Effects of Transmitters and Amyloid-Beta Peptide on Calcium Signals in Rat Cortical Astrocytes: Fura-2AM Measurements and Stochastic Model Simulations

BACKGROUND: To better understand the complex molecular level interactions seen in the pathogenesis of Alzheimer's disease, the results of the wet-lab and clinical studies can be complemented by mathematical models. Astrocytes are known to become reactive in Alzheimer's disease and their ionic equilibrium can be disturbed by interaction of the released and accumulated transmitters, such as serotonin, and peptides, including amyloid- peptides (A). We have here studied the effects of small amounts of A25-35 fragments on the transmitter-induced calcium signals in astrocytes by Fura-2AM fluorescence measurements and running simulations of the detected calcium signals. METHODOLOGY/PRINCIPAL FINDINGS: Intracellular calcium signals were measured in cultured rat cortical astrocytes following additions of serotonin and glutamate, or either of these transmitters together with A25-35. A25-35 increased the number of astrocytes responding to glutamate and exceedingly increased the magnitude of the serotonin-induced calcium signals. In addition to A25-35-induced effects, the contribution of intracellular calcium stores to calcium signaling was tested. When using higher stimulus frequency, the subsequent calcium peaks after the initial peak were of lower amplitude. This may indicate inadequate filling of the intracellular calcium stores between the stimuli. In order to reproduce the experimental findings, a stochastic computational model was introduced. The model takes into account the major mechanisms known to be involved in calcium signaling in astrocytes. Model simulations confirm the principal experimental findings and show the variability typical for experimental measurements. CONCLUSIONS/SIGNIFICANCE: Nanomolar A25-35 alone does not cause persistent change in the basal level of calcium in astrocytes. However, even small amounts of A25-35, together with transmitters, can have substantial synergistic effects on intracellular calcium signals. Computational modeling further helps in understanding the mechanisms associated with intracellular calcium oscillations. Modeling the mechanisms is important, as astrocytes have an essential role in regulating the neuronal microenvironment of the central nervous system

Medical student attitudes and educational interventions to prevent neurophobia: a longitudinal study

Abstract Background With an aging American population, the burden of neurologic disease is intensifying and the decline in neurology residents and practicing neurologists is leaving these patients helpless and unable to find care. ‘Neurophobia’, a chronic illness that begins early in medical school, has been identified as a cause for the low number of neurology residents. Methods A longitudinal study surveyed medical students at the beginning of their first year (M1) and then again at the beginning of their second year (M2). Three neuroscience educational interventions were studied: team based learning (TBL), case based teaching (CBT), and problem based learning (PBL). Participants provided self-reported neurophobia levels, attitudes about neuroscience, and the effectiveness of educational interventions. Results A total of 446 students during M1 and 206 students during M2 participated in the survey. A significant change in self-reported neurophobia (p = 0.035) was observed from 19% in M1 to 26% in M2. Neuroscience knowledge and confidence managing a neurologic condition also significantly increased (p < 0.001 and p = 0.038 respectively). Perceived interest, difficulty, and desire to pursue a career in neuroscience did not a change significantly. Majority of students perceived CBT (76%), TBL (56%), and PBL (66%) beneficial. Only CBT demonstrated a statistical difference (p = 0.026) when stratified by self-reported change in neurophobia. Conclusion An increase in neurophobia after completing a neuroscience was observed but the prevalence rate of 26% was lower than previous studies. Knowledge about neuroscience increased significantly and educational interventions were considered beneficial by students. Thus, interventions that increase knowledge and decrease neurophobia can lead to an increase in students pursuing neurology residencies

Simulated effects of high stimulus frequency on cytosolic Ca concentration.

<p>Model simulation of changes in cytosolic Ca concentration induced by external stimuli. 10 M stimuli, applied with a short interval at t = 115 s and t = 315 s, decrease the peak amplitude of the latter peak.</p

Changes in cytosolic Ca concentration induced by 5-HT, glutamate, and A25–35 given at different times.

<p>Small change in cytosolic Ca concentration is seen when 10 M 5-HT is added at t = 180 s. 50 M glutamate reduces the 5-HT-induced enhancement of cytosolic Ca concentration at t = 700 s, whereas additions of 1 M A25–35 do not show an increment to cytosolic Ca concentration at t = 1050, 1100, and 1130 s.</p