An agent-based model of the Notch signaling pathway elucidates three levels of complexity in the determination of developmental patterning.

BACKGROUND: The Notch signaling pathway is involved in cell fate decision and developmental patterning in diverse organisms. A receptor molecule, Notch (N), and a ligand molecule (in this case Delta or Dl) are the central molecules in this pathway. In early Drosophila embryos, these molecules determine neural vs. skin fates in a reproducible rosette pattern. RESULTS: We have created an agent-based model (ABM) that simulates the molecular components for this signaling pathway as agents acting within a spatial representation of a cell. The model captures the changing levels of these components, their transition from one state to another, and their movement from the nucleus to the cell membrane and back to the nucleus again. The model introduces stochastic variation into the system using a random generator within the Netlogo programming environment. The model uses these representations to understand the biological systems at three levels: individual cell fate, the interactions between cells, and the formation of pattern across the system. Using a set of assessment tools, we show that the current model accurately reproduces the rosette pattern of neurons and skin cells in the system over a wide set of parameters. Oscillations in the level of the N agent eventually stabilize cell fate into this pattern. We found that the dynamic timing and the availability of the N and Dl agents in neighboring cells are central to the formation of a correct and stable pattern. A feedback loop to the production of both components is necessary for a correct and stable pattern. CONCLUSIONS: The signaling pathways within and between cells in our model interact in real time to create a spatially correct field of neurons and skin cells. This model predicts that cells with high N and low Dl drive the formation of the pattern. This model also be used to elucidate general rules of biological self-patterning and decision-making.

Shortened Lifespan and Other Age-Related Defects in Bang Sensitive Mutants of Drosophila melanogaster.

Mitochondrial diseases are complex disorders that exhibit their primary effects in energetically active tissues. Damage generated by mitochondria is also thought to be a key component of aging and age-related disease. An important model for mitochondrial dysfunction is the bang sensitive (bs) mutants in Drosophila melanogaster Although these mutants all show a striking seizure phenotype, several bs mutants have gene products that are involved with mitochondrial function, while others affect excitability another way. All of the bs mutants (parabss , eas, jus, ses B, tko are examined here) paralyze and seize upon challenge with a sensory stimulus, most notably mechanical stimulation. These and other excitability mutants have been linked to neurodegeneration with age. In addition to these phenotypes, we have found age-related defects for several of the bs strains. The mutants eas, ses B, and tko display shortened lifespan, an increased mean recovery time from seizure with age, and decreased climbing ability over lifespan as compared to isogenic CS or w1118 lines. Other mutants show a subset of these defects. The age-related phenotypes can be rescued by feeding melatonin, an antioxidant, in all the mutants except ses B The age-related defects do not appear to be correlated with the seizure phenotype. Inducing seizures on a daily basis did not exacerbate the phenotypes and treatment with antiepileptic drugs did not increase lifespan. The results suggest that the excitability phenotypes and the age-related phenotypes may be somewhat independent and that these phenotypes mutants may arise from impacts on different pathways.

A new measure based on degree distribution that links information theory and network graph analysis.

BACKGROUND: Detailed connection maps of human and nonhuman brains are being generated with new technologies, and graph metrics have been instrumental in understanding the general organizational features of these structures. Neural networks appear to have small world properties: they have clustered regions, while maintaining integrative features such as short average pathlengths. RESULTS: We captured the structural characteristics of clustered networks with short average pathlengths through our own variable, System Difference (SD), which is computationally simple and calculable for larger graph systems. SD is a Jaccardian measure generated by averaging all of the differences in the connection patterns between any two nodes of a system. We calculated SD over large random samples of matrices and found that high SD matrices have a low average pathlength and a larger number of clustered structures. SD is a measure of degree distribution with high SD matrices maximizing entropic properties. Phi (Φ), an information theory metric that assesses a system's capacity to integrate information, correlated well with SD - with SD explaining over 90% of the variance in systems above 11 nodes (tested for 4 to 13 nodes). However, newer versions of Φ do not correlate well with the SD metric. CONCLUSIONS: The new network measure, SD, provides a link between high entropic structures and degree distributions as related to small world properties.

Creating Cross-disciplinary Courses.

Because of its focus on the biological underpinnings of action and behavior, neuroscience intersects with many fields of human endeavor. Some of these cross-disciplinary intersections have been long standing, while others, such as neurotheology or neuroeconomics, are more recently formed fields. Many undergraduate institutions have sought to include cross-disciplinary courses in their curriculum because this style of pedagogy is often seen as applicable to real world problems. However, it can be difficult for faculty with specialized training within their discipline to expand beyond their own fields to offer cross-disciplinary courses. I have been creating a series of multi- or cross-disciplinary courses and have found some strategies that have helped me successfully teach these classes. I will discuss general strategies and tools in developing these types of courses including: 1) creating mixed experience classrooms of students and contributing faculty 2) finding the right tools that will allow you to teach to a mixed population without prerequisites 3) examining the topic using multiple disciplinary perspectives 4) feeding off student experience and interest 5) assessing the impact of these courses on student outcomes and your neuroscience program. This last tool in particular is important in establishing the validity of this type of teaching for neuroscience students and the general student population.

Treatment with the antiepileptic drugs phenytoin and gabapentin ameliorates seizure and paralysis of Drosophila bang-sensitive mutants.

Drosophila bang-sensitive (bs) mutants exhibit a stereotypic seizure and paralysis following exposure to mechanical shock. In a physiological preparation, seizures and failures corresponding to the defective behavior are observed in response to high frequency stimulation. The amplitude of the stimulus necessary to produce bs behavior, or seizure threshold, varies with bs mutant and its gene dosage. In many respects, the bs defects are similar to those observed in mammalian seizure disorders. Antiepileptic drugs (AEDs) were administered by feeding to easily shocked(2) (eas(2)), a representative bs mutant. The mean recovery times of treated flies were examined in comparison to control cultures. Some of the drugs administered, including carbamazeprine, ethosuximide, and vigabactrin, had little or no effect on the bs behavior of eas(2). Gabapentin, however, showed a reduction in mean recovery time with chronic drug exposure. Phenytoin also had a significant effect on the bs behavior of treated flies. There was a reduction of both mean recovery time and the percentage of flies that displayed bang-sensitive behavior with both acute and chronic treatment. The adult giant fiber preparation was used to examine the effects of phenytoin physiologically. Treated eas(2) flies showed changes in their response to normal stimulation as well as alterations in seizure threshold in response to high frequency stimulation. Gabapentin was also effective against two other bs mutants, bangsenseless(1) and slamdance(iso7.8), at strain-specific concentrations, while phenytoin also reduced bang-sensitive behaviors in bangsenseless(1) in a dose dependent manner. AEDs, therefore, can be used to dissect aspects of bs behavior and this model may be useful in understanding the underlying basis of seizure disorders.