Robust neuronal signaling requires the coordinated function of several ionic currents (Hille, 2001). Voltage- dependent ionic currents have nonlinear dynamics and their effects on membrane potential are strongly interdependent (Bean, 2007). Adding to this complexity is the presence of rich genetic and epigenetic organismal variation, which is one of the many sources of animal-to-animal variability in a population (Gibson and Dworkin, 2004; Raj and van Oudenaarden, 2008; Schulz et al., 2006). Nevertheless, biological systems are extraordinarily robust, maintaining stability under a wide variety of physiologically relevant perturbations (Braendle and Flix, 2008; Kitano, 2004; Masel and Siegal, 2009; Whitacre, 2012). The proposed work investigates how degenerate neural circuits are related to one another and explores the consequences of these functional differences on system robustness. This study will advance our basic understanding of single neuron and circuit dynamics within a diverse population, which is relevant to the development of personalized medicine to treat neurological disorders (Hamburg and Collins, 2010; Katsios and Roukos, 2010). This project utilizes the crustacean stomatogastric ganglion (STG) model system. The STG is ideally suited for studies of robustness because it produces stereotyped rhythmic motor patterns that can easily be classified as robust or abnormal (Haddad and Marder, 2018; Marder and Bucher, 2007). Furthermore, the wild-caught population used for this study will effectively capture natural biological variation. Crustacean habitats can experience significant temperature fluctuations, and temperature robustness has been previously characterized in the STG (Tang et al., 2010). Examining network activity across temperature will facilitate the assessment of circuit robustness. The proposed research will use a combination of computational modeling and experimental approaches to explore the role of an ionic current in different contexts, whether that be across cell types or across variable genetic backgrounds. This work will test a hypothesis that functional degeneracy among ionic currents may be masked in standard conditions but revealed under perturbations such as elevated temperature. Another goal of this research is to characterize degeneracy between voltage- dependent and synaptic currents. If this functional degeneracy exists, it could provide the means for a single neuron to improve the function of a globally disrupted circuit. This would be a powerful mechanism of robustness that would also permit variability in degenerate voltage-dependent currents. The fellowship award will support a training plan consisting primarily of research activities in addition to undergraduate teaching and/or mentorship and attendance at meetings and conferences that will support the proposed research goals. The research training will be conducted at Brandeis University, an academic institution with vibrant neuroscience and quantitative biology research communities.
Treatments for neurological disorders can have mixed results due to rich genetic variation in the human population. To improve these treatments, it is crucial to advance our basic understanding of how neural systems function robustly in spite of genetic and epigenetic variation among individuals. This project will use a genetically heterogeneous population to characterize degeneracy among ionic currents and to determine the extent to which functional differences in a single neuron are relevant to function at the circuit level.
