As the primary source of norepinephrine (NE) in the brain, the locus coeruleus (LC) regulates both arousal and stress responses. However, how local neuromodulatory inputs contribute to LC function remains unresolved. Here we identify a network of transcriptionally and functionally diverse GABAergic neurons in the LC dendritic field that integrate distant inputs and modulate modes of LC firing to control arousal. We define peri-LC anatomy using viral tracing and combine single-cell RNA sequencing and spatial transcriptomics to molecularly define both LC and peri-LC cell types. We identify several cell types which underlie peri-LC functional diversity using a series of complementary approaches in behaving mice. Our findings indicate that LC and peri-LC neurons comprise transcriptionally and functionally heterogenous neuronal populations, alongside anatomically segregated features which coordinate specific influences on behavioral arousal and avoidance states. Defining the molecular, cellular and functional diversity in the LC provides a road map for understanding the neurobiological basis of arousal alongside hyperarousal-related neuropsychiatric phenotypes.

Catecholamine signaling is thought to modulate cognition in an inverted-U relationship, but the mechanisms are unclear. We measured norepinephrine and dopamine release, postsynaptic calcium responses, and interactions between tonic and phasic firing modes under various stimuli and conditions. High tonic activity in vivo depleted catecholamine stores, desensitized postsynaptic responses, and decreased phasic transmission. Together this provides a clearer understanding of the inverted-U relationship, offering insights into psychiatric disorders and neurodegenerative diseases with impaired catecholamine signaling.