Learning arises through the activity of large ensembles of cells, yet most of the data neuroscientists accumulate is at the level of individual neurons; we need models that can bridge this gap. We have taken spatial learning as our starting point, computationally modeling the activity of place cells using methods derived from algebraic topology, especially persistent homology. We previously showed that ensembles of hundreds of place cells could accurately encode topological information about different environments (“learn” the space) within certain values of place cell firing rate, place field size, and cell population; we called this parameter space the learning region. Here we advance the model both technically and conceptually. To make the model more physiological, we explored the effects of theta precession on spatial learning in our virtual ensembles. Theta precession, which is believed to influence learning and memory, did in fact enhance learning in our model, increasing both speed and the size of the learning region. Interestingly, theta precession also increased the number of spurious loops during simplicial complex formation. We next explored how downstream readout neurons might define co-firing by grouping together cells within different windows of time and thereby capturing different degrees of temporal overlap between spike trains. Our model's optimum coactivity window correlates well with experimental data, ranging from ∼150–200 msec. We further studied the relationship between learning time, window width, and theta precession. Our results validate our topological model for spatial learning and open new avenues for connecting data at the level of individual neurons to behavioral outcomes at the neuronal ensemble level. Finally, we analyzed the dynamics of simplicial complex formation and loop transience to propose that the simplicial complex provides a useful working description of the spatial learning process.

SummaryOxidative stress regulates cellular functions in multiple pathological conditions, including bone formation by osteoblastic cells. However, little is known about the cellular mechanisms responsible for the effects of oxidative stress on osteoblast functions in senescence. To clarify the inhibitory effects of oxidative stress on osteoblastic mineralization, we examined the relationship between the antioxidant system and bone formation in MC3T3-E1 cells. After a single exposure to H 2 O 2 within range of a non-toxic concentration for cells, the mineralization level was diminished half. Under the same conditions, gene expression of the transcription factor Nrf2, which regulates antioxidant enzymes, was upregulated. In addition, gene expression for the osteogenic markers Runx2, ALP, and BSP was lower than that in non-treated cells, whereas expression of the osteocalcin gene was up-regulated following H 2 O 2 exposure. These results suggest that reduced mineralization by MC3T3-E1 cells after H 2 O 2 exposure is the result of an up-regulated antioxidant system and altered osteogenic gene expression.

Insulin-like growth factor-I (IGF-I) promotes bone formation by stimulating proliferation and differentiation of osteoblasts. Bone sialoprotein (BSP), is thought to function in the initial mineralization of bone, is selectively expressed by differentiated osteoblast. To determine the molecular mechanism of IGF-I regulation of osteogenesis, we analyzed the effects of IGF-I on the expression of BSP in osteoblast-like Saos2 and in rat stromal bone marrow (RBMC-D8) cells. IGF-I (50 ng/ml) increased BSP mRNA levels at 12 h in Saos2 cells. In RBMC-D8 cells, IGF-I increased BSP mRNA levels at 3 h. From transient transfection assays, a twofold increase in transcription by IGF-I was observed at 12 h in pLUC3 construct that included the promoter sequence from -116 to +60. Effect of IGF-I was abrogated by 2-bp mutations in either the FGF2 response element (FRE) or homeodomain protein-binding site (HOX). Gel shift analyses showed that IGF-I increased binding of nuclear proteins to the FRE and HOX elements. Notably, the HOX-protein complex was supershifted by Smad1 antibody, while the FRE-protein complex was shifted by Smad1 and Cbfa1 antibodies. Dlx2 and Dlx5 antibodies disrupted the formation of the FRE- and HOX-protein complexes. The IGF-I effects on the formation of FRE-protein complexes were abolished by tyrosine kinase inhibitor herbimycin A (HA), PI3-kinase/Akt inhibitor LY249002, and MAP kinase kinase inhibitor U0126, while IGF-I effects on HOX-protein complexes were abolished by HA and LY249002. These studies demonstrate that IGF-I stimulates BSP transcription by targeting the FRE and HOX elements in the proximal promoter of BSP gene.

Sesame oil is known to be the most resistant to oxidative rancidity. Constituents of sesame oil such as sesamolin, sesamol and sesamol dimer (a possible intermediate of oxidative degradation of sesamol) were determined by high performance liquid chromatography using a reverse‐phase column. Sesamol was specifically determined in an alternative way by use of hydrogen peroxide/horseradish peroxidase. Sesamolin was relatively stable but sesamol and sesamol dimer were unstable when irradiated in benzene, and the final degradation products were identical. Whereas sesamolin was inactive, sesamol and sesamol dimer showed significant antioxidant activity in several kinds of fat and oils. Stability of Japan Pharmacopoeia sesame oil free from sesamol was relatively low; antioxidant activity of sesamol incorporated in the oil was unexpectedly low and was rapidly lost in the oil activated by oxygen. Edible sesame oil with intrinsic sesamol was highly stable. Activation of the edible oil gradually increased the sesamol content with concomitant decrease of sesamolin. High stability of edible sesame oil could not be ascribed to sesamol, but it could be explained by another powerful antioxidant(s) which might stabilize both the oil and unstable sesamol.