Descending motor circuitry required for NT-3 mediated locomotor recovery after spinal cord injury in mice

Abstract

Locomotor function, mediated by lumbar neural circuitry, is modulated by descending spinal pathways. Spinal cord injury (SCI) interrupts descending projections and denervates lumbar motor neurons (MNs). We previously reported that retrogradely transported neurotrophin-3 (NT-3) to lumbar MNs attenuated SCI-induced lumbar MN dendritic atrophy and enabled functional recovery after a rostral thoracic contusion. Here we functionally dissected the role of descending neural pathways in response to NT-3-mediated recovery after a T9 contusive SCI in mice. We find that residual projections to lumbar MNs are required to produce leg movements after SCI. Next, we show that the spared descending propriospinal pathway, rather than other pathways (including the corticospinal, rubrospinal, serotonergic, and dopaminergic pathways), accounts for NT-3-enhanced recovery. Lastly, we show that NT-3 induced propriospino-MN circuit reorganization after the T9 contusion via promotion of dendritic regrowth rather than prevention of dendritic atrophy.

Select neurotrophins promote oligodendrocyte progenitor cell process outgrowth in the presence of chondroitin sulfate proteoglycans

“…NT‐3 has also been shown to enhance neuronal survival and stimulate regenerative sprouting following SCI (Han et al., 2019; Li et al., 2016; Tobias et al., 2003; Xu et al., 2020). Moreover, it can enhance the survival of OPCs, both in vitro and in vivo (Kumar et al., 1998).…”

“…Another treatment strategy utilizes neurotrophic agents to promote neuronal survival and stimulate the regeneration of axons. Currently some of the most common neurotrophic agents utilized in spinal regeneration studies include brain‐derived neurotrophic factor (BDNF; Gransee et al., 2015; Hassannejad et al., 2019; Liu et al., 2017), glial cell line‐derived neurotrophic factor (GDNF; Chen et al., 2018; Haldeman & Manna, 2019; Tajdaran et al., 2016), and neurotrophic factor‐3 (NT‐3; Han et al., 2019; Li et al., 2016; Xu et al., 2020). In these studies, the application of neurotrophic factors can enhance neuron survival and axonal sprouting, depending on the neuronal population examined and the SCI model.…”

Epidural Electrical Stimulation: A Review of Plasticity Mechanisms That Are Hypothesized to Underlie Enhanced Recovery From Spinal Cord Injury With Stimulation

“…Contained within the spinal cord, PNs are well-suited to relay information to motor pools below a lesion site (Han et al, 2019 ). Many receive inputs from supraspinal motor systems, and after unilateral lesion, corticospinal tract (CST) or reticulospinal (ReST) tract axons can sprout onto cervical PNs to relay these motor commands past the lesion site (Bareyre et al, 2004 ; Filli et al, 2014 ).…”

Trunk sensory and motor cortex is preferentially integrated with hindlimb sensory information that supports trunk stabilization

“…At the same time, anatomical studies have suggested that this proprioceptive input from below the level of the lesion interacts with extensive reorganization of the spinal proprioceptive circuitry (93)(94)(95)(96) that can allow the proprioceptive input to reach the cortex through interactions with reorganized supraspinal circuits (87,(97)(98)(99)(100). Therefore, the hindlimb proprioceptive information that is enabled through epidural stimulation replaces the hindlimb proprioceptive information we now know to exist in intact animals.…”