The Role of Additive Neurogenesis and Synaptic Plasticity in a Hippocampal Memory Model with Grid-Cell Like Input

Recently, we presented a study of adult neurogenesis in a simplified hippocampal memory model. The network was required to encode and decode memory patterns despite changing input statistics. We showed that additive neurogenesis was a more effective adaptation strategy compared to neuronal turnover and conventional synaptic plasticity as it allowed the network to respond to changes in the input statistics while preserving representations of earlier environments. Here we extend our model to include realistic, spatially driven input firing patterns in the form of grid cells in the entorhinal cortex. We compare network performance across a sequence of spatial environments using three distinct adaptation strategies: conventional synaptic plasticity, where the network is of fixed size but the connectivity is plastic; neuronal turnover, where the network is of fixed size but units in the network may die and be replaced; and additive neurogenesis, where the network starts out with fewer initial units but grows over time. We confirm that additive neurogenesis is a superior adaptation strategy when using realistic, spatially structured input patterns. We then show that a more biologically plausible neurogenesis rule that incorporates cell death and enhanced plasticity of new granule cells has an overall performance significantly better than any one of the three individual strategies operating alone. This adaptation rule can be tailored to maximise performance of the network when operating as either a short- or long-term memory store. We also examine the time course of adult neurogenesis over the lifetime of an animal raised under different hypothetical rearing conditions. These growth profiles have several distinct features that form a theoretical prediction that could be tested experimentally. Finally, we show that place cells can emerge and refine in a realistic manner in our model as a direct result of the sparsification performed by the dentate gyrus layer

Dysregulation of heat shock protein 27 expression in oral tongue squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Recent proteomic studies identified Hsp27 as a highly over-expressed protein in oral squamous cell carcinoma (OSCC). Clinical studies that attempted to evaluate the prognostic values of Hsp27 yielded inconsistent results, which may be due to inclusion of OSCC cases from multiple anatomic sites. In this study, to determine the utility of Hsp27 for prognosis, we focused on oral tongue SCC (OTSCC), one of the most aggressive forms of OSCC.</p> <p>Methods</p> <p>Archival clinical samples of 15 normal oral tongue mucosa, 31 dysplastic lesions, 80 primary OTSCC, and 32 lymph node metastases were examined for Hsp27 expression by immunohistochemistry (IHC). Statistical analyses were carried out to assess the prognostic value of Hsp27 expression for patients with this disease.</p> <p>Results</p> <p>Dysregulation of Hsp27 expression was observed in dysplastic lesions, primary OTSCC, and lymph node metastases, and appears to be associated with disease progression. Statistical analysis revealed that the reduced Hsp27 expression in primary tumor tissue was associated with poor differentiation. Furthermore, the higher expression of Hsp27 was correlated with better overall survival.</p> <p>Conclusion</p> <p>Our study confirmed that the dysregulation of Hsp27 expression is a frequent event during the progression of OTSCC. The expression of Hsp27 appears to be an independent prognostic marker for patients with this disease.</p

Synergetic Effects of Granulocyte-Colony Stimulating Factor and Cognitive Training on Spatial Learning and Survival of Newborn Hippocampal Neurons

Granulocyte-Colony Stimulating Factor (G-CSF) is an endogenous hematopoietic growth factor known for its role in the proliferation and differentiation of cells of the myeloic lineage. Only recently its significance in the CNS has been uncovered. G-CSF attenuates apoptosis and controls proliferation and differentiation of neural stem cells. G-CSF activates upstream kinases of the cAMP response element binding protein (CREB), which is thought to facilitate the survival of neuronal precursors and to recruit new neurons into the dentate gyrus. CREB is also essential for spatial long-term memory formation. To assess the role and the potential of this factor on learning and memory-formation we systemically administered G-CSF in rats engaged in spatial learning in an eight-arm radial maze. G-CSF significantly improved spatial learning and increased in combination with cognitive training the survival of newborn neurons in the hippocampus as measured by bromodeoxyuridine and doublecortin immunohistochemistry. Additionally, G-CSF improved re-acquisition of spatial information after 26 days. These findings support the hypothesis that G-CSF can enhance learning and memory formation. Due to its easy applicability and its history as a well-tolerated hematological drug, the use of G-CSF opens up new neurological treatment opportunities in conditions where learning and memory-formation deficits occur

ANO1 amplification and expression in HNSCC with a high propensity for future distant metastasis and its functions in HNSCC cell lines

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is associated with poor survival. To identify prognostic and diagnostic markers and therapeutic targets, we studied ANO1, a recently identified calcium-activated chloride channel (CaCC). METHODS: High-resolution genomic and transcriptomic microarray analysis and functional studies using HNSCC cell line and CaCC inhibitors. RESULTS: Amplification and overexpression of genes within the 11q13 amplicon are associated with the propensity for future distance metastasis of HPV-negative HNSCC. ANO1 was selected for functional studies based on high correlations, cell surface expression and CaCC activity. ANO1 overexpression in cells that express low endogenous levels stimulates cell movement, whereas downregulation in cells with high endogenous levels has the opposite effect. ANO1 overexpression also stimulates attachment, spreading, detachment and invasion, which could account for its effects on migration. CaCC inhibitors decrease movement, suggesting that channel activity is required for the effects of ANO1. In contrast, ANO1 overexpression does not affect cell proliferation. INTERPRETATION: ANO1 amplification and expression could be markers for distant metastasis in HNSCC. ANO1 overexpression affects cell properties linked to metastasis. Inhibitors of CaCCs could be used to inhibit the tumourigenic properties of ANO1, whereas activators developed to increase CaCC activity could have adverse effects

Low Concentrations of Methamphetamine Can Protect Dopaminergic Cells against a Larger Oxidative Stress Injury: Mechanistic Study

Mild stress can protect against a larger insult, a phenomenon termed preconditioning or tolerance. To determine if a low intensity stressor could also protect cells against intense oxidative stress in a model of dopamine deficiency associated with Parkinson disease, we used methamphetamine to provide a mild, preconditioning stress, 6-hydroxydopamine (6-OHDA) as a source of potentially toxic oxidative stress, and MN9D cells as a model of dopamine neurons. We observed that prior exposure to subtoxic concentrations of methamphetamine protected these cells against 6-OHDA toxicity, whereas higher concentrations of methamphetamine exacerbated it. The protection by methamphetamine was accompanied by decreased uptake of both [3H] dopamine and 6-OHDA into the cells, which may have accounted for some of the apparent protection. However, a number of other effects of methamphetamine exposure suggest that the drug also affected basic cellular survival mechanisms. First, although methamphetamine preconditioning decreased basal pERK1/2 and pAkt levels, it enhanced the 6-OHDA-induced increase in these phosphokinases. Second, the apparent increase in pERK1/2 activity was accompanied by increased pMEK1/2 levels and decreased activity of protein phosphatase 2. Third, methamphetamine upregulated the pro-survival protein Bcl-2. Our results suggest that exposure to low concentrations of methamphetamine cause a number of changes in dopamine cells, some of which result in a decrease in their vulnerability to subsequent oxidative stress. These observations may provide insights into the development of new therapies for prevention or treatment of PD

Embryonic striatal grafts restore bi-directional synaptic plasticity in a rodent model of Huntington\u27s disease

Embryonic striatal grafts integrate with the host striatal circuitry, forming anatomically appropriate connections capable of influencing host behaviour. In addition, striatal grafts can influence host behaviour via a variety of non-specific, trophic and pharmacological mechanisms; however, direct evidence that recovery is dependent on circuit reconstruction is lacking. Recent studies suggest that striatal grafts alleviate simple motor deficits, and also that learning of complex motor skills and habits can also be restored. However, although the data suggest that such \u27re-learning\u27 requires integration of the graft into the host striatal circuitry, little evidence exists to demonstrate that such integration includes functional synaptic connections. Here we demonstrate that embryonic striatal grafts form functional connections with the host striatal circuitry, capable of restoring stable synaptic transmission, within an excitotoxic lesion model of Huntington\u27s disease. Furthermore, such \u27functional integration\u27 of the striatal graft enables the expression of host-graft bi-directional synaptic plasticity, similar to the normal cortico-striatal circuit. These results indicate that striatal grafts express synaptic correlates of learning, and thereby provide direct evidence of functional neuronal circuit repair, an essential component of \u27functional integration\u27