Combined with anti‐Nogo‐A antibody treatment, BDNF did not compensate the extra deleterious motor effect caused by large size cervical cord hemisection in adult macaques

In spinal cord injured adult mammals, neutralizing the neurite growth inhibitor Nogo‐A with antibodies promotes axonal regeneration and functional recovery, although axonal regeneration is limited in length. Neurotrophic factors such as BDNF stimulate neurite outgrowth and protect axotomized neurons. Can the effects obtained by neutralizing Nogo‐A, inducing an environment favorable for axonal sprouting, be strengthened by adding BDNF? A unilateral incomplete hemicord lesion at C7 level interrupted the main corticospinal component in three groups of adult macaque monkeys: control monkeys (n = 6), anti‐Nogo‐A antibody‐treated monkeys (n = 7), and anti‐Nogo‐A antibody and BDNF‐treated monkeys (n = 5). The functional recovery of manual dexterity was significantly different between the 3 groups of monkeys, the lowest in the control group. Whereas the anti‐Nogo‐A antibody‐treated animals returned to manual dexterity performances close to prelesion ones, irrespective of lesion size, both the control and the anti‐Nogo‐A/BDNF animals presented a limited functional recovery. In the control group, the limited spontaneous functional recovery depended on lesion size, a dependence absent in the combined treatment group (anti‐Nogo‐A antibody and BDNF). The functional recovery in the latter group was significantly lower than in anti‐Nogo‐A antibody‐treated monkeys, although the lesion was larger in three out of the five monkeys in the combined treatment group

Behavioral Assessment of Manual Dexterity in Non-Human Primates

The corticospinal (CS) tract is the anatomical support of the exquisite motor ability to skillfully manipulate small objects, a prerogative mainly of primates1. In case of lesion affecting the CS projection system at its origin (lesion of motor cortical areas) or along its trajectory (cervical cord lesion), there is a dramatic loss of manual dexterity (hand paralysis), as seen in some tetraplegic or hemiplegic patients. Although there is some spontaneous functional recovery after such lesion, it remains very limited in the adult. Various therapeutic strategies are presently proposed (e.g. cell therapy, neutralization of inhibitory axonal growth molecules, application of growth factors, etc), which are mostly developed in rodents. However, before clinical application, it is often recommended to test the feasibility, efficacy, and security of the treatment in non-human primates. This is especially true when the goal is to restore manual dexterity after a lesion of the central nervous system, as the organization of the motor system of rodents is different from that of primates1,2. Macaque monkeys are illustrated here as a suitable behavioral model to quantify manual dexterity in primates, to reflect the deficits resulting from lesion of the motor cortex or cervical cord for instance, measure the extent of spontaneous functional recovery and, when a treatment is applied, evaluate how much it can enhance the functional recovery

A case of polymicrogyria in macaque monkey: impact on anatomy and function of the motor system

Background: Polymicrogyria is a malformation of the cerebral cortex often resulting in epilepsy or mental retardation. It remains unclear whether this pathology affects the structure and function of the corticospinal (CS) system. The anatomy and histology of the brain of one macaque monkey exhibiting a spontaneous polymicrogyria (PMG monkey) were examined and compared to the brain of normal monkeys. The CS tract was labelled by injecting a neuronal tracer (BDA) unilaterally in a region where low intensity electrical microstimulation elicited contralateral hand movements (presumably the primary motor cortex in the PMG monkey). Results: The examination of the brain showed a large number of microgyri at macro- and microscopic levels, covering mainly the frontoparietal regions. The layered cortical organization was locally disrupted and the number of SMI-32 stained pyramidal neurons in the cortical layer III of the presumed motor cortex was reduced. We compared the distribution of labelled CS axons in the PMG monkey at spinal cervical level C5. The cumulated length of CS axon arbors in the spinal grey matter was not significantly different in the PMG monkey. In the red nucleus, numerous neurons presented large vesicles. We also assessed its motor performances by comparing its capacity to execute a complex reach and grasp behavioral task. The PMG monkey exhibited an increase of reaction time without any modification of other motor parameters, an observation in line with a normal CS tract organisation. Conclusion: In spite of substantial cortical malformations in the frontal and parietal lobes, the PMG monkey exhibits surprisingly normal structure and function of the corticospinal system

Cutaneous inputs to dorsal column nuclei in adult macaque monkeys subjected to unilateral lesion of the primary motor cortex or of the cervical spinal cord and treatments promoting axonal growth

The highly interconnected somatosensory and motor systems are subjected to connectivity changes at close or remote locations following a central nervous system injury. What is the impact of unilateral injury of the primary motor cortex (hand area; MCI) or of the cervical cord (hemisection at C7-C8 level; SCI) on the primary somatosensory (cutaneous) inputs to the dorsal column nuclei (DCN) in adult macaque monkeys? The effects of treatments promoting axonal growth were assessed. In the SCI group (n = 4), 1 monkey received a control antibody and 3 monkeys a combination treatment of anti-Nogo-A antibody and brain-derived neurotrophic factor (BDNF). In the MCI group (n = 4), 2 monkeys were untreated and 2 were treated with the anti-Nogo-A antibody. Using trans-ganglionic transport of cholera toxin B subunit injected in the first 2 fingers and toes on both sides, the areas of axonal terminal fields in the cuneate and gracile nuclei were bilaterally compared. Unilateral SCI at C7-C8 level, encroaching partially on the dorsal funiculus, resulted in an ipsilesional lower extent of the inputs from the toes in the gracile nuclei, not modified by the combined treatment. SCI at C7-C8 level did not affect the bilateral balance of primary inputs to the cuneate nuclei, neither in absence nor in presence of the combined treatment. MCI targeted to the hand area did not impact on the primary inputs to the cuneate nuclei in 2 untreated monkeys. After MCI, the administration of anti-Nogo-A antibody resulted in a slight bilateral asymmetrical extent of cutaneous inputs to the cuneate nuclei, with a larger extent ipsilesionally. Overall, remote effects following MCI or SCI have not been observed at the DCN level, except possibly after MCI and anti-Nogo-A antibody treatment

Anti-Nogo-A antibody treatment does not prevent cell body shrinkage in the motor cortex in adult monkeys subjected to unilateral cervical cord lesion-1

<p><b>Copyright information:</b></p><p>Taken from "Anti-Nogo-A antibody treatment does not prevent cell body shrinkage in the motor cortex in adult monkeys subjected to unilateral cervical cord lesion"</p><p>http://www.biomedcentral.com/1471-2202/9/5</p><p>BMC Neuroscience 2008;9():5-5.</p><p>Published online 14 Jan 2008</p><p>PMCID:PMC2242790.</p><p></p> monkeys. In the box and whisker plots, the thick horizontal line in the box corresponds to the median value, whereas the top and bottom of the box are for the 75 and 25 percentile values respectively. The top and bottom extremities of the vertical lines on each side of the box are for the 90 and 10 percentile values, respectively. All but one lesioned monkey (red and blue bars) exhibited a significant inter-hemispheric difference of cross-sectional soma area (* = p < 0.05; ** = p < 0.001; *** = p < 0.0001; Mann and Whitney test), whereas in the intact monkeys the difference was not statistically significant (n.s. = p > 0.05; Mann and Whitney test). B: Inter-hemispheric percent difference in the number of SMI-32 positive neurons per unit length in layer V in M1 for the same three groups of monkeys as in Figure 1C (same color code), plotted as a function of the lesion extent (percent of the territory corresponding to the CS and RS tracts affected by the lesion). Note that the differences are not systematic with respect to the side of the lesion in the two groups of lesioned animals (red squares and blue circles for the anti-Nogo-A and control antibody treated monkeys, respectively). In the percent comparison, 100% is for the number of SMI-32 positive neurons per unit length on the ipsilesional side (on the left side for the intact monkeys). The green triangles are for the intact monkeys. As the lesion extent could not be determined for Mk-AT (see Table 1), its corresponding percent value was represented by an horizontal dashed line. C: Inter-hemispheric percent difference of the median value of the cross-sectional soma area of SMI-32 positive neurons in layer V in M1 for the same three groups of monkeys as in panel A, plotted as a function of the lesion extent (percent of the territory corresponding to the CS and RS tracts affected by the lesion). Note that the difference is small for the intact monkeys (green symbols), but it is more prominent and systematic with respect to the side of the lesion for most lesioned monkeys, with considerable overlap between the two groups of lesioned monkeys. Same conventions as in panel B