Davy, O. | Search bioRxiv

bioRxiv2024

Diversity of ancestral brainstem noradrenergic neurons across species and multiple biological factors

The brainstem cell group, locus coeruleus (LC), is present across vertebrates and influences cardiorespiratory, metabolic, immune, and cognitive functions by activating in two putatively distinct firing patterns. Yet, the degree to which the LC firing rates and patterns are homogenous across species has never been assessed due to inherently limited sample sizes. To remedy this, we pooled cross-species data from 20 laboratories to show that firing rates differ across species and are modulated by sex, age, and type of in vitro or in vivo preparation. Contrary to the prevailing dual-mode firing pattern schema, we observed patterns spread across a low-dimensional manifold, with subregions enriched for specific biological factors and neurodegenerative disease models. Our findings show considerable diversity in an ancestral vertebrate neuromodulatory system.

neuroscience↗

bioRxiv2022

Noradrenergic cross-modular reciprocal inhibition within the Locus Coeruleus.

The Locus Coeruleus (LC) is the primary noradrenergic nucleus in the brain with widespread projections driving changes in cognitive state and animal behaviour. The LC is composed of multiple "modules" with specific efferent target domains enabling discretional neuromodulation. LC neuronal activity releases noradrenaline within the nucleus as a local feedback mechanism, but it is not known how this influences modular output. We address this question using whole-cell recordings and calcium imaging in rat pontine slices in combination with LC neuronal ensemble modelling to assess the influence of local noradrenaline release on cross-modular interactions. Electrophysiological recordings of LC neurons from rats transduced with the optogenetic actuator ChR2 showed auto-inhibition and lateral inhibition (of surrounding non-transduced neurons). This inhibition was strongly frequency dependent and was mediated by noradrenaline acting on alpha2-adrenceptors (2R). To allow calcium-imaging of LC neuronal ensembles a Canine-Adenoviral vector strategy was developed using the PRS promoter to drive selective expression GCaMP6s. Calcium imaging allowed resolution of both increases and decreases in LC activity (to TTX / clonidine or high potassium). Selective chemogenetic-activation of subsets of LC neurons (expressing the ionotropic actuator PSAM) revealed both a direct excitation (after application of PSEM308, 3-30{micro}M) and an 2R-mediated inhibition of neighbouring LC cells (non-transduced). Differential retrograde targeting of PSAM or GCaMP6s to specific LC modules showed the presence of strong, reciprocal cross-modular inhibition (shown for the LC-olfactory bulb vs LC bulbospinal modules) and a subsequent rebound activity inversion. This represents a preferential, targeted, cross-modular, lateral inhibition within the LC rather than a non-specific surround inhibition. Computational modelling showed the emergence of lateral inhibition and biphasic responses to modular activation when 2R signalling and noradrenergic reuptake saturation were included. This interaction may facilitate recruitment of neuronal ensembles by coherent inputs and represents a bottom-up differential contrast-enhancement mechanism within the LC to produce a modality specific focus.

neuroscience↗