Muscle Spindle Feedback Directs Locomotor Recovery and Circuit Reorganization after Spinal Cord Injury

Spinal cord injuries alter motor function by disconnecting neural circuits above and below the lesion, rendering sensory inputs a primary source of direct external drive to neuronal networks caudal to the injury. Here, we studied mice lacking functional muscle spindle feedback to determine the role of this sensory channel in gait control and locomotor recovery after spinal cord injury. High-resolution kinematic analysis of intact mutant mice revealed proficient execution in basic locomotor tasks but poor performance in a precision task. After injury, wildtype mice spontaneously recovered basic locomotor function, whereas mice with deficient muscle spindle feedback failed to regain control over the hindlimb on the lesioned side. Virus-mediated tracing demonstrated that mutant mice exhibit defective rearrangements of descending circuits projecting to deprived spinal segments during recovery. Our findings reveal an essential role for muscle spindle feedback in directing basic locomotor recovery and facilitating circuit reorganization after spinal cord injury.

Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury

Grégoire Courtine, Michael V. Sofroniew

Spinal cord injuries (SCIs) in humans and experimental animals are often associated with varying degrees of spontaneous functional recovery during the first months after injury. Such recovery is widely attributed to axons spared from injury that descend from the brain and bypass incomplete lesions, but its mechanisms are uncertain. To investigate the neural basis of spontaneous recovery, we used kinematic, physiological and anatomical analyses to evaluate mice with various combinations of spatially and temporally separated lateral hemisections with or without the excitotoxic ablation of intrinsic spinal cord neurons. We show that propriospinal relay connections that bypass one or more injury sites are able to mediate spontaneous functional recovery and supraspinal control of stepping, even when there has been essentially total and irreversible interruption of long descending supraspinal pathways in mice. Our findings show that pronounced functional recovery can occur after severe SCI without the maintenance or regeneration of direct projections from the brain past the lesion and can be mediated by the reorganization of descending and propriospinal connections. Targeting interventions toward augmenting the remodeling of relay connections may provide new therapeutic strategies to bypass lesions and restore function after SCI and in other conditions such as stroke and multiple sclerosis.

2008

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

Kay Alexander Bartholdi

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 in establishing a framework for the design of targeted neuromodulation therapies after SCI in human patients.

EPFL2019

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

Kay Alexander Bartholdi

EPFL2019