Reduced neurogenesis in the rat hippocampus following high fructose consumption.

In this study, we investigated how prolonged consumption of sugar solution affects hippocampal neurogenesis. We gave rats sucrose or fructose solution for four weeks and observed a 40% reduction in BrdU/NeuN-immunoreactive cells in the hippocampal dentate gyrus. This reduction in hippocampal neurogenesis was accompanied by increased apoptosis in the hippocampus and increased circulating levels of TNF-α. Therefore, we hypothesize that the reduction in hippocampal neurogenesis may be due to the increased apoptosis induced by TNF-α. Our results suggest that chronic ingestion of fructose is detrimental to the survival of newborn hippocampal neurones. The results presented in the present study add to the list of harmful effects associated with prolonged and excessive consumption of sugary beverages and soft drinks.

Testosterone decrease does not play a major role in the suppression of hippocampal cell proliferation following social defeat stress in rats.

Stress of social defeat in rodents is known to have a strong and long-lasting effect on brain, physiology and behavior, which bears similarities with certain human stress related psychopathologies. Previous experiments in this lab showed that social defeat stress suppresses testosterone secretion and causes a lasting desensitization of the serotonergic 5-HT(1A) receptors. Testosterone supplementation in socially stressed tree shrews prevented a decrease in hippocampal 5-HT(1A) receptor binding. These receptors are hypothesized to play an important role in neurogenesis in this brain structure. We designed the present experiment to test if social defeat reduces hippocampal cell proliferation and neurogenesis in rats and if testosterone supplementation can prevent this reduction. The results indicate that repeated social defeat stress on 5 successive days induces a significant drop in plasma testosterone levels in male rats and suppresses hippocampal cell proliferation 24h and 3weeks after the end of the stress period. Testosterone supplementation prevented the social stress induced drop in plasma testosterone levels. The hormone supplementation also reduced the negative effect of stress on hippocampal BrdU labeling at 3weeks post-defeat. This effect was, however, rather weak and was caused by the tendency of the hormone in itself to suppress proliferation and the failure to fully recover the proliferation rate. Survival of dentate gyrus cells that either proliferated prior to the stress period or 24h after the last defeat was not affected by the social defeats. Thus the stress-induced lowering of hippocampal cell proliferation is not likely to be caused by transient inhibition of testosterone secretion during social stress.

Physical exercise leads to rapid adaptations in hippocampal vasculature: temporal dynamics and relationship to cell proliferation and neurogenesis.

Increased levels of angiogenesis and neurogenesis possibly mediate the beneficial effects of physical activity on hippocampal plasticity. This study was designed to investigate the temporal dynamics of exercise-induced changes in hippocampal angiogenesis and cell proliferation. Mice were housed with a running wheel for 1, 3, or 10 days. Analysis of glucose transporter Glut1-positive vessel density showed a significant increase after 3 days of wheel running. Cell proliferation in the dentate gyrus showed a trend towards an increase after 3 days of running and was significantly elevated after 10 days of physical exercise. Ten days of wheel running resulted in a near-significant increase in the number of immature neurons, as determined by a doublecortin (DCX) staining. In the second part of the study, the persistence of the exercise-induced changes in angiogenesis and cell proliferation was determined. The running wheel was removed from the cage after 10 days of physical activity. Glut-1 positive vessel density and hippocampal cell proliferation were determined 1 and 6 days after removal of the wheel. Both parameters had returned to baseline 24 h after cessation of physical activity. The near-significant increase in the number of DCX-positive immature neurons persisted for at least 6 days, indicating that new neurons formed during the period of increased physical activity had survived. Together these experiments show that the hippocampus displays a remarkable angiogenic and neurogenic plasticity and rapidly responds to changes in physical activity.

Exercise improves memory acquisition and retrieval in the Y-maze task: relationship with hippocampal neurogenesis.

Enhanced physical activity is associated with improvements in cognitive function in rodents as well as in humans. The authors examined in detail which aspects of learning and memory are influenced by exercise, using a spatial Y-maze test combined with a 14-day exercise paradigm at different stages of learning. The authors show that 14 days of wheel running promotes memory acquisition, memory retention, and reversal learning. The exercise paradigm that was employed also significantly increased the number of maturing neurons, suggesting that an increase in neurogenesis underlies the positive effects of exercise on Y-maze performance. Finally, the authors show that memory acquisition in itself does not have a major impact on the number of immature neurons. However, memory retention testing and reversal learning both cause a significant reduction in the number of doublecortin and Ser133- phosphorylated pCREB-positive cells, indicating that a decrease in neurogenesis might be a prerequisite for optimal memory retrieval.

Reduced expression of PSA-NCAM in the hippocampus and piriform cortex of the R6/1 and R6/2 mouse models of Huntington's disease.

Cognitive deficits and impaired olfactory function are observed in early stages of Huntington's disease (HD). The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) is strongly associated with plastic events in the brain. During adulthood, it is most abundantly expressed in the hippocampus and the piriform cortex, which are involved in cognition and olfaction, respectively. We show that the numbers of PSA-NCAM-positive cells in the hippocampus and piriform cortex are dramatically reduced in the R6/1 and the R6/2 mouse models of HD. We hypothesize that the decrease in NCAM polysialylation reflects an impaired plasticity and might underlie some of the early symptoms in HD.

Hippocampal cell proliferation across the day: increase by running wheel activity, but no effect of sleep and wakefulness.

The present study investigated whether proliferation of hippocampal progenitors is subject to circadian modulation. Mice were perfused using 3h intervals throughout the light-dark cycle and brains were stained for Ki-67. Since Ki-67 is not expressed during the G0 phase of the cell cycle, we expected a decline in Ki-67 expression at the moment cells synchronously exit the cell cycle. However, despite the fact that various hippocampal factors fluctuate across the day, the number of dividing cells remained constant. In a second experiment, we studied whether disturbance of normal sleep affected the stable rate in cell proliferation. Our data show that 12h of sleep deprivation during the light phase did not influence proliferating cell number. A third experiment investigated whether physical activity, a condition known to enhance hippocampal cell proliferation, caused an elevation of the steady baseline number of proliferating progenitors, or a peak directly following the active phase of the animals. Mice were housed with a running wheel for 9 days. On the last day, animals were sacrificed either directly before or directly after the active phase. Exercise significantly promoted cell proliferation and this effect appeared to be strongest directly after the active period and to disappear during the resting phase. Our data suggest that hippocampal cell proliferation is not synchronized under basal conditions and is unchanged by sleep deprivation. However, running affected cell proliferation differentially at two times of day. These data demonstrate that the steady rate in cell proliferation is not indispensable, but can be changed by behavioral activity.

Sleep restriction by forced activity reduces hippocampal cell proliferation.

Mounting evidence suggests that sleep loss negatively affects learning and memory processes through disruption of hippocampal function. In the present study, we examined whether sleep loss alters the generation, differentiation, and survival of new cells in the dentate gyrus. Rats were sleep restricted by keeping them awake in slowly rotating drums for 1 day or repeatedly for 20 h/day over a period of 8 days. In addition to home cage controls, we included forced activity controls which, compared to sleep restricted rats, walked at double speed for half the time. These animals thus walked the same distance but had sufficient time to sleep. The results show that a single day of sleep deprivation significantly reduced hippocampal cell proliferation in the hilus of the dentate gyrus as measured by immunostaining for the proliferation marker Ki-67. Repeated partial sleep deprivation reduced cell proliferation in both the hilus and the subgranular zone. However, the latter was also found after chronic forced activity, and may not have been specific for sleep loss. To study neuronal survival, rats received a single intraperitoneal injection of 5-bromo-2'-deoxyuridine (BrdU) 5 days before the experiment. The number of surviving, BrdU-positive cells was not affected by sleep restriction. Also, the differentiation of BrdU-positive new cells into NeuN-positive neuronal and GFAP-positive glial phenotypes was not significantly altered by sleep loss. In conclusion, since new cells in the hilus mostly differentiate into glia, our findings indicate that sleep loss may reduce hippocampal gliogenesis.

Morris water maze learning in two rat strains increases the expression of the polysialylated form of the neural cell adhesion molecule in the dentate gyrus but has no effect on hippocampal neurogenesis.

In the current study, the authors investigated whether Morris water maze learning induces alterations in hippocampal neurogenesis or neural cell adhesion molecule (NCAM) polysialylation in the dentate gyrus. Two frequently used rat strains, Wistar and Sprague-Dawley, were trained in the spatial or the nonspatial version of the water maze. Both training paradigms did not have an effect on survival of newly formed cells that were labeled 7-9 days prior to the training or on progenitor proliferation in the subgranular zone. However, the granule cell layer of the spatially trained rats contained significantly more positive cells of the polysialylated form of the NCAM. These data demonstrate that Morris water maze learning causes plastic change in the dentate gyrus without affecting hippocampal neurogenesis.

Input from the medial septum regulates adult hippocampal neurogenesis.

Neural progenitors in the subgranular zone of the hippocampal formation form a continuously proliferating cell population, generating new granule neurons throughout adult life. Between 10 days and 1 month after their formation, many of the newly generated cells die. The present study investigated whether a partial lesion of one of the main nuclei projecting to the hippocampus, the medial septum (MS), affects survival and differentiation of cells during this critical period. Rats were injected with BrdU and 5 days later excitotoxic lesion of the MS was applied by infusion of either 30 or 60 nmol of N-methyl-D-aspartate (NMDA). One week after the lesion, quantification of immunopositive cells revealed that the number of GABAergic cells was significantly reduced in both lesioned groups, whereas a decline in cholinergic cell number was observed only after injection of 60 nmol of NMDA. The partial septohippocampal denervation significantly reduced hippocampal neurogenesis. Survival of newly generated neurons was decreased by approximately 40%. The MS lesion did not affect proliferation of hippocampal progenitors. The present study points out the importance of a functional septohippocampal pathway for the regulation of hippocampal neurogenesis and highlights the potential role of GABA as a mediator in this phenomenon.

Effects of active shock avoidance learning on hippocampal neurogenesis and plasma levels of corticosterone.

Hippocampal granule neurons that are newly formed during adulthood might be involved in learning and memory processes. Experimental data suggest that only hippocampus-dependent learning tasks stimulate neurogenesis. To further address this issue, the effects of active shock avoidance (ASA) learning on hippocampal progenitor proliferation and survival of newly formed cells were investigated. ASA training, although considered as hippocampus-independent, is known to induce several neurobiological alterations in the hippocampus. Adult Wistar rats were trained in a shuttle box using a 1-day or 4-day paradigm and brains were analyzed for the mitotic marker Ki-67. Effects on survival of newly generated cells were examined by immunocytochemistry for 5-bromo-2-deoxyuridine (BrdU), which was injected 1 week before the training. Neither proliferation nor survival was affected by the ASA learning task. Because elevated glucocorticoid levels have a negative impact on hippocampal neurogenesis, blood samples were taken throughout the 4-day training paradigm. Both trained animals and control rats that were only placed in the shuttle box without receiving foot shocks showed a similar rise in corticosterone, enabling us to exclusively investigate the effects of ASA learning on neurogenesis without differential interference of stress between groups. On the other hand, the finding that ASA induced elevations in plasma corticosterone, but did not influence proliferation or survival of newly formed cells, indicates that this type of stress does not affect neurogenesis. The present study shows that, in line with the existing data on other hippocampus-independent learning tasks, ASA training has no effect on hippocampal neurogenesis.