Action Potential Initiation in the Hodgkin-Huxley Model

A recent paper of B. Naundorf et al. described an intriguing negative correlation between variability of the onset potential at which an action potential occurs (the onset span) and the rapidity of action potential initiation (the onset rapidity). This correlation was demonstrated in numerical simulations of the Hodgkin-Huxley model. Due to this antagonism, it is argued that Hodgkin-Huxley-type models are unable to explain action potential initiation observed in cortical neurons in vivo or in vitro. Here we apply a method from theoretical physics to derive an analytical characterization of this problem. We analytically compute the probability distribution of onset potentials and analytically derive the inverse relationship between onset span and onset rapidity. We find that the relationship between onset span and onset rapidity depends on the level of synaptic background activity. Hence we are able to elucidate the regions of parameter space for which the Hodgkin-Huxley model is able to accurately describe the behavior of this system

Magnesium induces neuronal apoptosis by suppressing excitability

In clinical obstetrics, magnesium sulfate (MgSO4) use is widespread, but effects on brain development are unknown. Many agents that depress neuronal excitability increase developmental neuroapoptosis. In this study, we used dissociated cultures of rodent hippocampus to examine the effects of Mg++ on excitability and survival. Mg++-induced caspase-3-associated cell loss at clinically relevant concentrations. Whole-cell patch-clamp techniques measured Mg++ effects on action potential threshold, action potential peak amplitude, spike number and changes in resting membrane potential. Mg++ depolarized action potential threshold, presumably from surface charge screening effects on voltage-gated sodium channels. Mg++ also decreased the number of action potentials in response to fixed current injection without affecting action potential peak amplitude. Surprisingly, Mg++ also depolarized neuronal resting potential in a concentration-dependent manner with a +5.2 mV shift at 10 mM. Voltage ramps suggested that Mg++ blocked a potassium conductance contributing to the resting potential. In spite of this depolarizing effect of Mg++, the net inhibitory effect of Mg++ nearly completely silenced neuronal network activity measured with multielectrode array recordings. We conclude that although Mg++ has complex effects on cellular excitability, the overall inhibitory influence of Mg++ decreases neuronal survival. Taken together with recent in vivo evidence, our results suggest that caution may be warranted in the use of Mg++ in clinical obstetrics and neonatology

Seasonal changes in patterns of gene expression in avian song control brain regions.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Photoperiod and hormonal cues drive dramatic seasonal changes in structure and function of the avian song control system. Little is known, however, about the patterns of gene expression associated with seasonal changes. Here we address this issue by altering the hormonal and photoperiodic conditions in seasonally-breeding Gambel's white-crowned sparrows and extracting RNA from the telencephalic song control nuclei HVC and RA across multiple time points that capture different stages of growth and regression. We chose HVC and RA because while both nuclei change in volume across seasons, the cellular mechanisms underlying these changes differ. We thus hypothesized that different genes would be expressed between HVC and RA. We tested this by using the extracted RNA to perform a cDNA microarray hybridization developed by the SoNG initiative. We then validated these results using qRT-PCR. We found that 363 genes varied by more than 1.5 fold (>log(2) 0.585) in expression in HVC and/or RA. Supporting our hypothesis, only 59 of these 363 genes were found to vary in both nuclei, while 132 gene expression changes were HVC specific and 172 were RA specific. We then assigned many of these genes to functional categories relevant to the different mechanisms underlying seasonal change in HVC and RA, including neurogenesis, apoptosis, cell growth, dendrite arborization and axonal growth, angiogenesis, endocrinology, growth factors, and electrophysiology. This revealed categorical differences in the kinds of genes regulated in HVC and RA. These results show that different molecular programs underlie seasonal changes in HVC and RA, and that gene expression is time specific across different reproductive conditions. Our results provide insights into the complex molecular pathways that underlie adult neural plasticity

Special Care and School Difficulties in 8-Year-Old Very Preterm Children: The Epipage Cohort Study

OBJECTIVES: To investigate school difficulties, special care and behavioral problems in 8 year-old very preterm (VPT) children. PATIENT AND METHODS: Longitudinal population-based cohort in nine regions of France of VPT children and a reference group born at 39-40 weeks of gestation (WG). The main outcome measures were information about school, special care and behavioral problems using Strengths and Difficulties Questionnaire from a questionnaire to parents. RESULTS: Among the 1439 VPT children, 5% (75/1439) were in a specialised school or class, 18% (259/1439) had repeated a grade in a mainstream class and 77% (1105/1439) were in the appropriate grade-level in mainstream class; these figures were 1% (3/327) , 5% (16/327) and 94% (308/327) , respectively, for the reference group. Also, 15% (221/1435) of VPT children in a mainstream class received support at school versus 5% (16/326) of reference group. More VPT children between the ages of five and eight years received special care (55% (794/1436)) than children born at term (38% (124/325)); more VPT children (21% (292/1387)) had behavioral difficulties than the reference group (11% (35/319)). School difficulties, support at school, special care and behavioral difficulties in VPT children without neuromotor or sensory deficits varied with gestational age, socioeconomic status, and cognitive score at the age of five. CONCLUSIONS: Most 8-year-old VPT children are in mainstream schools. However, they have a high risk of difficulty in school, with more than half requiring additional support at school and/or special care. Referral to special services has increased between the ages of 5 and 8 years, but remained insufficient for those with borderline cognitive scores

Retaining young people in a longitudinal sexual health survey: a trial of strategies to maintain participation

<p>BACKGROUND:There is an increasing trend towards lower participation in questionnaire surveys. This reduces representativeness, increases costs and introduces particular challenges to longitudinal surveys, as researchers have to use complex statistical techniques which attempt to address attrition. This paper describes a trial of incentives to retain longitudinal survey cohorts from ages 16 to 20, to question them on the sensitive topic of sexual health.</p> <p>METHODS: A longitudinal survey was conducted with 8,430 eligible pupils from two sequential year groups from 25 Scottish schools. Wave 1 (14 years) and Wave 2 (16 years) were conducted largely within schools. For Wave 3 (18 years), when everyone had left school, the sample was split into 4 groups that were balanced across predictors of survey participation: 1) no incentive; 2) chance of winning one of twenty-five vouchers worth 20 pounds; 3) chance of winning one 500 pounds voucher; 4) a definite reward of a 10 pounds voucher sent on receipt of their completed questionnaire. Outcomes were participation at Wave 3 and two years later at Wave 4. Analysis used logistic regression and adjusted for clustering at school level.</p> <p>RESULTS: The only condition that had a significant and beneficial impact for pupils was to offer a definite reward for participation (Group 4). Forty-one percent of Group 4 participated in Wave 3 versus 27% or less for Groups 1 to 3. At Wave 4, 35% of Group 4 took part versus 25% or less for the other groups. Similarly, 22% of Group 4 participated in all four Waves of the longitudinal study, whereas for the other three groups it was 16% or less that participated in full.</p> <p>CONCLUSIONS: The best strategy for retaining all groups of pupils and one that improved retention at both age 18 and age 20 was to offer a definite reward for participation. This is expensive, however, given the many benefits of retaining a longitudinal sample, we recommend inclusion of this as a research cost for cohort and other repeat-contact studies.</p&gt

Assessing the Potential Impacts to Riparian Ecosystems Resulting from Hemlock Mortality in Great Smoky Mountains National Park

Hemlock Woolly Adelgid (Adelges tsugae) is spreading across forests in eastern North America, causing mortality of eastern hemlock (Tsuga canadensis [L.] Carr.) and Carolina hemlock (Tsuga caroliniana Engelm.). The loss of hemlock from riparian forests in Great Smoky Mountains National Park (GSMNP) may result in significant physical, chemical, and biological alterations to stream environments. To assess the influence of riparian hemlock stands on stream conditions and estimate possible impacts from hemlock loss in GSMNP, we paired hardwood- and hemlock-dominated streams to examine differences in water temperature, nitrate concentrations, pH, discharge, and available photosynthetic light. We used a Geographic Information System (GIS) to identify stream pairs that were similar in topography, geology, land use, and disturbance history in order to isolate forest type as a variable. Differences between hemlock- and hardwood-dominated streams could not be explained by dominant forest type alone as forest type yields no consistent signal on measured conditions of headwater streams in GSMNP. The variability in the results indicate that other landscape variables, such as the influence of understory Rhododendron species, may exert more control on stream conditions than canopy composition. The results of this study suggest that the replacement of hemlock overstory with hardwood species will have minimal impact on long-term stream conditions, however disturbance during the transition is likely to have significant impacts. Management of riparian forests undergoing hemlock decline should, therefore, focus on facilitating a faster transition to hardwood-dominated stands to minimize long-term effects on water quality

Spontaneous and radiation-induced chromosomal instability and persistence of chromosome aberrations after radiotherapy in lymphocytes from prostate cancer patients

The aim of the study was to compare the spontaneous and ex vivo radiation-induced chromosomal damage in lymphocytes of untreated prostate cancer patients and age-matched healthy donors, and to evaluate the chromosomal damage, induced by radiotherapy, and its persistence. Blood samples from 102 prostate cancer patients were obtained before radiotherapy to investigate the excess acentric fragments and dicentric chromosomes. In addition, in a subgroup of ten patients, simple exchanges in chromosomes 2 and 4 were evaluated by fluorescent in situ hybridization (FISH), before the onset of therapy, in the middle and at the end of therapy, and 1 year later. Data were compared to blood samples from ten age-matched healthy donors. We found that spontaneous yields of acentric chromosome fragments and simple exchanges were significantly increased in lymphocytes of patients before onset of therapy, indicating chromosomal instability in these patients. Ex vivo radiation-induced aberrations were not significantly increased, indicating proficient repair of radiation-induced DNA double-strand breaks in lymphocytes of these patients. As expected, the yields of dicentric and acentric chromosomes, and the partial yields of simple exchanges, were increased after the onset of therapy. Surprisingly, yields after 1 year were comparable to those directly after radiotherapy, indicating persistence of chromosomal instability over this time. Our results indicate that prostate cancer patients are characterized by increased spontaneous chromosomal instability. This instability seems to result from defects other than a deficient repair of radiation-induced DNA double-strand breaks. Radiotherapy-induced chromosomal damage persists 1 year after treatment

Fast- or Slow-inactivated State Preference of Na+ Channel Inhibitors: A Simulation and Experimental Study

Sodium channels are one of the most intensively studied drug targets. Sodium channel inhibitors (e.g., local anesthetics, anticonvulsants, antiarrhythmics and analgesics) exert their effect by stabilizing an inactivated conformation of the channels. Besides the fast-inactivated conformation, sodium channels have several distinct slow-inactivated conformational states. Stabilization of a slow-inactivated state has been proposed to be advantageous for certain therapeutic applications. Special voltage protocols are used to evoke slow inactivation of sodium channels. It is assumed that efficacy of a drug in these protocols indicates slow-inactivated state preference. We tested this assumption in simulations using four prototypical drug inhibitory mechanisms (fast or slow-inactivated state preference, with either fast or slow binding kinetics) and a kinetic model for sodium channels. Unexpectedly, we found that efficacy in these protocols (e.g., a shift of the “steady-state slow inactivation curve”), was not a reliable indicator of slow-inactivated state preference. Slowly associating fast-inactivated state-preferring drugs were indistinguishable from slow-inactivated state-preferring drugs. On the other hand, fast- and slow-inactivated state-preferring drugs tended to preferentially affect onset and recovery, respectively. The robustness of these observations was verified: i) by performing a Monte Carlo study on the effects of randomly modifying model parameters, ii) by testing the same drugs in a fundamentally different model and iii) by an analysis of the effect of systematically changing drug-specific parameters. In patch clamp electrophysiology experiments we tested five sodium channel inhibitor drugs on native sodium channels of cultured hippocampal neurons. For lidocaine, phenytoin and carbamazepine our data indicate a preference for the fast-inactivated state, while the results for fluoxetine and desipramine are inconclusive. We suggest that conclusions based on voltage protocols that are used to detect slow-inactivated state preference are unreliable and should be re-evaluated