Spatial Cell Atlas of Lateral Septum Reveals Changes Underlying Anxiety and Fear Learning Deficits in Mice with...

The lateral septum (LS) regulates affective-cognitive processes and is dysregulated in human psychiatric disorders. Its functional complexity stems from heterogeneous connectivities and neuronal subtype compositions across anatomical subregions. Comprehensive understanding of LS function has been hindered by the lack of a three-dimensional (3D) neuronal atlas. Moreover, the association between peripheral immune disturbances and psychiatric disorders underscores the necessity to investigate potential 3D LS neuronal heterogeneities across distinct immunological states. This study employed single-nucleus RNA sequencing to analyze LS differences in C57J, BALB/c, and nude mice with distinct immune contexts (i.e., immunocompetent, enhanced Th2 reactivity, and T-cell deficiency, respectively), and identified global alterations in non-neuronal cells alongside with neuron-specific changes. Through combining publicly available multiplexed error-robust fluorescence in situ hybridization (MERFISH) data with neural circuit tracing, this study further constructed a 3D neuronal atlas of the entire LS with their projection connectivities. Notably, an Esr1-positive neuronal subpopulation distributed in the ventral LS exhibited potential responsiveness to changes in peripheral immunity and may participate in anxiety regulation. Furthermore, the dorsal LS demonstrated heterogeneity in fear memory regulation associated with T cell homeostasis. These findings underscore the critical role of immune-neural crosstalk in emotional regulation while shedding light on potential therapeutic targets for emotion-related disorders linked to T-cell homeostatic disturbances.