Autocrine feedback maintains homeostatic neuropeptide expression in a peptidergic hub neuron

Abstract Neuronal circuits sustain stable function by self-regulating their gene expression and neurosecretion. Patterns for autocrine feedback by neuropeptides are widespread across nervous systems, but how they contribute to neuronal homeostasis remains poorly understood. Here, we identify an autocrine homeostatic mechanism in a C. elegans peptidergic hub neuron. FLP-1 neuropeptide release activates the inhibitory receptor DMSR-7 on the AVK hub neurons to self-regulate flp-1 transcription, dense-core vesicle accumulation, and peptide secretion. We show that a parallel PDF-1/PDFR-1 pathway drives flp-1 expression, establishing a “push-and-pull” peptidergic feedback on the AVK neurons. AVK’s peptidergic output also depends on the number of FLP-1 peptides encoded in its precursor, revealing a dosage mechanism in behavioral regulation. Moreover, flp-1 expression coordinates transcript levels of additional neuropeptides in AVK. These findings uncover FLP-1 as a self-regulating homeostatic controller within a peptidergic hub neuron and illustrate how precursor-encoded redundancy supports stable yet adaptable circuit states.