Multimodal classification of neurons in the lateral septum

Abstract

The lateral septum (LS) is a nucleus in the ventral forebrain that modulates complex social and affective behaviors. However, the specific mechanisms through which LS neurons influence these behaviors remain unclear, as the existing research has often yielded ambiguous or conflicting findings. This ambiguity can largely be attributed to a lack of cell-type specificity. While functionally and anatomically distinct LS neurons have been identified, a comprehensive multimodal classification of neurons in the LS is currently lacking. To address this, we profiled the transcriptional identity of mature LS neurons originating from either the rostral or caudal embryonic septum. Our findings revealed 12 transcriptionally distinct subtypes of LS neurons that fall into two main groups: those that have a history of Nkx2.1 expression (Nkx2.1-neurons) and those that do not. Interestingly, we found that developmentally distinct subtypes can be transcriptionally related, and that Nkx2.1-neurons displayed a differential enrichment for cell adhesion and communication molecules compared to other LS neurons. We then examined the spatial relationships of neurons in the LS and discovered each subtype occupies a discrete anatomical domain. Notably, these domains are overlayed by patterns of gene expression that correlated with the transcriptional taxonomy of LS neuron subtypes. Lastly, we leveraged our transcriptomic data to label non-overlapping subgroups of LS neurons, and detail their connective, morphological, and electrophysiological properties. Our findings offer a deeper understanding of neuronal heterogeneity in the LS, paving the way for targeted studies to discern how the defining characteristics of these cells influence the behaviors they modulate.