice were exposed to environmental enrichment (EE) or standard housing (SH). We found that EE primed sensory dorsal root ganglia neurons, inducing a lasting increase in their regenerative potential after SCI. This EE-mediated increase in regenerative potential was confined to proprioceptive afferent neurons and characterized through increased calcium signalling and CBP-dependent histone acetylation which is associated with enhanced gene expression. In a next step, we mimicked the exposure to EE using pharmacology. The pharmacological activation of CBP after injury enhanced axonal growth of proprioceptive afferent fibers and enhanced the recovery of sensory and motor functions.

Here, we provide direct and conclusive experimental evidence for the mechanistic understanding of EES and EE and how they mediate functional recovery after SCI. Based on this knowledge, we identified specific receptors and epigenetic mechanisms for pharmacological modulation. Our findings demonstrate the importance of large-diameter afferent fibers in mediating functional recovery and will be important