Resource and energy usage in a neural system
In an BBSRC-funded collaboration with Prof. Ian Forsythe (Cell Physiology and Pharmacology, Leicester) and Dr Matthias Hennig (Informatics, Edinburgh) we are studying how the availability of resources (ion channels, synaptic vesicles etc) and the consumption of energy affect the function and configuration of a particular neural system: the calyx of Held / MNTB principle neuron complex in the brainstem auditory system.
We will use a systems biology approach, consisting of a tightly integrated programme of experiments and computational modelling, to study activity-dependent regulation in the medial nucleus of the trapezoid body (MNTB) in the mammalian auditory brainstem, which plays a key role in sound source localisation (SSL). We will examine how different intrinsic plasticity mechanisms, evoked by incoming neural activity, obtain satisfactory functional performance in this nucleus from a limited set of noisy resources (neurons, ion channels, synapses etc) while minimising energy usage. Experimental recordings will be made in tissue slices from mouse. A combination of electrophysiology, pharmacology, immunohistochemistry and genetic manipulation will provide data on the resource distribution in the MNTB neurons and associated calyx of Held synapse, and the regulation of these resources by activity. The experimental data will be used to fit the parameters of a computational model, which will be in the form of a Hodgkin-Huxley-style compartmental model of an MNTB neuron and its synapse. The model will include heterogeneous distributions of identified ion channels types, stochastic neurotransmitter release, and multiple mechanisms of short-term synaptic plasticity. Advanced statistical optimisation techniques will be used to fit model parameters. The model will be analysed to determine information transmission through this system and associated energy usage as estimated by ATP consumption. We postulate that the amount of information transmitted as a fraction of energy used will be different between the high sound frequency and low sound frequency poles of the MNTB.
The computational models were fit to experimental data from the calyx of Held / Medial Nucleus of the Trapezoid Body (MNTB) synaptic pathway in the mammalian auditory brain stem. This pathway must be capable of transmitting high frequency signals with precise timing in response to sound stimuli to allow, in particular, sound source localisation. Our major objective was to explore the hypothesis that synaptic transmission at the calyx of Held and excitability in the postsynaptic MNTB neuron are dynamically regulated in an activity-dependent manner to maintain both functional signal transmission and metabolic efficiency. Our key findings do support this hypothesis:
During this work we have developed an algorithm for identifying neuronal membrane-bound ion channel dynamics from limited electrophysiological data. This algorithm could be employed in neuroscientific studies of neuron characteristics throughout the brain, and potentially minimises the number of experiments that need to be carried out to collect the required data (Michel et al, 2015a).
This is not the end of the story and work is continuing to refine the models as we obtain more experimental data. In particular, we need to further integrate the metabolic and synaptic transmission biochemical pathways to produce a truly comprehensive picture of this synapse that can be used as a platform for exploring in detail the impact of key components on metabolism and neurotransmitter cycling, and hence signal throughput by chemical synapses.
See also our earlier work on the calyx of Held synapse.
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