All Publications

  • Dendritic trafficking faces physiologically critical speed-precision tradeoffs ELIFE Williams, A. H., O'Donnell, C., Sejnowski, T. J., O'Leary, T. 2016; 5


    Nervous system function requires intracellular transport of channels, receptors, mRNAs, and other cargo throughout complex neuronal morphologies. Local signals such as synaptic input can regulate cargo trafficking, motivating the leading conceptual model of neuron-wide transport, sometimes called the 'sushi-belt model' (Doyle and Kiebler, 2011). Current theories and experiments are based on this model, yet its predictions are not rigorously understood. We formalized the sushi belt model mathematically, and show that it can achieve arbitrarily complex spatial distributions of cargo in reconstructed morphologies. However, the model also predicts an unavoidable, morphology dependent tradeoff between speed, precision and metabolic efficiency of cargo transport. With experimental estimates of trafficking kinetics, the model predicts delays of many hours or days for modestly accurate and efficient cargo delivery throughout a dendritic tree. These findings challenge current understanding of the efficacy of nucleus-to-synapse trafficking and may explain the prevalence of local biosynthesis in neurons.

    View details for DOI 10.7554/eLife.20556

    View details for Web of Science ID 000392121600001

    View details for PubMedID 28034367

    View details for PubMedCentralID PMC5201421

  • Distinct or shared actions of peptide family isoforms: II. Multiple pyrokinins exert similar effects in the lobster stomatogastric nervous system JOURNAL OF EXPERIMENTAL BIOLOGY Dickinson, P. S., Kurland, S. C., Qu, X., Parker, B. O., Sreekrishnan, A., Kwiatkowski, M. A., Williams, A. H., Ysasi, A. B., Christie, A. E. 2015; 218 (18): 2905-2917


    Many neuropeptides are members of peptide families, with multiple structurally similar isoforms frequently found even within a single species. This raises the question of whether the individual peptides serve common or distinct functions. In the accompanying paper, we found high isoform specificity in the responses of the lobster (Homarus americanus) cardiac neuromuscular system to members of the pyrokinin peptide family: only one of five crustacean isoforms showed any bioactivity in the cardiac system. Because previous studies in other species had found little isoform specificity in pyrokinin actions, we examined the effects of the same five crustacean pyrokinins on the lobster stomatogastric nervous system (STNS). In contrast to our findings in the cardiac system, the effects of the five pyrokinin isoforms on the STNS were indistinguishable: they all activated or enhanced the gastric mill motor pattern, but did not alter the pyloric pattern. These results, in combination with those from the cardiac ganglion, suggest that members of a peptide family in the same species can be both isoform specific and highly promiscuous in their modulatory capacity. The mechanisms that underlie these differences in specificity have not yet been elucidated; one possible explanation, which has yet to be tested, is the presence and differential distribution of multiple receptors for members of this peptide family.

    View details for DOI 10.1242/jeb.124818

    View details for Web of Science ID 000362006300016

    View details for PubMedID 26206359

    View details for PubMedCentralID PMC4582171

  • Summary of the DREAM8 Parameter Estimation Challenge: Toward Parameter Identification for Whole-Cell Models. PLoS computational biology Karr, J. R., Williams, A. H., Zucker, J. D., Raue, A., Steiert, B., Timmer, J., Kreutz, C., Wilkinson, S., Allgood, B. A., Bot, B. M., Hoff, B. R., Kellen, M. R., Covert, M. W., Stolovitzky, G. A., Meyer, P. 2015; 11 (5): e1004096


    Whole-cell models that explicitly represent all cellular components at the molecular level have the potential to predict phenotype from genotype. However, even for simple bacteria, whole-cell models will contain thousands of parameters, many of which are poorly characterized or unknown. New algorithms are needed to estimate these parameters and enable researchers to build increasingly comprehensive models. We organized the Dialogue for Reverse Engineering Assessments and Methods (DREAM) 8 Whole-Cell Parameter Estimation Challenge to develop new parameter estimation algorithms for whole-cell models. We asked participants to identify a subset of parameters of a whole-cell model given the model's structure and in silico "experimental" data. Here we describe the challenge, the best performing methods, and new insights into the identifiability of whole-cell models. We also describe several valuable lessons we learned toward improving future challenges. Going forward, we believe that collaborative efforts supported by inexpensive cloud computing have the potential to solve whole-cell model parameter estimation.

    View details for DOI 10.1371/journal.pcbi.1004096

    View details for PubMedID 26020786

    View details for PubMedCentralID PMC4447414

  • Cell Types, Network Homeostasis, and Pathological Compensation from a Biologically Plausible Ion Channel Expression Model NEURON O'Leary, T., Williams, A. H., Franci, A., Marder, E. 2014; 82 (4): 809-821


    How do neurons develop, control, and maintain their electrical signaling properties in spite of ongoing protein turnover and perturbations to activity? From generic assumptions about the molecular biology underlying channel expression, we derive a simple model and show how it encodes an "activity set point" in single neurons. The model generates diverse self-regulating cell types and relates correlations in conductance expression observed in vivo to underlying channel expression rates. Synaptic as well as intrinsic conductances can be regulated to make a self-assembling central pattern generator network; thus, network-level homeostasis can emerge from cell-autonomous regulation rules. Finally, we demonstrate that the outcome of homeostatic regulation depends on the complement of ion channels expressed in cells: in some cases, loss of specific ion channels can be compensated; in others, the homeostatic mechanism itself causes pathological loss of function.

    View details for DOI 10.1016/j.neuron.2014.04.002

    View details for Web of Science ID 000336379800012

    View details for PubMedID 24853940

    View details for PubMedCentralID PMC4109293

  • Many Parameter Sets in a Multicompartment Model Oscillator Are Robust to Temperature Perturbations JOURNAL OF NEUROSCIENCE Caplan, J. S., Williams, A. H., Marder, E. 2014; 34 (14): 4963-4975


    Neurons in cold-blooded animals remarkably maintain their function over a wide range of temperatures, even though the rates of many cellular processes increase twofold, threefold, or many-fold for each 10°C increase in temperature. Moreover, the kinetics of ion channels, maximal conductances, and Ca(2+) buffering each have independent temperature sensitivities, suggesting that the balance of biological parameters can be disturbed by even modest temperature changes. In stomatogastric ganglia of the crab Cancer borealis, the duty cycle of the bursting pacemaker kernel is highly robust between 7 and 23°C (Rinberg et al., 2013). We examined how this might be achieved in a detailed conductance-based model in which exponential temperature sensitivities were given by Q10 parameters. We assessed the temperature robustness of this model across 125,000 random sets of Q10 parameters. To examine how robustness might be achieved across a variable population of animals, we repeated this analysis across six sets of maximal conductance parameters that produced similar activity at 11°C. Many permissible combinations of maximal conductance and Q10 parameters were found over broad regions of parameter space and relatively few correlations among Q10s were observed across successful parameter sets. A significant portion of Q10 sets worked for at least 3 of the 6 maximal conductance sets (∼11.1%). Nonetheless, no Q10 set produced robust function across all six maximal conductance sets, suggesting that maximal conductance parameters critically contribute to temperature robustness. Overall, these results provide insight into principles of temperature robustness in neuronal oscillators.

    View details for DOI 10.1523/JNEUROSCI.0280-14.2014

    View details for Web of Science ID 000334076000020

    View details for PubMedID 24695714

    View details for PubMedCentralID PMC3972722

  • The Neuromuscular Transform of the Lobster Cardiac System Explains the Opposing Effects of a Neuromodulator on Muscle Output JOURNAL OF NEUROSCIENCE Williams, A. H., Calkins, A., O'Leary, T., Symonds, R., Marder, E., Dickinson, P. S. 2013; 33 (42): 16565-16575


    Motor neuron activity is transformed into muscle movement through a cascade of complex molecular and biomechanical events. This nonlinear mapping of neural inputs to motor behaviors is called the neuromuscular transform (NMT). We examined the NMT in the cardiac system of the lobster Homarus americanus by stimulating a cardiac motor nerve with rhythmic bursts of action potentials and measuring muscle movements in response to different stimulation patterns. The NMT was similar across preparations, which suggested that it could be used to predict muscle movement from spontaneous neural activity in the intact heart. We assessed this possibility across semi-intact heart preparations in two separate analyses. First, we performed a linear regression analysis across 122 preparations in physiological saline to predict muscle movements from neural activity. Under these conditions, the NMT was predictive of contraction duty cycle but was unable to predict contraction amplitude, likely as a result of uncontrolled interanimal variability. Second, we assessed the ability of the NMT to predict changes in motor output induced by the neuropeptide C-type allatostatin. Wiwatpanit et al. (2012) showed that bath application of C-type allatostatin produced either increases or decreases in the amplitude of the lobster heart contractions. We show that an important component of these preparation-dependent effects can arise from quantifiable differences in the basal state of each preparation and the nonlinear form of the NMT. These results illustrate how properly characterizing the relationships between neural activity and measurable physiological outputs can provide insight into seemingly idiosyncratic effects of neuromodulators across individuals.

    View details for DOI 10.1523/JNEUROSCI.2903-13.2013

    View details for Web of Science ID 000325809800014

    View details for PubMedID 24133260

    View details for PubMedCentralID PMC3797375

  • Correlations in ion channel expression emerge from homeostatic tuning rules PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA O'Leary, T., Williams, A. H., Caplan, J. S., Marder, E. 2013; 110 (28): E2645-E2654


    Experimental observations reveal that the expression levels of different ion channels vary across neurons of a defined type, even when these neurons exhibit stereotyped electrical properties. However, there are robust correlations between different ion channel expression levels, although the mechanisms that determine these correlations are unknown. Using generic model neurons, we show that correlated conductance expression can emerge from simple homeostatic control mechanisms that couple expression rates of individual conductances to cellular readouts of activity. The correlations depend on the relative rates of expression of different conductances. Thus, variability is consistent with homeostatic regulation and the structure of this variability reveals quantitative relations between regulation dynamics of different conductances. Furthermore, we show that homeostatic regulation is remarkably insensitive to the details that couple the regulation of a given conductance to overall neuronal activity because of degeneracy in the function of multiple conductances and can be robust to "antihomeostatic" regulation of a subset of conductances expressed in a cell.

    View details for DOI 10.1073/pnas.1309966110

    View details for Web of Science ID 000321827000016

    View details for PubMedID 23798391

    View details for PubMedCentralID PMC3710808

  • Animal-to-animal variability in the phasing of the crustacean cardiac motor pattern: an experimental and computational analysis JOURNAL OF NEUROPHYSIOLOGY Williams, A. H., Kwiatkowski, M. A., Mortimer, A. L., Marder, E., Zeeman, M. L., Dickinson, P. S. 2013; 109 (10): 2451-2465


    The cardiac ganglion (CG) of Homarus americanus is a central pattern generator that consists of two oscillatory groups of neurons: "small cells" (SCs) and "large cells" (LCs). We have shown that SCs and LCs begin their bursts nearly simultaneously but end their bursts at variable phases. This variability contrasts with many other central pattern generator systems in which phase is well maintained. To determine both the consequences of this variability and how CG phasing is controlled, we modeled the CG as a pair of Morris-Lecar oscillators coupled by electrical and excitatory synapses and constructed a database of 15,000 simulated networks using random parameter sets. These simulations, like our experimental results, displayed variable phase relationships, with the bursts beginning together but ending at variable phases. The model suggests that the variable phasing of the pattern has important implications for the functional role of the excitatory synapses. In networks in which the two oscillators had similar duty cycles, the excitatory coupling functioned to increase cycle frequency. In networks with disparate duty cycles, it functioned to decrease network frequency. Overall, we suggest that the phasing of the CG may vary without compromising appropriate motor output and that this variability may critically determine how the network behaves in response to manipulations.

    View details for DOI 10.1152/jn.01010.2012

    View details for Web of Science ID 000319121400003

    View details for PubMedID 23446690

    View details for PubMedCentralID PMC3653045