TRACKING THE EARLY DEVELOPMENT AND FUNCTIONAL DIVERSITY OF THE ZEBRAFISH LOCUS COERULEUS AND NORADRENERGIC SYSTEM

The locus coeruleus (LC) is a small, yet powerful brainstem nucleus that is highly conserved across vertebrate species. As the primary source of norepinephrine (NE) to the brain, the LC-NE system has been historically recognised as a global modulator of arousal, attention and overall brain states. Recent developments suggest that the LC is not a uniform structure but instead consists of heterogeneous subpopulations that drive its broad neuromodulatory effects. However, the mechanisms that drive LC-NE system heterogeneity remain poorly understood.
Here, we used larval zebrafish as a genetically accessible vertebrate model to characterise the structural and functional maturation of the LC-NE system in vivo. Using Tg(dbh:mScarlet) and confocal imaging, we quantified the development of the LC neuron number across early development and found rapid expansion from ~2 days post-fertilisation (dpf), reaching a more stable population from ~6dpf. This developmental stabilisation timepoint then guided subsequent functional imaging studies.
Using Tg(dbh:Gal4;UAS:GCaMP7c) and selective plane illumination microscopy, we recorded spontaneous calcium activity from the LC-NE population at this structurally mature stage. Unsupervised clustering of calcium activity revealed that spontaneous LC-NE activity can be organised into up to four spatially distinct functional clusters.
Together, these findings suggest that the LC-NE system rapidly reaches structural maturity quickly and exhibits functional specialisation by early larval stages. Future work will examine the contexts that drive these functional clusters, such as discrete neuromodulatory states, transitions in global brain state, or encoding of sensory information.