Ephron S. Rosenzweig

Impact of aging on hippocampal function: plasticity, network dynamics, and cognition

Aging is associated with specific impairments of learning and memory, some of which are similar to those caused by hippocampal damage. Studies of the effects of aging on hippocampal anatomy, physiology, plasticity, and network dynamics may lead to a better understanding of age-related cognitive deficits. Anatomical and electrophysiological studies indicate that the hippocampus of the aged rat sustains a loss of synapses in the dentate gyrus, a loss of functional synapses in area CA1, a decrease in the NMDA-receptor-mediated response at perforant path synapses onto dentate gyrus granule cells, and an alteration of Ca(2+) regulation in area CA1. These changes may contribute to the observed age-related impairments of synaptic plasticity, which include deficits in the induction and maintenance of long-term potentiation (LTP) and lower thresholds for depotentiation and long-term depression (LTD). This shift in the balance of LTP and LTD could, in turn, impair the encoding of memories and enhance the erasure of memories, and therefore contribute to cognitive deficits experienced by many aged mammals. Altered synaptic plasticity may also change the dynamic interactions among cells in hippocampal networks, causing deficits in the storage and retrieval of information about the spatial organization of the environment. Further studies of the aged hippocampus will not only lead to treatments for age-related cognitive impairments, but may also clarify the mechanisms of learning in adult mammals.

Long-Distance Growth and Connectivity of Neural Stem Cells after Severe Spinal Cord Injury

Neural stem cells (NSCs) expressing GFP were embedded into fibrin matrices containing growth factor cocktails and grafted to sites of severe spinal cord injury. Grafted cells differentiated into multiple cellular phenotypes, including neurons, which extended large numbers of axons over remarkable distances. Extending axons formed abundant synapses with host cells. Axonal growth was partially dependent on mammalian target of rapamycin (mTOR), but not Nogo signaling. Grafted neurons supported formation of electrophysiological relays across sites of complete spinal transection, resulting in functional recovery. Two human stem cell lines (566RSC and HUES7) embedded in growth-factor-containing fibrin exhibited similar growth, and 566RSC cells supported functional recovery. Thus, properties intrinsic to early-stage neurons can overcome the inhibitory milieu of the injured adult spinal cord to mount remarkable axonal growth, resulting in formation of new relay circuits that significantly improve function. These therapeutic properties extend across stem cell sources and species.

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.

Rodent models for treatment of spinal cord injury: research trends and progress toward useful repair.

Purpose of reviewIn this review, we have documented some current research trends in rodent models of spinal cord injury. We have also catalogued the treatments used in studies published between October 2002 and November 2003, with special attention given to studies in which treatments were delayed for at least 4 days after injury. Recent findingsMost spinal cord injury studies are performed with one of three general injury models: transection, compression, or contusion. Although most treatments are begun immediately after injury, a growing number of studies have used delayed interventions. Mice and the genetic tools they offer are gaining in popularity. Some researchers are setting their sights beyond locomotion, to issues more pressing for people with spinal cord injury (especially bladder function and pain). SummaryDelayed treatment protocols may extend the window of opportunity for treatment of spinal cord injury, whereas continued progress in the prevention of secondary cell death will reduce the severity of new cases. The use of mice will hopefully accelerate progress towards useful regeneration in humans. Researchers must improve cross-study comparability to allow balanced decisions about potentially useful treatments.

Role of temporal summation in age-related long-term potentiation–induction deficits

Hippocampal long‐term potentiation (LTP) is reduced in aged relative to young F‐344 rats when peri‐threshold stimulation protocols (several stimulus pulses at 100–200 Hz) are used. The present study was designed to examine the possibility that this LTP‐induction deficit is caused by a reduced overlap of Schaffer‐collateral inputs onto CA1 pyramidal cells (input cooperativity). This reduced input cooperativity would decrease the levels of postsynaptic depolarization during LTP induction, which might account for the age‐related LTP deficit.

Extensive Spinal Decussation and Bilateral Termination of Cervical Corticospinal Projections in Rhesus Monkeys

To examine neuroanatomical mechanisms underlying fine motor control of the primate hand, adult rhesus monkeys underwent injections of biotinylated dextran amine (BDA) into the right motor cortex. Spinal axonal anatomy was examined using detailed serial‐section reconstruction and modified stereological quantification. Eighty‐seven percent of corticospinal tract (CST) axons decussated in the medullary pyramids and descended through the contralateral dorsolateral tract of the spinal cord. Eleven percent of CST axons projected through the dorsolateral CST ipsilateral to the hemisphere of origin, and 2% of axons projected through the ipsilateral ventromedial CST. Notably, corticospinal axons decussated extensively across the spinal cord midline. Remarkably, nearly 2‐fold more CST axons decussated across the cervical spinal cord midline (≈12,000 axons) than were labeled in all descending components of the CST (≈6,700 axons). These findings suggest that CST axons extend multiple segmental collaterals. Furthermore, serial‐section reconstructions revealed that individual axons descending in either the ipsilateral or contralateral dorsolateral CST can: 1) terminate in the gray matter ipsilateral to the hemisphere of origin; 2) terminate in the gray matter contralateral to the hemisphere of origin; or 3) branch in the spinal cord and terminate on both sides of the spinal cord. These results reveal a previously unappreciated degree of bilaterality and complexity of corticospinal projections in the primate spinal cord. This bilaterality is more extensive than that of the rat CST, and may resemble human CST organization. Thus, augmentation of sprouting of these extensive bilateral CST projections may provide a novel target for enhancing recovery after spinal cord injury. J. Comp. Neurol. 513:151–163, 2009.

Local and Remote Growth Factor Effects after Primate Spinal Cord Injury

Primate models of spinal cord injury differ from rodent models in several respects, including the relative size and functional neuroanatomy of spinal projections. Fundamental differences in scale raise the possibility that retrograde injury signals, and treatments applied at the level of the spinal cord that exhibit efficacy in rodents, may fail to influence neurons at the far greater distances of primate systems. Thus, we examined both local and remote neuronal responses to neurotrophic factor-secreting cell grafts placed within sites of right C7 hemisection lesions in the rhesus macaque. Six months after gene delivery of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) into C7 lesion sites, we found both local effects of growth factors on axonal growth, and remote effects of growth factors reflected in significant reductions in axotomy-induced atrophy of large pyramidal neurons within the primary motor cortex. Additional examination in a rodent model suggested that BDNF, rather than NT-3, mediated remote protection of corticospinal neurons in the brain. Thus, injured neural systems retain the ability to respond to growth signals over the extended distances of the primate CNS, promoting local axonal growth and preventing lesion-induced neuronal degeneration at a distance. Remote cortical effects of spinally administered growth factors could “prime” the neuron to respond to experimental therapies that promote axonal plasticity or regeneration.

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.