Semaphorin 7A restricts serotonergic innervation and ensures recovery after spinal cord injury.

Descending serotonergic (5-HT) projections originating from the raphe nuclei form an important input to the spinal cord that control basic locomotion. The molecular signals that control this projection pattern are currently unknown. Here, we identify Semaphorin7A (Sema7A) as a critical cue that restricts serotonergic innervation in the spinal cord. Sema7A deficient mice show a marked increase in serotonergic fiber density in all layers of the spinal cord while the density of neurons expressing the corresponding 5-HTR2α receptor remains unchanged. These alterations appear to be successfully compensated as no obvious changes in rhythmic locomotion and skilled stepping are observed in adult mice. When the system is challenged with a spinal lesion, serotonergic innervation patterns in both Sema7A-deficient and -competent mice evolve over time with excessive innervation becoming most pronounced in the dorsal horn of Sema7A-deficient mice. These altered serotonergic innervation patterns correlate with diminished functional recovery that predominantly affects rhythmic locomotion. Our findings identify Sema7A as a critical regulator of serotonergic circuit formation in the injured spinal cord.

Corticospinal circuit remodeling after central nervous system injury is dependent on neuronal activity.

The remodeling of supraspinal axonal circuits mediates functional recovery after spinal cord injury. This process critically depends on the selection of appropriate synaptic connections between cortical projection and spinal relay neurons. To unravel the principles that guide this target selection, we used genetic and chemogenetic tools to modulate NMDA receptor (NMDAR) integrity and function, CREB-mediated transcription, and neuronal firing of relay neurons during injury-induced corticospinal remodeling. We show that NMDAR signaling and CREB-mediated transcription maintain nascent corticospinal tract (CST)-relay neuron contacts. These activity-dependent signals act during a defined period of circuit remodeling and do not affect mature or uninjured circuits. Furthermore, chemogenetic modulation of relay neuron activity reveals that the regrowing CST axons select their postsynaptic partners in a competitive manner and that preventing such activity-dependent shaping of corticospinal circuits limits motor recovery after spinal cord injury.

Combining molecular intervention with in vivo imaging to untangle mechanisms of axon pathology and outgrowth following spinal cord injury.

In vivo imaging of the spinal cord has allowed the observation of single axons over relatively long periods in the living mouse. After spinal cord injury, this methodology has helped to differentiate several pathological stages and tissue processes which impact axon morphology. In addition, the combination of in vivo imaging techniques with particular molecular intervention has shown that specific pathological axon changes can respond to distinct treatments. Combining in vivo imaging with molecular interventions is, hence, a powerful approach to extend our knowledge of the pathological processes leading to axonal loss. It also allows testing possible treatment options to, for example, increase axonal outgrowth. This review will provide a detailed description and critical examination of several studies that have combined the two methodologies in spinal cord injury research and pinpoints the specificities of the approach.