Neurotransmitter phenotypes of descending systems in the rat lumbar spinal cord

Beau, Amy Du; Shrestha, Sony; Bannatyne, B. Anne; Jalicy, Susan M.; Linnen, S; Maxwell, David

doi:10.1016/j.neuroscience.2012.09.037

Cited by 78 publications

(87 citation statements)

References 66 publications

(92 reference statements)

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“…Notably, these biological effects were exerted by hMSCs in the progenitor state, without mesenchymal lineage differentiation or neural transdifferentiation. Thereby, hMSCs may provide their therapeutic impacts mainly through functional multipotency events, conducive to post-SCI coordination of four components essential for hindlimb locomotor recovery: (i) serotonergic reticulospinal reinnervation caudal to the lesion; (ii) propriospinal projection network plasticity; (iii) NMJ integrity; and (iv) CPG reactivation (40,(43)(44)(45). In regard to CST axonal regrowth as the frequently pursued central regenerative goal in treating SCI, these outcomes collectively introduce a different theoretical and experimental platform to investigate stem cell-based therapy that sets forth an interactive set of recovery neurobiology mechanisms for lesioned adult mammalian spinal cord.…”

Section: Discussionmentioning

confidence: 99%

“…There was no evidence of rubrospinal tract (RST) regrowth beyond the lesion site, as determined (Fig. S4) by ICC of vGluT2, a primary marker of RST terminals (43). We thereby used a novel "peripheral-central" and "bottom-up" tracing strategy to elucidate the neural pathways responsible for the observed recovery of locomotion in the treated rats.…”

Section: Neurobiological Mechanisms Underlying Post-sci Recovery Follmentioning

confidence: 99%

“…We specifically investigated whether the rodent central pattern generator (CPG) for hindlimb locomotion might be partially activated by submidbrain inputs (40,44); this was done by injecting different retrograde tracers [i.e., DiI, Fast Blue (FB), and Fluoro-Gold (FG)] into the cervical, thoracic, abdominal, and hindlimb muscles and performing 5HT ICC (Fig. 6 A and B; Materials and Methods) (40,43,44). We also immunochemically evaluated the distribution and quantity of synaptophysin, a pansynaptic vesicle protein and vGluT1, the primary proprioceptive terminal glutamate transporter interacting with propriospinal interneurons (PSNs) in Rexed's Laminae (RL) IV-VIII and RL IX motor neurons (45).…”

Section: Neurobiological Mechanisms Underlying Post-sci Recovery Follmentioning

confidence: 99%

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Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation

Ropper

Thakor

Han

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Mesenchymal stromal stem cells (MSCs) isolated from adult tissues offer tangible potential for regenerative medicine, given their feasibility for autologous transplantation. MSC research shows encouraging results in experimental stroke, amyotrophic lateral sclerosis, and neurotrauma models. However, further translational progress has been hampered by poor MSC graft survival, jeopardizing cellular and molecular bases for neural repair in vivo. We have devised an adult human bone marrow MSC (hMSC) delivery formula by investigating molecular events involving hMSCs incorporated in a uniquely designed poly(lactic-co-glycolic) acid scaffold, a clinically safe polymer, following inflammatory exposures in a dorsal root ganglion organotypic coculture system. Also, in rat T9-T10 hemisection spinal cord injury (SCI), we demonstrated that the tailored scaffolding maintained hMSC stemness, engraftment, and led to robust motosensory improvement, neuropathic pain and tissue damage mitigation, and myelin preservation. The scaffolded nontransdifferentiated hMSCs exerted multimodal effects of neurotrophism, angiogenesis, neurogenesis, antiautoimmunity, and antiinflammation. Hindlimb locomotion was restored by reestablished integrity of submidbrain circuits of serotonergic reticulospinal innervation at lumbar levels, the propriospinal projection network, neuromuscular junction, and central pattern generator, providing a platform for investigating molecular events underlying the repair impact of nondifferentiated hMSCs. Our approach enabled investigation of recovery neurobiology components for injured adult mammalian spinal cord that are different from those involved in normal neural function. The uncovered neural circuits and their molecular and cellular targets offer a biological underpinning for development of clinical rehabilitation therapies to treat disabilities and complications of SCI.spinal cord injury | recovery neurobiology | mesenchymal stromal stem cell | PLGA | locomotion R epair of neurotrauma, stroke, and neurodegenerative diseases remains an unmet medical demand because of their pathophysiological complexity and the limited spontaneous healing capacity of adult mammalian CNS. Human mesenchymal stromal stem cells (hMSCs) offer autologous transplantation feasibility (1-4) and have been studied both experimentally and clinically for traumatic brain injury (TBI) and spinal cord injury (SCI) (5-8). Although MSCs possess homeostatic and proneurogenic activities (7, 9), studies relying on neural transdifferentiation (i.e., putative differentiations of MSCs into neural cells without reentering the pluripotency phase) did not show long-term functional improvement in SCI models. The poor outcomes were attributed mainly to suboptimal survival of MSCs, leaving key therapeutic mechanisms undetermined (10). We previously established a 3D cell delivery technology by seeding neural stem cells (NSCs) in biodegradable polymer scaffolds that significantly improved donor efficacy and enabled investigation of NSC repair mechanisms in t...

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Section: Discussionmentioning

confidence: 99%

Section: Neurobiological Mechanisms Underlying Post-sci Recovery Follmentioning

confidence: 99%

Section: Neurobiological Mechanisms Underlying Post-sci Recovery Follmentioning

confidence: 99%

See 1 more Smart Citation

Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation

Ropper

Thakor

Han

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Another possibility that does not invoke homeostasis of muscle-afferent terminal number, posits that VGLUT1 ϩ terminals from other spinal or descending neurons sprout to account for the increased number of VGLUT1 ϩ terminals on calbindin ϩ neurons. It is known that corticospinal (Du Beau et al 2012) and dorsal spinocerebellar (Hantman and Jessell 2010) neurons express VGLUT1 at their synapses. To our knowledge, there is no evidence that either class of neuron synapses with calbindin ϩ Renshaw cells.…”

Section: Discussionmentioning

confidence: 99%

Preservation of VGLUT1 synapses on ventral calbindin-immunoreactive interneurons and normal locomotor function in a mouse model of spinal muscular atrophy

Thirumalai

Behrend

Birineni

et al. 2013

Journal of Neurophysiology

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Here, we examined the density of proprioceptive and cholinergic synapses on calbindin-immunoreactive interneurons ventral to the lateral motor column. This population includes inhibitory Renshaw interneurons that are known to receive synaptic input from muscle spindle afferents and from motoneurons. At postnatal day (P)13, near the end stage of the disease, the somatic area of calbindin ϩ neurons in the L1/L2 and L5/L6 segments was reduced in SMA⌬7 mice compared with controls. In addition, the number and density of terminals expressing the glutamate vesicular transporter (VGLUT1) and the vesicular acetylcholine transporter (VAChT) were increased on calbindin ϩ cells in the L1-L2 but not in the L5-L6 segments of SMA⌬7 mice. In addition, the isolated spinal cord of SMA mice was able to generate locomotor-like activity at P4-P6 in the presence of a drug cocktail or in response to dorsal root stimulation. These results argue against a generalized loss of proprioceptive input to spinal circuits in SMA and suggest that the loss of proprioceptive synapses on motoneurons may be secondary to motoneuron pathology. The increased number of VGLUT1 ϩ and VAChT ϩ synapses on calbindin ϩ neurons in the L1/L2 segments may be the result of homeostatic mechanisms. Finally, we have shown that abnormal locomotor network function is unlikely to account for the motor deficits observed in SMA mice at P4 -6.

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“…Reticulospinal axons may be uniquely suited to mediate anatomical detours relaying cortical input around CNS damage to spinal interneurons due to the fact that they project both excitatory and inhibitory inputs onto propriospinal neurons, in contrast to cortiocospinal, vestibulospinal, and rubrospinal tracts which have been shown to have almost exclusive excitatory inputs (Du Beau, Shakya Shrestha et al 2012, Brockett, Seenan et al 2013, as identified based on analysis of neurotransmitter phenotypes. Also with regard to the formation of de novo circuits, the propriospinal cell bodies are in close anatomical approximation to reitculospinal axon terminals in laminae VII and VIII (Reed, Shum-Siu et al 2006, Brockett, Seenan et al 2013, Mitchell, McCallum et al 2016 Until recently, it was thought that reticulospinal input was required for locomotion, although rythymic leg movements can still be seen in SCI rats after 5-HT antagonist application.…”

Section: Propriospinal Tract Assessmentmentioning

confidence: 99%

Identification of residual descending pathways after human spinal cord injury.

Atkinson¹

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Neurotransmitter phenotypes of descending systems in the rat lumbar spinal cord

Cited by 78 publications

References 66 publications

Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation

Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation

Preservation of VGLUT1 synapses on ventral calbindin-immunoreactive interneurons and normal locomotor function in a mouse model of spinal muscular atrophy

Identification of residual descending pathways after human spinal cord injury.

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