Deciphering molecular inputs to CRH neurons from POMC neurons

Classical neurophysiological studies have highlighted the adaptive role of stress hormones in energy homeostasis and survival-related behaviors in response to intrinsic biological factors and external stimuli. Subsequently, viral tracing research in mice has uncovered that physically restrained, activated corticotropin-releasing hormone neurons (CRHNs) in the hypothalamic paraventricular nucleus (PVN) have direct synaptic input from proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC), which are classically known to be associated with satiety and autonomic adaptations in metabolic responses. However, the regulatory mechanism, particularly neurotransmitter-based complex connections, still needs to be thoroughly explained. In this study, we have leveraged an integrative approach to comprehend neuron-to-neuron interactions by analyzing publicly available single-cell RNA sequencing (scRNA-seq) datasets and uncovered a dominance of glutamatergic signaling in POMC-CRHNs interactions, which may modulate the autonomic stress response. To explore the evolutionary conservation of this interaction, we further analyzed the human hypothalamic scRNA-seq dataset, confirming that glutamatergic signaling remains dominant with a wider range of ligands from POMC neurons compared to GABAergic signaling. This was further confirmed by viral tracing experiments, indicating that restraint-activated POMC neurons primarily employ significant glutamatergic gene expression. Our study explains molecular mechanisms underpinning glutamatergic signaling in POMC-CRHNs in stress-responsive hypothalamic networks.