Targeting Noradrenergic Neurons of the Locus Coeruleus: A Comparison of Model Systems and Strategies

The locus coeruleus (LC) norepinephrine (NE) system is involved in a variety of physiological and pathophysiological processes. Refining our understanding of LC function largely relies on selective transgene expression in LC-NE neurons, allowing targeted manipulation and readout of noradrenergic neurons. Here, we performed a side-by-side comparison of the most commonly used strategies to genetically target the LC, including different cre driver lines and promoter-mediated transgene expression. We report differences between these strategies in terms of transgene expression efficacy and specificity. Parallelly, we found no behavioral alterations in cre-expressing mice of any mouse line compared to wild-type littermates. Finally, to further facilitate the investigation of LC-NE function, we created a suite of constructs, including a reporter protein, a calcium indicator, and a light-driven cation channel, whose expression is mediated by the previously described PRSx8 promoter. These constructs allow identification, monitoring, and manipulation of LC-NE activity either in wild-type mice, or in combination with tissue-specific manipulations of different cre driver lines. The results of our study are crucial for the interpretation of previous experiments using the respective targeting strategies, as well as for the design of future studies. BlurbThis study reports substantial heterogeneity in transgene expression patterns when using different strategies to virally transduce noradrenergic neurons of the locus coeruleus, highlighting the need to carefully validate each experimental approach in order to avoid misinterpretations when studying locus coeruleus function. Highlights- Heterogeneous expression patterns with different targeting strategies for LC-NE neurons - Substantial ectopic transgene expression observed in some approaches - No behavioral alterations in heterozygous cre mice as compared to wild-types - PRSx8-driven reporters, indicators and actuators as a resource to investigate LC function