Structural synaptic changes have been suggested to underlie long-term memory formation. In this work, we investigate if hippocampal mossy fiber synaptogenesis induced by water maze overtraining can be related with long-term spatial memory performance. Rats were trained in a Morris water maze for one to five identical daily sessions and tested for memory retrieval 1 week and 1 month after training. After the last test session, the rat brains were obtained and processed for Timm's staining to analyze mossy fiber projection. The behavioral results showed that with more training, animals showed a better performance in the memory tests, and this performance positively correlates with Timm's staining in the stratum oriens. Furthermore, with the use of the NMDA antagonist MK801 before, but not after acquisition, water maze spatial memory was impaired. Increased Timm's staining in the stratum oriens was observed in the animals treated with MK801 after acquisition but not in those treated before. Finally, we observed that mossy fiber synaptogenesis occurs mainly in the septal region of the dorsal hippocampus, supporting the idea that this anterior region is important for spatial memory. Altogether, these results suggest that mossy fiber synaptogenesis can be related with spatial long-term memory formation.

Hebb (1949) proposed that after learning both presynaptic and postsynaptic structural changes form the neural substrate of long-lasting memory. Despite this, there are few instances linking presynaptic remodeling with learning. Here the authors demonstrate in two different rat strains that learning the location of a hidden platform induces expansion of the presynaptic hippocampal mossy fiber terminal field (MFTF) from the stratum lucidum to the distal stratum oriens (dSO). Prior to any training, Long Evans rats (LER) showed an extensive endogenous MFTF innervation of DSO, in contrast to Wistar rats (WR) that showed minimal innervation. LER showed better recall than WR on the hidden platform water maze task and a visible reversal water maze task. In both strains, significant MFTF expansion to dSO, spanning approximately 200 mum, was detected 7 days after training on the hidden platform task, but only LER showed significant MFTF expansion 24 h after training. It is attractive to think that the MFTF expansion to dSO contributes both to long-lasting memory formation and to facilitating spatial navigation strategies. The present results establish learning-induced axonal remodeling of the hippocampal MF system in adult rats as an especially useful system for exploring presynaptic morphological adjustments consequent to learning.

Subtle accumulation of beta-amyloid peptide (Abeta) oligomers of Abeta42 species in particular, is known to correlate with cognitive deficits independent of Abeta plaque deposition in the brain. Majority of the research showing behavioral improvement after cerebral Abeta reduction has been reported when the animals carried fewer/abundant amyloid plaques in the brain. Very few studies have addressed whether or not behavioral deficits exist even at the pre-plaque stage or in the absence of plaques that would parallel the mild cognitive impairment (MCI) stage of Alzheimer's disease (AD). Current study was undertaken to determine whether there exists any cognitive impairment during the pre-plaque stage which may parallel the MCI stage of AD, and to confirm whether the observed behavioral deficits correlate with Abeta42 predominance. In addition, the study determined whether anti-amyloidogenic effects of dietary aged garlic extract would prevent progressive behavioral impairment. For this purpose we used Tg2576 model showing slow plaque development with a predominance of Abeta40, and the TgCRND8 model showing accelerated plaque development with a predominance of Abeta42. The results show that at 2 months of age Tg2576 mice did not exhibit behavioral impairment in any of the tasks studied. While 2-month-old TgCRND8 mice displayed only a subtle behavioral deficit that matched the behavioral deficits observed in 7-month-old Tg2576 mice which may correlate with the MCI stage of AD. TgCRND8 mice at 7 months of age exhibited advanced deterioration in all behavioral tasks studied, suggesting that accelerated Abeta accumulation and the predominance of Abeta42 species may account for the pronounced cognitive deficits observed in TgCRND8. Feeding of aged garlic extract prevented deterioration of hippocampal based memory tasks in these mice, suggesting that aged garlic extract has a potential for preventing AD progression.

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Entamoeba histolytica is the parasite responsible for human amoebiasis. The analysis of the natural resistance mechanisms of some rodents to amoebic liver abscess (ALA) may reveal alternative pathogenicity mechanisms to those previously discovered in the experimental model of ALA in hamsters. In this work the natural resistance of BALB/c mice to ALA was explored by performing: (i) in vivo chemotaxis analysis with a specifically designed chamber; (ii) in vitro amoebic survival in fresh and decomplemented serum; (iii) histological temporal course analysis of ALA development in mice with different treatments (hypocomplementemic, hyperimmune and treated with iNOS and NADPH oxidase inhibitors) and (iv) mouse liver amoebic infection by both in situ implantation of ALA from hamsters and inoculation of parasites into the peritoneal cavity. The results show that E. histolytica clearance from the mouse liver is related to a low chemotactic activity of complement, which results in poor inflammatory response and parasite inability to cause tissue damage. Also, the absence of amoebic tropism for the mouse liver is correlated with resistance to experimental liver amoebiasis.

Through a structure activity relationship study, we have identified a more potent analogue of this compound with properties suggesting efficient blood brain barrier penetration, which we are testing in a mouse model of Alzheimer disease-like pathology. P2-322 IN VITRO CALORIC RESTRICTION INDUCES SIRT1 TO MODULATE APP METABOLISMBackground: Caloric restriction (CR) is the only non-genetic method to "slow" aging and increase lifespan in mammals. CR (a ϳ40% reduction in the total number of calories) "slows" aging by increasing the survival of critical cell types against a variety of stressors. Advanced age is the largest risk factor for developing Alzheimer's disease (AD). In AD, there is a large loss of neurons. The molecular events that lead to this neuronal loss are dependent on proteolytic processing of the amyloid precursor protein (APP). APP processing can lead to the generation of the A␤ peptide which is neurotoxic.In model organisms, the effects of caloric restriction on aging is mediated by the NAD-dependent deacetylase, Sir2 or SirT1 (Silencing Information Regulator) in humans. Methods: Here we are investigating if CR modulates the production of A␤ thereby reducing the AD associated neuronal loss. Here we utilize an established cell culture model that recapitulates the major cellular phenotypes of CR. We find that in this in vitro CR model, A␤ levels and APP metabolism are decreased due to CR treatment. To determine if SirT1 activity modulates APP metabolism in vivo, we utilized an established Drosophila model of AD. Results: Our findings suggest that effects of caloric restriction on A␤ accumulation and APP metabolism may be dependent on the deacetylase activity of SirT1. Exposure of these cells to in vitro CR conditions results in an increase in SirT1 levels. We show here for the first time that in vitro CR decreases full-length APP levels also by SirT1 induction. We further show that Drosophila Sir2 over-expression decreases the AD phenotype of these flies, while Sir2 loss-of-function mutations enhance the fly AD phenotype. Conclusions:Our study suggests that in vitro caloric restriction decreases APP metabolism by inducing SirT1. These results are confirmed in our Drosophila model of AD.