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

Abstract

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.

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

“…Boutons on 5-HT collaterals were counted (40–70 collaterals per group were analyzed). A bouton was defined as a thick varicosity along a comparably thin 5-HT collateral in the lumbar spinal cord (at least twice bigger and brighter than the adjacent collateral and rounded shape [ 31 ]). The total number of boutons per animal was divided by the total length in micrometers of collaterals per animal to calculate the density in boutons/μm.…”

Formation of somatosensory detour circuits mediates functional recovery following dorsal column injury

“…Our study now indicates that common principles guide these rewiring processes both in the motor and somatosensory system and suggests the formation of intraspinal detour circuits as a key structural element of these rewiring processes. As the mechanisms that guide the formation of detour circuits are beginning to be unraveled 24 and strategies that support their formation are emerging, such circuits might represent a particular promising therapeutic target for the restoration of motor and sensory function in spinal cord injured patients.…”

“…All single planes from the image stacks were analyzed in order to assess the presence of boutons (as described above) in close apposition to a cuneate nucleus-projecting neuron (on the neurites or cell body). A contact was defined as the presence of a bouton, a thick varicosity (about three time the diameter of a relatively thick DRG axon 24 ) closely apposed to an interneuron's soma or neurite. To facilitate counting for each subtype in each area (dorsal, intermediate, ventral) the cell counter tool of ImageJ was used to point the contacts on the maximum intensity projections.…”

A deep-learning-based toolbox for Automated Limb Motion Analysis (ALMA) in murine models of neurological disorders

“…Once the mice presented no reflex reaction from paw pinching, their backs were shaved and a laminectomy was performed at T8 levels. The dura was exposed, and a dorsal hemisection was performed using irridectomy scissors 33,49 (Bradley et al, 2019;Loy et al, 2018). After the hemisection, the wound was closed, and the skin was sutured.…”