Abstract
The Locus Coeruleus (LC) is the brain's primary noradrenergic nucleus, with widespread projection driving changes in brain state and behaviour, particularly those relevant to attention, arousal, and acute stress responses. Recent studies indicate that the LC is composed of multiple noradrenergic cell ensembles “modules”, with anatomical specificity in their efferent targets. It is not understood how these LC modules might interact. I have investigated this question using electrophysiology and calcium imaging of LC neuronal networks in ex-vivo slices from rats and computational modelling to explore the biological mechanisms.The dynamics of LC neurons, including pacemaker firing, calcium-based action potentials, and sub-threshold membrane oscillations (STMOs) were characterised using whole-cell patch-clamp recordings. Computational modelling suggested that an interplay between oscillations in intracellular calcium, and a calcium-activated potassium current may drive STMOs. A low-voltage activated calcium current was necessary to generate calcium spikes, suggesting that heterogeneity in calcium channel expression underlies the different basal dynamics.
To drive GCaMP6s expression and facilitate imaging of LC networks, a Canine Adenovirus based vector strategy was developed with the synthetic PRS promoter to drive expression in noradrenergic neurons. GCaMP6s signal in LC neurons was shown to be capable of resolving bidirectional changes in activity following pharmacological and chemogenetic stimuli. Chemogenetic activation of subsets of LC neurons revealed an α2-adrenoceptor-mediated inhibition of neighbouring LC cells. Activation of one specific anatomically-defined LC module showed strong inhibition of other LC modules. This suggests that this phenomenon represents a targeted, cross-modular, lateral
inhibition within the LC rather than a non-specific surround inhibition. Computational modelling showed emergence of lateral inhibition and biphasic responses to modular activation when α2-adrenoceptor signalling and noradrenergic reuptake saturation were included. This cross-modular interaction may facilitate module-specific recruitment by coherent inputs and represents a low level contrast-enhancement mechanism within the LC to produce a modality specific focus.
Date of Award | 21 Jun 2022 |
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Original language | English |
Awarding Institution |
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Supervisor | Michael C Ashby (Supervisor), Anthony Edward Pickering (Supervisor) & Krasimira Tsaneva-Atanasova (Supervisor) |