Sarah C. Strand

Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury.

Although axonal regeneration after CNS injury is limited, partial injury is frequently accompanied by extensive functional recovery. To investigate mechanisms underlying spontaneous recovery after incomplete spinal cord injury, we administered C7 spinal cord hemisections to adult rhesus monkeys and analyzed behavioral, electrophysiological and anatomical adaptations. We found marked spontaneous plasticity of corticospinal projections, with reconstitution of fully 60% of pre-lesion axon density arising from sprouting of spinal cord midline-crossing axons. This extensive anatomical recovery was associated with improvement in coordinated muscle recruitment, hand function and locomotion. These findings identify what may be the most extensive natural recovery of mammalian axonal projections after nervous system injury observed to date, highlighting an important role for primate models in translational disease research.

Animal Models of Neurologic Disorders: A Nonhuman Primate Model of Spinal Cord Injury

Primates are an important and unique animal resource. We have developed a nonhuman primate model of spinal cord injury (SCI) to expand our knowledge of normal primate motor function, to assess the impact of disease and injury on sensory and motor function, and to test candidate therapies before they are applied to human patients. The lesion model consists of a lateral spinal cord hemisection at the C7 spinal level with subsequent examination of behavioral, electrophysiological, and anatomical outcomes. Results to date have revealed significant neuroanatomical and functional differences between rodents and primates that impact the development of candidate therapies. Moreover, these findings suggest the importance of testing some therapeutic approaches in nonhuman primates prior to the use of invasive approaches in human clinical trials. Our primate model is intended to: 1) lend greater positive predictive value to human translatable therapies, 2) develop appropriate methods for human translation, 3) lead to basic discoveries that might not be identified in rodent models and are relevant to human translation, and 4) identify new avenues of basic research to “reverse-translate” important questions back to rodent models.

Pronounced species divergence in corticospinal tract reorganization and functional recovery after lateralized spinal cord injury favors primates

Fundamental differences in the anatomy and function of the corticospinal tract support enhanced recovery of leg and hand function after lateralized spinal cord injury in primates compared to rodents, emphasizing the importance of primate models for spinal cord repair therapies. Species-specific recovery Despite decades of research and success in rodent models, there are no therapies that repair the human spinal cord. Friedli et al. looked at the reorganization and function of the corticospinal tract after spinal cord injury (SCI) in rats, monkeys, and humans. In humans with lateralized SCI (affecting only one side of the spinal cord), there was greater recovery in motor function than those with more symmetric injuries; this recovery was mirrored in monkeys with a similar SCI, but not in rats. The authors looked into why such a species divergence exists, and revealed that monkeys had a greater number of bilateral axonal projections that sprouted into denervated spinal segments below the injury, whereas rats had interrupted projections and near-complete depletion of corticospinal fibers. Thus, monkeys and humans have the potential for synaptic reorganization above and below the lesion, and this corticospinal tract reorganization correlates with functional recovery. The authors suggest that primate models should be considered more frequently for research aimed at SCI repair and therapeutics, but acknowledge the importance of rodent models in the field. Furthermore, because the degree of laterality correlates with a positive outcome, the authors suggest that it be factored into clinical trial design. Experimental and clinical studies suggest that primate species exhibit greater recovery after lateralized compared to symmetrical spinal cord injuries. Although this observation has major implications for designing clinical trials and translational therapies, advantages in recovery of nonhuman primates over other species have not been shown statistically to date, nor have the associated repair mechanisms been identified. We monitored recovery in more than 400 quadriplegic patients and found that functional gains increased with the laterality of spinal cord damage. Electrophysiological analyses suggested that corticospinal tract reorganization contributes to the greater recovery after lateralized compared with symmetrical injuries. To investigate underlying mechanisms, we modeled lateralized injuries in rats and monkeys using a lateral hemisection, and compared anatomical and functional outcomes with patients who suffered similar lesions. Standardized assessments revealed that monkeys and humans showed greater recovery of locomotion and hand function than did rats. Recovery correlated with the formation of corticospinal detour circuits below the injury, which were extensive in monkeys but nearly absent in rats. Our results uncover pronounced interspecies differences in the nature and extent of spinal cord repair mechanisms, likely resulting from fundamental differences in the anatomical and functional characteristics of the motor systems in primates versus rodents. Although rodents remain essential for advancing regenerative therapies, the unique response of the primate corticospinal tract after injury reemphasizes the importance of primate models for designing clinically relevant treatments.

Methods for functional assessment after C7 spinal cord hemisection in the rhesus monkey

Background. Reliable outcome measures are essential for preclinical modeling of spinal cord injury (SCI) in primates. Measures need to be sensitive to both increases and decreases in function in order to demonstrate potential positive or negative effects of therapeutics. Objectives. To develop behavioral tests and analyses to assess recovery of function after SCI in the nonhuman primate. Methods. In all, 24 male rhesus macaques were subjected to complete C7 lateral hemisection. The authors scored recovery of function in an open field and during hand tasks in a restraining chair. In addition, EMG analyses were performed in the open field, during hand tasks, and while animals walked on a treadmill. Both control and treated monkeys that received candidate therapeutics were included in this report to determine whether the behavioral assays were capable of detecting changes in function over a wide range of outcomes. Results. The behavioral assays are shown to be sensitive to detecting a wide range of motor functional outcomes after cervical hemisection in the nonhuman primate. Population curves on recovery of function were similar across the different tasks; in general, the population recovers to about 50% of baseline performance on measures of forelimb function. Conclusions. The behavioral outcome measures that the authors developed in this preclinical nonhuman primate model of SCI can detect a broad range of motor recovery. A set of behavioral assays is an essential component of a model that will be used to test efficacies of translational candidate therapies for SCI.

Early social experience affects behavioral and physiological responsiveness to stressful conditions in infant rhesus macaques (Macaca mulatta)

Studies on early development have demonstrated the profound effects of early social experience on the behavioral development and physiology of young rhesus macaques. Given these relationships, we hypothesized that rhesus macaques exposed to different nursery‐rearing conditions may develop unique biobehavioral profiles. If this is true, the assessment of temperament may allow us to pinpoint successful rearing environments, thus improving the overall health of nonhuman primates that are raised in captive environments. We conducted biobehavioral assessments in order to examine differences in the development of infants raised under four different peer‐rearing conditions (continuous pairing (CP), intermittent pairing, CP with partner rotation, and intermittent rotational pairing) and compared these animals with data from a mother‐reared control group. Overall, continuous rotationally paired animals were most similar to mother‐reared controls on most behavioral and temperament measures, suggesting that more socially complex rearing environments (greater number of social partners) favor a more active behavioral style. Cortisol profiles of mother‐reared controls were similar to both CP groups, and these three groups had higher cortisol concentrations than the intermittent rotational‐pairing group. In addition, intermittently paired infants displayed a significantly higher frequency of self‐stroke behavior during a human intruder challenge, an abnormal behavior also known as floating limb which has been shown to be a precursor of self‐biting. Overall, the data are consistent with the idea that social complexity in the nursery, as operationalized in our continuous rotational pairing, leads to a biobehavioral profile that is most similar to that of infants raised by their mothers in large, socially complex, cages. Am. J. Primatol. 73:692–701, 2011.

A Unilateral Cervical Spinal Cord Contusion Injury Model in Non-Human Primates (Macaca mulatta)

Abstract The development of a non-human primate (NHP) model of spinal cord injury (SCI) based on mechanical and computational modeling is described. We scaled up from a rodent model to a larger primate model using a highly controllable, friction-free, electronically-driven actuator to generate unilateral C6-C7 spinal cord injuries. Graded contusion lesions with varying degrees of functional recovery, depending upon pre-set impact parameters, were produced in nine NHPs. Protocols and pre-operative magnetic resonance imaging (MRI) were used to optimize the predictability of outcomes by matching impact protocols to the size of each animals spinal canal, cord, and cerebrospinal fluid space. Post-operative MRI confirmed lesion placement and provided information on lesion volume and spread for comparison with histological measures. We evaluated the relationships between impact parameters, lesion measures, and behavioral outcomes, and confirmed that these relationships were consistent with our previous studies in the rat. In addition to providing multiple univariate outcome measures, we also developed an integrated outcome metric describing the multivariate cervical SCI syndrome. Impacts at the higher ranges of peak force produced highly lateralized and enduring deficits in multiple measures of forelimb and hand function, while lower energy impacts produced early weakness followed by substantial recovery but enduring deficits in fine digital control (e.g., pincer grasp). This model provides a clinically relevant system in which to evaluate the safety and, potentially, the efficacy of candidate translational therapies.

Growth factor neuroprotection in Alzheimer's disease: Long-term effects of AAV2-BDNF gene delivery in the entorhinal cortex of non-human primates

deleting these protease genes on memory deficits in the AD mouse model expressing human APP containing the WT beta-secretase site sequence and the London gamma-secretase site (APPWT/Lon mice), as well as the effects of administering the cysteine protease inhibitor E64d on memory deficits in that model. Methods: Firstly, transgenic APPWT/Lon mice with deletion of the cathepsin B or BACE1 gene were generated. Secondly, APPWT/Lonmicewere treated with E64d by oral administration. Both gene deletion and E64d treated animals were assessed for memory deficits by the Morris water maze test, for brain amyloid plaques by immunohistophathology, and for brain Abeta peptides and APP-derived fragments by ELISA and western analyses. Results: Knockout of the CatB gene in the APPWT/Lon mice improved memory deficits and altered the pattern of Abeta-related biomarkers in a manner consistent with CatB having WT beta-secretase activity. But deletion of the BACE1 gene had no effect on these parameters in the APPWT/Lon mice. These data are the first to show that knockout of a putative beta-secretase gene results in improved memory in an AD animal model expressing the WT beta-secretase site sequence of APP, present in the majority of AD patients. Furthermore, treatment of these mice with E64d, by oral administration, resulted in improvedmemory deficits and reduced brain Abeta.Conclusions: CatB may be an effective drug target and E64d may be an effective oral therapeutic agent for improving memory deficits in the majority of AD patients.