Neonatal hypoxia-ischemia (HI) is an important cause of mortality and morbidity in infants. Human umbilical cord blood (HUCB) is a potential source of cellular therapy in perinatology. We investigated the effects of HUCB cells on spatial memory, motor performance, and brain morphologic changes in neonate rats submitted to HI. Seven-day-old rats underwent right carotid artery occlusion followed by exposure to 8% O 2 inhalation for 2 h. Twenty-four hours after HI, rats received either saline solution or HUCB cells i.v. After 3 wk, rats were assessed using a Morris Water Maze and four motor tests. Subsequently, rats were killed for histologic, immunohistochemical, and polymerase chain reaction (PCR) analyses. HI rats showed significant spatial memory deficits and a volumetric decrease in the hemisphere ipsilateral to arterial occlusion. These deficits and decreases were not significantly attenuated by the injection of HUCB cells. Moreover, immunofluorescence and PCR analysis revealed few HUCB cells located in rat brain. Intravenous administration of HUCB cells requires optimization to achieve improved therapeutic outcomes in neonatal hypoxic-ischemic injury. (Pediatr Res 65: 631-635, 2009) N eonatal hypoxia-ischemia (HI) is a major cause of mortality and morbidity in infants and occurs in approximately 2-4 per 1000 full-term births. Between 20 and 50% of asphyxiated newborns with hypoxic-ischemic encephalopathy die within the neonatal period, and up to 25% of the survivors will exhibit neurodevelopment morbidity, such as cerebral palsy, mental retardation, and epilepsy. The most widely used and accepted animal model of neonatal HI is the Levine method as modified by Rice et al. (1), which represents a useful tool to study long-term effects of neuroprotective strategies in behavioral changes, especially in learning and memory tasks (2). Although promising neuroprotective strategies have been studied in animal models and clinical trials, current management techniques have reached only limited success (3).Human umbilical cord blood (HUCB), is rich in adult stem cells and seems to be a potential source for transplantation, especially for perinatal neuronal repair. Studies have shown behavioral and neurologic recovery in stroke (4 -7) and HIinsulted animals (8,9) that received i.v. injection of HUCB, indicating that cells migrate toward ischemic regions and cross the blood brain barrier (BBB), especially in acute periods postischemia (10). The i.v. route is less invasive and a safer access to clinical applications when compared with intracerebral delivery. However, very few transplanted cells are found in the brain when delivered intravascularly. Therefore, evidence suggests that these cells increase endogenous mechanisms of brain repair by trophic factor secretion rather than by replacing the damaged tissue (11,12).The aim of this study was to assess the effects of HUCB cells on spatial memory, motor performance, and brain morphologic changes in 30-d-old rats after neonatal HI on postnatal d 7. In addition, w...

Maternal deprivation during the first 10 days of life induces significant behavioral alterations in rodents which persist through adulthood. Physical exercise reduces the cognitive deficits associated with pharmacologic and pathological conditions. Here we investigated whether forced physical exercise alters memory deficits caused by postnatal maternal deprivation. Male rats were divided into four groups: (1) control, (2) deprived, (3) exercised, and (4) deprived+exercised. In groups 2 and 4, pups were deprived from their mothers for 3h/day during the first 10 days post-birth. In groups 3 and 4, from postnatal day 45 (PND-45) on, animals were submitted to forced treadmill exercise. At adulthood, animals were submitted to four different behavioral tasks: open field, Morris water maze (MWM), object recognition (OR) and inhibitory avoidance (IA). Maternal deprivation had no effect on open field behavior, but disrupted memory in the three other tasks. Physical exercise alone had no effect, except for a slight enhancement of MWM learning. Importantly, physical exercise reversed the deficit of IA and reduced the deficit of spatial memory but not that of OR seen in deprived animals. It is possible that physical exercise may counteract the influence of maternal deprivation on neurohumoral or hormonal memory modulatory systems related to stress. Indeed, the decreasing order of the effect of exercise on the memory disturbances induced by deprivation roughly follows the descending degree of stress associated with each task (IA>MWM>OR). Maternal deprivation is known to hinder hormonal mechanisms involved in coping with stress.

Long-term potentiation (LTP) is the enhancement of postsynaptic responses for hours, days or weeks following the brief repetitive afferent stimulation of presynaptic afferents. It has been proposed many times over the last 30 years to be the basis of long-term memory. Several recent findings finally supported this hypothesis: a) memory formation of one-trial avoidance learning depends on a series of molecular steps in the CA1 region of the hippocampus almost identical to those of LTP in the same region; b) hippocampal LTP in this region accompanies memory formation of that task and of another similar task. However, CA1 LTP and the accompanying memory processes can be dissociated, and in addition plastic events in several other brain regions (amygdala, entorhinal cortex, parietal cortex) are also necessary for memory formation of the one-trial task, and perhaps of many others.

Early postnatal maternal deprivation is known to cause long-lasting neurobiological effects. Here, we investigated whether some of the cognitive aspects of these deficits might be related to a disruption of the cholinergic system. Pregnant Wistar rats were individually housed and maintained on a 12:12h light/dark cycle with food and water freely available. The mothers were separated from their pups for 3h per day from postnatal day 1 (PND-1) to PND-10. To do that, the dams were moved to a different cage and the pups maintained in the original home cage, which was transferred to a different room kept at 32 degrees C. After they reached 120-150 days of age, maternal-deprived and non-deprived animals were either sacrificed for brain acetylcholinesterase measurement, or trained and tested in an object recognition task and in a social recognition task as described by Rossato et al. (2007) [Rossato, J.I., Bevilaqua, L. R.M., Myskiw, J.C., Medina, J.H., Izquierdo, I., Cammarota, M. 2007. On the role hippocampal synthesis in the consolidation and reconsolidation of object recognition memory. Learn. Mem. 14, 36-46] and Lévy et al. (2003) [Lévy, F., Melo. A.I., Galef. B.G. Jr., Madden, M., Fleming. A.S. 2003. Complete maternal deprivation affects social, but not spatial, learning in adult rats. Dev. Psychobiol. 43, 177-191], respectively. There was increased acetylcholinesterase activity in hippocampus and perirhinal cortex of the deprived animals. In addition, they showed a clear impairment in memory of the two recognition tasks measured 24h after training. Oral administration of the acetylcholinesterase inhibitors, donepezil or galantamine (1mg/kg) 30min before training reversed the memory impairments caused by maternal deprivation. The findings suggest that maternal deprivation affects memory processing at adulthood through a change in brain cholinergic systems.