Spatial Training Promotes Short-term Survival And Neuron-like Differentiation Of Newborn Cells In Hippocampus Of A?_1-42 Injected Rat

[Background]Alzheimer's disease (AD), the most common type of dementia, is characterized by a progressive decline of memory and other cognitive functions and still lacks effective treatments. Of the 25 categories of non-pharmacologic therapies reviewed in the Cochrane Database, only cognitive stimulation had findings that suggested a beneficial effect, but the exact molecular underlying mechanism is unknown.Neurogenesis occurs throughout adulthood in the mammalian brain and mainly takes place in two brain regions, the subgranular zone (SGZ) and the subventricular zone (SVZ) located in the dentate gyrus of the hippocampus and the lateral ventricles. Neurogenesis seems to play a role in hippocampal-mediated learning and in AD transgenic mice and AD patients, impaired neurogenesis strong correlates with cognitive impairment. Spatial training influences the production and the fate of the newly born cells of hippocampus, however, in Alzheimer-like animal models, little is known the influence of spatial training on neurogenesis.[Objective]To determine the effects of spatial training on adult neurogenesis in the hippocampal dentate gyrus region of an AD-like animal model.[Methods]We took advantage of intracerebroventricular injection of A?1-42 to establish an Alzheimer-like animal model and trained animals for 6 consecutive days in Morris water maze. The fate of new cells born before training, during the early phase and the late phase of training was examined by labelling with the thymidine analog bromodeoxyuridine (BrdU), a thymidine analogue that is incorporated by dividing cells. We investigated the effect of spatial training on the survival of newborn cells by counting the total number of BrdU-IR cells in DG. The proliferation of neural cells was measured by counting the total number of Ki67-IR cells in DG. The migration and differentiation of newly born cells was examined by immunofluorescence double-labeling of BrdU/NeuN and BrdU/GFAP in the DG. We assessed the recent and remote memory abilities by contextual fear conditioning.[Results]In Alzheimer-like animal model, we first demonstrate that spatial training increases the survival of newborn cells generated before training, during the early or late phase of training when animals perfused at 24h after the last day of spatial training, but has no effect on the survival of cells generated at three different times after 4 weeks from the last BrdU labeling. Spatial training noticeably improves proliferation when animals perfused at 24h or 4 weeks after the last day of spatial training. We also show that spatial training causes more new born cells generated before training, during the early or late phase of training differentiate into the mature neuron, not the astrocyte. Finally, we show that spatial training improves the recent memory ability, not remote memory ability in the contextual fear conditioning test. However, the migration from SGZ to the granular layer (GCL) of newborn neurons did not affected by spatial training in AD-like animal model.[Conclusions]Spatial training increased the neurogenesis which is independent of the birth time of newborn cells in hippocampal DG of Alzheimer-like animal models. Spatial training also promoted newborn cells proliferation and differentiation preferentially to the neuron direction, while had no effects on the long term survival of new cells. Furthermore, spatial training could facilitate recent memory of the A?1-42 injected rats.