We are interested in the mechanisms used within the brain to mediate cognitive processes and guide learned behaviours.
Our research addresses two goals. First, we aim to determine the molecular substrates for computations carried out by neurons in cerebellar and entorhinal-hippocampal circuits.
We are focussing in particular on ion channel molecules that play roles in processing of synaptic inputs and control of neuronal excitability.
Second, we wish to understand the roles of neural computations in learned behaviours. Our approach here explores the cellular computations underlying hippocampal- and cerebellar-dependent forms of memory, using molecular manipulations that disrupt specific components of neural information processing.
These experimental studies are complimented by the use and development of computational tools to model neurons and neural circuits.
Many neurons do not simply passively integrate their synaptic inputs, but rather ion channels in their cell body and dendrites enable active transformations of synaptic responses.
These transformations may in principle greatly expand the number of computations that a neural circuit can perform. However, the identity, selection and sub-cellular targeting of particular ion channels responsible for these key aspects of neural computation are not well understood.
To address these key questions, we are developing new molecular and genetic tools to manipulate ion channels. We study the consequences of these manipulations using patch-clamp and other electrophysiological methods for recording neuronal activity in brain slices.
Dendritic integration of synaptic inputs may play a key role in transforming representations as they are communicated through neural circuits that store memories.
However, by contrast to the strong hypotheses we have to account for the roles of synapses in memory, we have relatively little idea about how the complex integrative properties of dendrites contribute to cognitive processes, including learning and memory.
To address this issue we are studying the effects on behaviour of molecular and genetic manipulations of ion channel signalling in dendrites.
Our focus is on learned motor behaviours that require the cerebellum, and forms of spatial memory that require the entorhinal cortex and hippocampus.
While it’s well known that opening and closing of ion channels involves stochastic transitions between discrete molecular states, most theoretical studies of neural computation treat ion channel gating as a deterministic process and do not take account of stochastic fluctuations in membrane currents.
Indeed, it is at present quite difficult to explore the implications of stochastic ion channel gating for computations carried out by neurons with complex axonal or dendritic architectures.
We are therefore working in collaboration with Robert Cannon at Textensor to develop general-purpose software tools that substantially reduce the time required for development and simulation of morphologically complex neurons containing stochastic ion channels throughout their axonal and dendritic membranes.
For more information on this project, please see our website.
Cristina Martinez Gonzalez (Research Assistant)
Sürmeli, G., Marcu, D.C., McClure, C., Garden, D.L.F., Pastoll, H., Nolan, M.F., 2015. Molecularly Defined Circuitry Reveals Input-Output Segregation in Deep Layers of the Medial Entorhinal Cortex. Neuron 88, 1040–53.
Chadwick A, van Rossum MC, Nolan MF. (2015) Independent theta phase coding accounts for CA1 population sequences and enables flexible remapping. Elife. 4.[Epub ahead of print]
Ramsden HL, Sürmeli G, McDonagh SG, Nolan MF. (2015) Laminar and Dorsoventral Molecular Organization of the Medial Entorhinal Cortex Revealed by Large-scale Anatomical Analysis of Gene Expression. PLoS Comput Biol. 11(1):e1004032.
Gonzalez-Sulser A, Parthier D, Candela A, McClure C, Pastoll H, Garden D, Sürmeli G, Nolan MF. (2014) GABAergic projections from the medial septum selectively inhibit interneurons in the medial entorhinal cortex. J Neurosci. 34(50):16739-43.
Rinaldi A., Defterali C., Mialot A., Garden D.L.F., Beraneck M., Nolan M.F. (2013) HCN1 channels in cerebellar Purkinje cell promote late stages of learning and constrain synaptic inhibition. Journal of Physiology 591, 5691-709.
Pastoll H., Solanka L., van Rossum M.C.W. & Nolan M.F. (2013). Feedback inhibition enables theta-nested gamma oscillations and grid firing fields. Neuron 77, 141-154.
Pastoll, H., Ramsden, H. Nolan, M.F. (2012). Intrinsic electrophysiological properties of entorhinal cortex stellate cells and their contribution to grid firing fields. Frontiers in Neural Circuits 6, 17, 1-21. doi: 10.3389/fncir.2012.00017.
O’Donnell, C., Nolan, M.F. and Van Rossum, M.C.W. (2011). Dendritic spine structural plasticity enables synapses to be both plastic and stable. Journal of Neuroscience 31: 16142-16156.
White, M.D., Milne, R. & Nolan, M.F. (2011). A molecular toolbox for rapid generation of viral vectors to up- or down-regulate in vivo neuronal gene expression. Frontiers in Molecular Neuroscience. 4:8. doi: 10.3389/fnmol.2011.00008.
Dodson, P.D., Pastoll, H. & Nolan, M.F. (2011). Dorsal-ventral organization of theta-like activity intrinsic to entorhinal stellate neurons is mediated by differences in stochastic current fluctuations. Journal of Physiology 598, 2993-3008.
Zonta, B., Desmazieres, A., Rinaldi, A., Tait, S., Sherman, D.L., Nolan, M.F., and Brophy, P.J. (2011). A Critical Role for Neurofascin in Regulating Action Potential Initiation through Maintenance of the Axon Initial Segment. Neuron 69, 945-956.
O’Donnell, C. and Nolan, M.F. (2011). Tuning of synaptic integration: an organizing principle for optimization of neural circuits. Trends in Neurosciences 34, 51-60. DOI: 10.1016/j.tins.2010.10.003.
Cannon, R.C., O’Donnell, C. & Nolan, M.F. (2010). Stochastic ion channel gating in dendritic neurons: morphology dependence and probabilistic synaptic activation of dendritic spikes. PLoS Computational Biology 6(8): e1000886. doi:10.1371/journal.pcbi.1000886.