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Timothy O'Leary
Engineering Department

Tim's lab studies living systems using ideas from control engineering and classical biology, with the goal of divining "engineering-like" principles that apply to cellular systems, what makes them adaptive, flexible and robust, how they self-organise during development. The lab uses experimental approaches and neural network models to understand complex regulatory control.

 

Lab members

Timothy O’Leary (principal investigator)

Adrianna Loback (postdoc)

Dhruva Raman (postdoc)

Andrey Stoychev (PhD - collaborating with Marta Zlatic)

Adriano Bellotti (MD/PhD - collaborating with Dax Hoffman)

Ulrika Andersson (masters)

Jaza Syed (masters)

Ying Li (masters)

Jamil Jami (masters)

 

Research

 An example of a mathematical model of feedback regulation in a Central Pattern Generator - a small neural network that controls muscle movement. Internal cellular signals allow neurons to robustly develop a rhythmic bursting activity. This robustness can be compromised by loss of specific ion channel genes.

An example of a mathematical model of feedback regulation in a Central Pattern Generator - a small neural network that controls muscle movement. Internal cellular signals allow neurons to robustly develop a rhythmic bursting activity. This robustness can be compromised by loss of specific ion channel genes.

Cellular systems need to regulate their properties in a way that compensates fluctuations in physiological activity and the environment (O’Leary & Marder 2016). However, robustness can imply diminished flexibility in how an organism grows and responds to environmental cues. Similarly, robustness and flexibility can trade-off with metabolic efficiency and information transmission. These constraints shape how cellular systems - including nervous systems - develop and operate throughout life, but the engineering constrains are relatively unexplored at present because most work tends to focus on the consequences of optimizing a single property, such as energy efficiency.

We are investigating relationships between robustness, flexibility and performance of cellular systems using ideas from control engineering. Preliminary results (O’Leary et al 2014) show how homeostatic regulation mechanisms can provide robustness to ‘normal’ physiological perturbations (such as developmental changes in physiological signals) but can also cause pathological sensitivity to ‘unexpected’ perturbations, such as loss of specific genes.

 

Publications

O'Leary T (2018) Homeostasis, failure of homeostasis and degenerate ion channel regulation. Current Opinion in Physiology 2, 129-138.

Williams AH, O'Donnell C, Sejnowski T, O'Leary T (2016) Dendritic trafficking faces physiologically critical speed-precision tradeoffs. eLife, e20556.

O'Leary T & Marder E (2016) Temperature-robust neural function from activity dependent ion channel regulation. Current Biology 26 (21), 2935-2941.

Takeishi A, Yanxun VY, Hapiak VM, Bell, HW, O’Leary T, & Sengupta P (2016) Receptor-type Guanylyl Cyclases Confer Thermosensory Responses in C. elegans. Neuron 90(2), 235-244.

Drion G, O’Leary T, & Marder, E (2015) Ion channel degeneracy enables robust and tunable neuronal firing rates. Proceedings of the National Academy of Sciences 112(38), E5361-E5370.

O’Leary T, Sutton A, Marder E (2015) Computational Models in the age of large data sets.Current Opinion in Neurobiology 32, 87-94.

O’Leary T, Marder E (2014) Mapping Neural Activation onto Behavior in an Entire Animal Science 344(6182).

O’Leary T, Williams AH, Franci A, Marder E (2014) Cell types, network homeostasis and pathological compensation from a biologically plausible ion channel expression model. Neuron 82(4), 809-821.

Marder E, O’Leary T, Shruti S (2014) Neuromodulation of Circuits with Variable Parameters: Small Circuits Reveal Principles of State-Dependent and Robust Neuromodulation. Annual Review of Neuroscience 37(1), 329-346.

Williams AH, Calkins A, O’Leary T, Symonds R, Marder E, & Dickinson PS (2013) The Neuromuscular Transform of the Lobster Cardiac System Explains the Opposing Effects of a Neuromodulator on Muscle Output. The Journal of Neuroscience 33(42), 16565-16575.

Nowakowski TJ, Mysiak KS, O‘Leary T, Fotaki V, Pratt T, Price DJ. (2013) Loss of functional Dicer in mouse radial glia cell-autonomously prolongs cortical neurogenesis. Developmental Biology 382(2), 530–537.

O’Leary T, Williams AH, Caplan JC, Marder E. (2013) Correlations in ion channel expression emerge from homeostatic tuning rules. Proceedings of the National Academy of Sciences 110(28), E2645-E2654.

Williams AH, O’Leary T*, Marder E (2013) Homeostatic Regulation of Neuronal Excitability. Scholarpedia 8(1):1656 (* = curator).

Gutierrez GJ, O’Leary T, Marder E. (2013) Multiple mechanisms switch an electrically coupled, synaptically inhibited neuron between competing rhythmic oscillators. Neuron77(5), 845-858.

McMahon A, Barnett M, O’Leary T, Stoney P, Collins M, Papadia S, Choudhari J, Komiyama N, Grant S, Hardingham G, Wyllie DJ, Kind PC (2012) Activity-dependent alternative promoter usage and alternative splicing enable SynGAP isoforms to exert opposing effects on synaptic strength. Nature Communications 3(900).

O’Leary T, Wyllie DJ. (2011) Neuronal Homeostasis: time for a change? The Journal of Physiology 589(20), 4811-4826.

O’Leary T, van Rossum MC, Wyllie DJ. (2010) Homeostasis of intrinsic excitability in hippocampal neurones: dynamics and mechanism of the response to chronic depolarization. The Journal of Physiology 588(1), 157-170.

Clayton EL, Sue N, Smillie KJ, O’Leary T, Bache N, Cheung G, Cole AR, Wyllie DJ, Sutherland C, Robinson PJ, Cousin MA. (2010) Dynamin I phosphorylation by GSK3 controls activity-dependent bulk endocytosis of synaptic vesicles. Nature Neuroscience 13(7), 845-851.

O’Leary T, Wyllie DJ. (2009) Single-channel properties of N-methyl-D-aspartate receptors containing chimaeric GluN2A/GluN2D subunits. Biochem Soc Trans. 37(6), 1347-1354.

Otton HJ, Janssen A, O’Leary T, Chen PE, Wyllie DJ. (2009) Inhibition of rat recombinant GluN1/GluN2A and GluN1/GluN2B NMDA receptors by ethanol at concentrations based on the US/UK drink-drive limit. Eur J Pharmacol. 614(1-3), 14-21.

O'Leary T, Wyllie DJ. (2008) The ups and downs of synaptic plasticity: influences on this particular 'market'. The Journal of Physiology 586(24), 5839-5840.

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