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Interplay of neuronal and neuromodulatory dynamics in cortical microcircuits

Principal Supervisor: Dr. Michael Okun, Department of Neuroscience, Psychology and Behaviour

Co-supervisor: Dr. James McCutcheon

PhD project title: Interplay of neuronal and neuromodulatory dynamics in cortical microcircuits

University of Registration: University of Leicester

Project outline:

The aim of this project is to provide quantitative, temporally precise information on the relationship between the neuronal activity in the cortex and the norepinephrine neuromodulatory inputs.

It is well established that neuromodulators such as norepinephrine (NE), acetylcholine (ACh) and dopamine (DA) have a fundamental role in regulating neuronal activity in many areas of the mammalian brain including the cortex in particular. Recently, in order to understand neuromodulation, systems neuroscientists, whose primary objective is studying neuronal population activity in the rodent cortex, started incorporating measurements of changes in pupil diameter (pupillometry) into their experiments; pupil diameter is strongly correlated with cognitive processing and is even used in humans to determine neurological status. The research in rodents has provided a valuable insight into the way cortical networks respond to changes in their neuromodulatory input, however, it still remains the case that pupil diameter is an indirect measure of the neuromodulatory activity, and the precise mechanisms controlling pupil dilation are not even presently known.

In the present project, we will supplement pupillometry with direct measurement of neuromodulator concentration using fast-scan cyclic voltammetry (FSCV). FSCV is a method originating in analytical chemistry for inferring concentrations of electroactive substances based on their oxidation/reduction at the surface of a carbon-fibre microelectrode. FSCV’s important advantages are high spatiotemporal resolution (to within a few μm and a small fraction of a second), and the fact that it can be used in awake animals, including humans.

Our specific goal in the present project is to combine FSCV with electrophysiology and pupillometry to uncover the quantitative relationship between the spiking of local neuronal populations and NE release. NE is one of the primary neuromodulators in the cortex and has been previously shown to have a strong depolarising effect on cortical neurons [1]. This goal will be achieved by performing recordings in awake, head-fixed mice. In these experiments, measurement of pupil diameter and of neuronal population activity using multi-electrode arrays inserted into primary sensory or frontal areas of the cortex will be combined with FSCV in bed nucleus of the stria terminalis or anteroventral thalamic nucleus, brain areas receiving abundant NE input from locus coeruleus [2]. This data will unveil the precise temporal relationship between the change in NE concentration and the changes in the activity of different cell-types of cortical neurons, which is impossible with other methods for measuring NE (e.g. microdialysis) due to their low temporal resolution.

In the following stages of the project, we will attempt to perform FSCV measurements of NE concentration in the immediate vicinity of the multi-electrode array, in order to understand how neuromodulatory inputs differ between cortical areas and layers. We will also explore the possibility to use a novel ACh FSCV methodology (standard FSCV does not detect ACh because the molecule is not electroactive) in our in vivo experiments [3].

Dr. Okun (the principal supervisor) has a strong background in experimental and computational study of cortical population activity, with publications in top journals. Dr. McCutcheon (the co-supervisor) has extensive experience with FSCV, resulting in > 10 publications.

References:

  1. Polack P-O, Friedman J, Golshani P: Cellular mechanisms of brain state-dependent gain modulation in visual cortex. Nat Neurosci 2013, 16:1331–1339.
  2. Park J, Kile BM, Mark Wightman R: In vivo voltammetric monitoring of norepinephrine release in the rat ventral bed nucleus of the stria terminalis and anteroventral thalamic nucleus. Eur J Neurosci 2009, 30:2121–2133.
  3. Asri R, O’Neill B, Patel JC, Siletti KA, Rice ME: Detection of evoked acetylcholine release in mouse brain slices. Analyst 2016, 141:6416–6421.

BBSRC Strategic Research Priority: Molecules, cells and systems

Techniques that will be undertaken during the project:

  • Population recordings using high density multielectrode arrays (area of expertise of both supervisors).
  • Fast-scan cyclic voltammetry (area of expertise of the co-supervisor).
  • Analysis of the highly dimensional datasets using Python and/or MATLAB software (area of expertise of the principal supervisor).
Contact: Dr Michael Okun, University of Leicester