Contribution of propriospinal neurons to recovery of hand dexterity after corticospinal tract lesions in monkeys

Abstract

The direct cortico-motoneuronal connection is believed to be essential for the control of dexterous hand movements, such as precision grip in primates. It was reported, however, that even after lesion of the corticospinal tract (CST) at the C4-C5 segment, precision grip largely recovered within 1-3 mo, suggesting that the recovery depends on transmission through intercalated neurons rostral to the lesion, such as the propriospinal neurons (PNs) in the midcervical segments. To obtain direct evidence for the contribution of PNs to recovery after CST lesion, we applied a pathway-selective and reversible blocking method using double viral vectors to the PNs in six monkeys after CST lesions at C4-C5. In four monkeys that showed nearly full or partial recovery, transient blockade of PN transmission after recovery caused partial impairment of precision grip. In the other two monkeys, CST lesions were made under continuous blockade of PN transmission that outlasted the entire period of postoperative observation (3-4.5 mo). In these monkeys, precision grip recovery was not achieved. These results provide evidence for causal contribution of the PNs to recovery of hand dexterity after CST lesions; PN transmission is necessary for promoting the initial stage recovery; however, their contribution is only partial once the recovery is achieved.spinal cord injury | plasticity | neural circuit | nonhuman primates | viral vector A s a potential treatment for brain and spinal cord injury, regeneration of the injured axons has been attempted in animal models, often using rodents with corticospinal tract (CST) lesions. Regeneration of the injured CST fibers was facilitated by treatments such as peripheral nerve graft (1), application of an antibody against neurite growth inhibitors IN-1 (2), combined application of the antibody and neurotrophic factor NT-3 (3), and transplantation of neural stem cells derived from induced pluripotent stem cells (4). A more recent study showed that regenerated CST axons increased the connection to the spinal motoneurons (MNs) after spinal cord injury in monkeys (5). However, in these studies, the causal contribution of such regenerated fibers to the functional recovery was not directly demonstrated. Therefore, recent debates address the question whether these therapies should target repairing the injured CST fibers and/or facilitating compensation by indirect cortico-motoneuronal (CM) connections via other descending motor pathways (6-9).Traditionally, the neural control of dexterous hand movements in higher primates has primarily been associated with development of the direct pathway from the motor cortex to MNs, known as the CM pathway (10-12). Lesion of the CST at the brainstem level in nonhuman primates caused near-permanent loss of dexterous hand movements (13). The authors also argued for partial compensation of grasping movements by the brainstemmediated descending pathways such as the rubrospinal tract (14). More recent studies on the neural basis of functional recovery following CST lesions ...

Cell biology of spinal cord injury and repair

“…22-24, 30, 32, 135-138; Figure 2; and Figure 3, B and C). Functional studies show that relay circuits formed between supraspinal pathways and descending propriospinal neurons can relay supraspinal commands that control voluntary locomotion in rodents (31), and can mediate fine finger movements in nonhuman primates (138)(139)(140). Such observations provide a rationale for repair strategies that seek either to augment spontaneous relay circuit formation and efficacy after incomplete SCI ( Figure 3B), or to restore short-distance neural connectivity across anatomically complete SCI lesions ( Figure 3C).…”

Global connectivity and function of descending spinal input revealed by 3D microscopy and retrograde transduction

“…Surprisingly, AAV2-Retro also displayed relatively low efficiency in propriospinal neurons. Other AAV serotypes can transduce thousands of propriospinal neurons more than 1cm from injection sites, (Klaw et al, 2013;Tohyama et al, 2017), yet AAV2-Retro produced sparse transduction just millimeters away. Taken together, our data indicate that AAV2-Retro uptake is highly effective from most projection neurons located in higher brain centers, while some AAV serotypes would be preferable to target propriospinal neurons.…”

Dynamic Interaction between Cortico-Brainstem Pathways during Training-Induced Recovery in Stroke Model Rats

“…Reorganization of motor pathways, such as unmasking of silent pathways or generation of new synaptic connections by axonal sprouting, has been considered as the underlying mechanism for functional recovery and is a key factor in poststroke rehabilitation (Taub et al, 2002;Murphy and Corbett, 2009). Various forms of motor circuit reorganization after lesion of the primary motor cortex or the cortico-spinal tract (CST) have been demonstrated, such as recruitment of premotor cortex (Liu and Rouiller, 1999;Fridman et al, 2004), sprouting from the contralateral CST ( Bareyre et al, 2004;Maier et al, 2008), and using alternative pathways, such as propriospinal neurons (Tohyama et al, 2017). The cortico-brainstem pathways may also be potential compensatory pathways after stroke.…”