Skilled movement and posture deficits in rat string-pulling behavior following low dose space radiation (28Si) exposure.

Deep space flight missions beyond the Van Allen belt have the potential to expose astronauts to space radiation which may damage the central nervous system and impair function. The proposed mission to Mars will be the longest mission-to-date and identifying mission critical tasks that are sensitive to space radiation is important for developing and evaluating the efficacy of counter measures. Fine motor control has been assessed in humans, rats, and many other species using string-pulling behavior. For example, focal cortical damage has been previously shown to disrupt the topographic (i.e., path circuity) and kinematic (i.e., moment-to-moment speed) organization of rat string-pulling behavior count to compromise task accuracy. In the current study, rats were exposed to a ground-based model of simulated space radiation (5 cGy 28Silicon), and string-pulling behavior was used to assess fine motor control. Irradiated rats initially took longer to pull an unweighted string into a cage, exhibited impaired accuracy in grasping the string, and displayed postural deficits. Once rats were switched to a weighted string, some deficits lessened but postural instability remained. These results demonstrate that a single exposure to a low dose of space radiation disrupts skilled hand movements and posture, suggestive of neural impairment. This work establishes a foundation for future studies to investigate the neural structures and circuits involved in fine motor control and to examine the effectiveness of counter measures to attenuate the effects of space radiation on fine motor control.

Nogo-A interacts with TrkA to alter nerve growth factor signaling in Nogo-A-overexpressing PC12 cells.

The Nogo-A protein, originally discovered as a potent myelin-associated inhibitor of neurite outgrowth, is also expressed by certain neurons, especially during development and after injury, but its role in neuronal function is not completely known. In this report, we overexpressed Nogo-A in PC12 cells to use as a model to identify potential neuronal signaling pathways affected by endogenously expressed Nogo-A. Unexpectedly, our results show that viability of Nogo-A-overexpressing cells was reduced progressively due to apoptotic cell death following NGF treatment, but only after 24 h. Inhibitors of neutral sphingomyelinase prevented this loss of viability, suggesting that NGF induced the activation of a ceramide-dependent cell death pathway. Nogo-A over-expression also changed NGF-induced phosphorylation of TrkA at tyrosines 490 and 674/675 from sustained to transient, and prevented the regulated intramembrane proteolysis of p75NTR, indicating that Nogo-A was altering the function of the two neurotrophin receptors. Co-immunoprecipitation studies revealed that there was a physical association between TrkA and Nogo-A which appeared to be dependent on interactions in the Nogo-A-specific region of the protein. Taken together, our results indicate that Nogo-A influences NGF-mediated mechanisms involving the activation of TrkA and its interaction with p75NTR.

Kinematic analysis of motor recovery with human adult bone marrow-derived somatic cell therapy in a rat model of stroke.

BACKGROUND: The extent to which pharmaceutical and behavioral therapies following central nervous system injury may either deter or encourage the development of compensatory movement patterns is a topic of considerable interest in neurorehabilitation. However, functional outcome measures alone are relatively insensitive to compensatory changes in movement patterns per se. OBJECTIVE: This study used both functional outcome measures and kinematic analysis of forelimb movements to examine the effects of human adult bone marrow-derived somatic cells (hABM-SCs) on motor recovery in a rat model of stroke. METHODS: Adult male Long-Evans black-hooded rats (n = 12) were trained in a forelimb reaching task and then underwent surgical middle cerebral artery occlusion, producing a stroke that impaired the trained paw. One week poststroke, animals were randomly assigned to either a hABM-SC injection or control injection group. Reaching behaviors were then compared at baseline and at 10 weeks poststroke. RESULTS: Both groups improved their outcome scores during the 10-week recovery period. However, the hABM-SC group recovered significantly more function than controls in terms of the number of pellets retrieved. Furthermore, the control group appeared to improve their functional performance by using compensatory strategies that involved an increased number of trajectory adjustments, whereas the hABM-SC group's kinematics more closely resembled prestroke movement patterns. CONCLUSIONS: This study demonstrates that kinematic measures established in stroke research on humans are also sensitive to performance differences prestroke versus poststroke in the rat model, reinforcing the utility of this method to evaluate treatments that may ultimately translate to patient populations.

Delayed anti-nogo-a therapy improves function after chronic stroke in adult rats.

BACKGROUND AND PURPOSE: we have shown that anti-Nogo-A immunotherapy to neutralize the neurite growth inhibitory protein Nogo-A results in functional improvement and enhanced plasticity after ischemic stroke in the adult rat. The present study investigated whether functional improvement and neuronal plasticity can be induced by this immunotherapy when administered to the chronic stroke-impaired rat. METHODS: adult rats were trained to perform the skilled forelimb reaching test, followed by permanent middle cerebral artery occlusion to impair the preferred forelimb. Nine weeks after stroke, animals showing a profound deficit were randomly distributed to 3 groups: no treatment, control antibody, or anti-Nogo-A antibody (11C7). Animals were tested weekly after stroke surgery and daily after antibody treatment until the end of the study. Biotin dextran amine tracing was injected into the nonlesioned forelimb motor cortex at the end of behavioral testing to determine axonal plasticity. RESULTS: all rats showed similar forelimb impairment before treatment. Animals treated with anti-Nogo-A immunotherapy started to show improvement 3 weeks after treatment. Such improvement became significantly better than stroke-only control and control Ab-treated animals, and persisted to the end of the study. Biotin dextran amine-labeled axonal fiber analysis also showed significant enhanced corticorubral axonal sprouting from the contralesional forelimb motor cortex to the deafferented red nucleus in the anti-Nogo-A immunotherapy rats. CONCLUSIONS: these results indicate that improvement of chronic neurological deficits and enhancement of neuronal plasticity can be induced in the adult rat with anti-Nogo-A immunotherapy, and that this therapy may be used to restore function even when administered long after ischemic brain damage has occurred.

Neuronal plasticity and functional recovery after ischemic stroke.

Ischemic stroke affects many new patients each year. The sequelae of brain ischemia can include lasting sensorimotor and cognitive deficits, which negatively impact quality of life. Currently, treatment options for improving poststroke deficits are limited, and the development of new clinical alternatives to improve functional recovery after stroke is actively under investigation. Anti-Nogo-A immunotherapy to reduce the central nervous system inhibitory environment, cell transplantation strategies, pharmacological agents, and movement-based therapies represent emerging treatments of poststroke deficits through enhancement of neuroanatomical plasticity.